|
PRIN 2010-11Title
Identification of optimal delivery systems for the Nucleic Acid Based Drugs and study of the action mechanisms in some models of human tumoral and inflammatory pathologies
Principal Investigator: Mario Grassi
Abstract
For hepatocellular carcinoma, prostate adenocarcinoma, coronary restenosis, abdominal aortic aneurism, inflammatory bowel and lung diseases, a significant improvement in the efficacies of the therapeutic approaches so far available is urgently required. The use of “nucleic acid based drugs” (NABDs), a novel and emergent class of molecules, is considered very promising. However, a limitation in NABD use as drugs depends on the lack of optimal delivery systems able to minimize NABD degradation in the biological fluid and allow the targeting to the diseased tissue.
The aim of this project is to develop novel delivery systems for NABDs, appropriate for the considered human pathologies. Our approach will take into consideration the different problematics related to the engineering field, but also chemical, pharmaceutical and biomedical filed. Nine University groups will take part to the project together with eigtheen other non-University research groups.
Research units
| Unit | Team manager | Activities |
| 01. UNITS | Mario Grassi | Read More
|
| 02. UNISA | Gaetano Lamberti | Read More
|
| 03. UNIPV | Piersandro Pallavicini | Read More
To individuate an efficient therapy for hepatocellular carcinoma we will study the delivery NABDs, developed by Unit 01, by means of nanovectors based on gold asymmetric branched nanoparticles (ABN) and on spherical magnetite nanoparticles (MNP). |
| 04. UNINA | Stefano Guido | Read More
The activity is focused on the study of the interaction between human blood cells, in particular red blood cells, and either vessel walls or micro/nano particles, developed by the other Unit, for NABD delivery. |
| 05. CNR NA | Domenico Larobina | Read More
The aim is to support the other research units involved in the project with appropriate structural information on the gel systems employed in the release of NABD. For this specific purpose, we will adopt both mechanical and spectroscopic techniques. Such characterizations represent a useful support to set up the specific polymeric device able to release NABDs. |
| 06. UNIPA1 | Gennara Cavallaro | Read More
We will produce and characterize NABD delivery systems appropriate for the pathological conditions proposed by Units 01, 02 and 08; in particular we will evaluate:
|
| 07. UNIPA2 | Valerio Brucato | Read More
We will prepare polymeric scaffolds (made of PLLA and/or PLLA/PLA mixtures) pre-angiogenized as from proprietary patent, and will carry out advanced “in vitro” tests on the NABD release. PLLA scaffold, featuring a pseudo-vascular structure, prepared as for the proprietary patent, will be cultured with mixed population of mesenchymal cells (to promote the ECM formation) and tumoral cells (of interest for the pathologies of this project) showing different metastatic strenght to generate structure close to a tumoral mass. By the “pseudo-vascular” system an “in vitro” evaluation of the performance shown by the specific NABDs dose release on tumoral mass will be evaluated. |
| 08. UNIFG | Sante Di Gioia | Read More
In order to tackle the limits of available therapeutic approaches in severe asthma, we plan to use NABDs targeting GM-CSF, HMGB1, and TGF-ß1. In collaboration with Unit I appropriate NABDs will be selected; with support of Units 02, 05 and 06 adequate delivery systems will be developed. |
| 09. POLIMI | Davide Manca | Read More
Our contribution consists of the modelling service for the other research Units. The modeling will be devoted to two different topics:
For both topics, a relevant model will be the one developed by Unit 07 |
Research products
Articles published on international journals
Read More2017
Barba, Anna Angela; Grassi, Gabriele; Grassi, Mario; Lamberti, Gaetano
New Trends in Gene Therapy: Multidisciplinary Approaches to siRNAs Controlled Delivery Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 156-157, 2017.
Abstract | Links | BibTeX | Tags: Micro and Nano Vectors
@article{Barba2017b,
title = {New Trends in Gene Therapy: Multidisciplinary Approaches to siRNAs Controlled Delivery},
author = {Anna Angela Barba and Gabriele Grassi and Mario Grassi and Gaetano Lamberti},
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/01.-Barba-et-al-CDD-142-156-157-2017.pdf
http://www.eurekaselect.com/149727},
doi = {10.2174/156720181402170202202808},
year = {2017},
date = {2017-02-09},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {156-157},
abstract = {Nucleic acid based drugs (NABDs), powerful in principle, can be of great importance for health care applications if and
only if effective delivery systems are available. Among NABDs, small interfering RNAs (siRNAs) show revolutionary potentiality
due to the ability to silencing the expression of gene-causing diseases. Thus, siRNA drugs have huge therapeutic potentials,
even in the treatment of life threatening diseases. However, the use of siRNAs is limited because of some inconveniences:
they are large macromolecules, negatively charged, undergo rapid degradation by plasma enzymes, are subjected to fast renal
clearance/hepatic sequestration and can hardly cross cellular membranes. These aspects seriously impair siRNAs usability as
therapeutics. To overcome these obstacles, the scientific problem has to be faced out through a multidisciplinary approach, integrating
all relevant and necessary expertise. In this Full-Thematic Issue of the Current Drug Delivery, the development of
siRNAs delivery approaches is described from different points of view by several research groups, which have been jointly
working on the subject in the last years.
The Thematic Issue starts with the paper by Chiarappa et al., devoted to describe the potentiality of the Chemical Engineering
expertise in the “Bio world” through reminding the foundation of Biological Engineering (BE) that develops, with its current
and multidisciplinary approaches, winning strategies in modern research. The concepts of unit operations and transport
phenomena, with which chemical engineers are confident, are applied to the description of the biomedical/pharmaceutical
world and to the study of siRNAs delivery, in order to get a better understanding and description of how biological systems
work.
The engineering approach to siRNA delivery is, then, reported analyzing two topics. In particular, the paper by Caccavo
et al. deals with the modeling of hydrogel based drug delivery systems, materials widely used in controlled drug delivery,
which could be adopted also for siRNAs delivery. Abbiati and Manca report the use of a physiologically-based pharmacokinetic
model, useful in order to assess the fate of drugs, including siRNAs, once administered. The novel preparative methods to
be used in siRNAs delivery are the subjects of the paper by Bochicchio et al., focusing on both the lipid-based and the polymerbased
carriers. More specifically, Dalmoro et al. discuss the use of injectable chitosan/β-glycerophosphate systems, whereas
Cavallaro et al. report the uses of polycation-based smart carriers for siRNAs delivery. Advanced testing methods for the study
of drug delivery systems and the interactions between delivery systems and living systems are discussed in the paper by
D’Apolito et al. and Carf\`{i}-Pavia et al. D’Apolito et al. focus on the effect of liposomal carriers in microcirculation; Carf\`{i}-Pavia
et al. concentrate the attention on a novel bioreactor able to mimic the vascular behavior for in-vitro tests of drug delivery. Last
but not the least, the medical applications of novel delivery systems and siRNAs are discussed in the paper by Piazza et al.,
focusing on the delivery of siRNAs by liposomes in order to silence cycline D1 in ex-vivo human tissues. Moreover, the paper
by Di Gioia et al., deals with the siRNAs’ based therapies against inflammatory respiratory diseases, while the paper by Farra
et al., discusses the role of the transcription factor E2F1 in hepatocellular carcinoma and the opportunity of its silencing by siRNAs.
In conclusion, the papers presented strongly indicate that only a multidisciplinary approach can successfully overcome the
still existing limitation in the use of siRNAs, molecules with an extraordinary therapeutic potential.},
keywords = {Micro and Nano Vectors},
pubstate = {published},
tppubtype = {article}
}
Nucleic acid based drugs (NABDs), powerful in principle, can be of great importance for health care applications if and
only if effective delivery systems are available. Among NABDs, small interfering RNAs (siRNAs) show revolutionary potentiality
due to the ability to silencing the expression of gene-causing diseases. Thus, siRNA drugs have huge therapeutic potentials,
even in the treatment of life threatening diseases. However, the use of siRNAs is limited because of some inconveniences:
they are large macromolecules, negatively charged, undergo rapid degradation by plasma enzymes, are subjected to fast renal
clearance/hepatic sequestration and can hardly cross cellular membranes. These aspects seriously impair siRNAs usability as
therapeutics. To overcome these obstacles, the scientific problem has to be faced out through a multidisciplinary approach, integrating
all relevant and necessary expertise. In this Full-Thematic Issue of the Current Drug Delivery, the development of
siRNAs delivery approaches is described from different points of view by several research groups, which have been jointly
working on the subject in the last years.
The Thematic Issue starts with the paper by Chiarappa et al., devoted to describe the potentiality of the Chemical Engineering
expertise in the “Bio world” through reminding the foundation of Biological Engineering (BE) that develops, with its current
and multidisciplinary approaches, winning strategies in modern research. The concepts of unit operations and transport
phenomena, with which chemical engineers are confident, are applied to the description of the biomedical/pharmaceutical
world and to the study of siRNAs delivery, in order to get a better understanding and description of how biological systems
work.
The engineering approach to siRNA delivery is, then, reported analyzing two topics. In particular, the paper by Caccavo
et al. deals with the modeling of hydrogel based drug delivery systems, materials widely used in controlled drug delivery,
which could be adopted also for siRNAs delivery. Abbiati and Manca report the use of a physiologically-based pharmacokinetic
model, useful in order to assess the fate of drugs, including siRNAs, once administered. The novel preparative methods to
be used in siRNAs delivery are the subjects of the paper by Bochicchio et al., focusing on both the lipid-based and the polymerbased
carriers. More specifically, Dalmoro et al. discuss the use of injectable chitosan/β-glycerophosphate systems, whereas
Cavallaro et al. report the uses of polycation-based smart carriers for siRNAs delivery. Advanced testing methods for the study
of drug delivery systems and the interactions between delivery systems and living systems are discussed in the paper by
D’Apolito et al. and Carfì-Pavia et al. D’Apolito et al. focus on the effect of liposomal carriers in microcirculation; Carfì-Pavia
et al. concentrate the attention on a novel bioreactor able to mimic the vascular behavior for in-vitro tests of drug delivery. Last
but not the least, the medical applications of novel delivery systems and siRNAs are discussed in the paper by Piazza et al.,
focusing on the delivery of siRNAs by liposomes in order to silence cycline D1 in ex-vivo human tissues. Moreover, the paper
by Di Gioia et al., deals with the siRNAs’ based therapies against inflammatory respiratory diseases, while the paper by Farra
et al., discusses the role of the transcription factor E2F1 in hepatocellular carcinoma and the opportunity of its silencing by siRNAs.
In conclusion, the papers presented strongly indicate that only a multidisciplinary approach can successfully overcome the
still existing limitation in the use of siRNAs, molecules with an extraordinary therapeutic potential.
only if effective delivery systems are available. Among NABDs, small interfering RNAs (siRNAs) show revolutionary potentiality
due to the ability to silencing the expression of gene-causing diseases. Thus, siRNA drugs have huge therapeutic potentials,
even in the treatment of life threatening diseases. However, the use of siRNAs is limited because of some inconveniences:
they are large macromolecules, negatively charged, undergo rapid degradation by plasma enzymes, are subjected to fast renal
clearance/hepatic sequestration and can hardly cross cellular membranes. These aspects seriously impair siRNAs usability as
therapeutics. To overcome these obstacles, the scientific problem has to be faced out through a multidisciplinary approach, integrating
all relevant and necessary expertise. In this Full-Thematic Issue of the Current Drug Delivery, the development of
siRNAs delivery approaches is described from different points of view by several research groups, which have been jointly
working on the subject in the last years.
The Thematic Issue starts with the paper by Chiarappa et al., devoted to describe the potentiality of the Chemical Engineering
expertise in the “Bio world” through reminding the foundation of Biological Engineering (BE) that develops, with its current
and multidisciplinary approaches, winning strategies in modern research. The concepts of unit operations and transport
phenomena, with which chemical engineers are confident, are applied to the description of the biomedical/pharmaceutical
world and to the study of siRNAs delivery, in order to get a better understanding and description of how biological systems
work.
The engineering approach to siRNA delivery is, then, reported analyzing two topics. In particular, the paper by Caccavo
et al. deals with the modeling of hydrogel based drug delivery systems, materials widely used in controlled drug delivery,
which could be adopted also for siRNAs delivery. Abbiati and Manca report the use of a physiologically-based pharmacokinetic
model, useful in order to assess the fate of drugs, including siRNAs, once administered. The novel preparative methods to
be used in siRNAs delivery are the subjects of the paper by Bochicchio et al., focusing on both the lipid-based and the polymerbased
carriers. More specifically, Dalmoro et al. discuss the use of injectable chitosan/β-glycerophosphate systems, whereas
Cavallaro et al. report the uses of polycation-based smart carriers for siRNAs delivery. Advanced testing methods for the study
of drug delivery systems and the interactions between delivery systems and living systems are discussed in the paper by
D’Apolito et al. and Carfì-Pavia et al. D’Apolito et al. focus on the effect of liposomal carriers in microcirculation; Carfì-Pavia
et al. concentrate the attention on a novel bioreactor able to mimic the vascular behavior for in-vitro tests of drug delivery. Last
but not the least, the medical applications of novel delivery systems and siRNAs are discussed in the paper by Piazza et al.,
focusing on the delivery of siRNAs by liposomes in order to silence cycline D1 in ex-vivo human tissues. Moreover, the paper
by Di Gioia et al., deals with the siRNAs’ based therapies against inflammatory respiratory diseases, while the paper by Farra
et al., discusses the role of the transcription factor E2F1 in hepatocellular carcinoma and the opportunity of its silencing by siRNAs.
In conclusion, the papers presented strongly indicate that only a multidisciplinary approach can successfully overcome the
still existing limitation in the use of siRNAs, molecules with an extraordinary therapeutic potential.
Chiarappa, Gianluca; Grassi, Mario; Abrami, Michela; Abbiati, Roberto Andrea; Barba, Anna Angela; Boisen, Anja; Brucato, Valerio; Ghersi, Giulio; Caccavo, Diego; Cascone, Sara; Caserta, Sergio; Elvassore, Nicola; Giomo, Monica; Guido, Stefano; Lamberti, Gaetano; Larobina, Domenico; Manca, Davide; Marizza, Paolo; Tomaiuolo, Giovanna; Grassi, Gabriele
Chemical Engineering in the “BIO” world Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 158 - 178, 2017.
Abstract | Links | BibTeX | Tags:
@article{Chiarappa2016,
title = {Chemical Engineering in the “BIO” world},
author = {Gianluca Chiarappa and Mario Grassi and Michela Abrami and Roberto Andrea Abbiati and Anna Angela Barba and Anja Boisen and Valerio Brucato and Giulio Ghersi and Diego Caccavo and Sara Cascone and Sergio Caserta and Nicola Elvassore and Monica Giomo and Stefano Guido and Gaetano Lamberti and Domenico Larobina and Davide Manca and Paolo Marizza and Giovanna Tomaiuolo and Gabriele Grassi },
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/02.-Chiarappa-et-al-CDD-142-158-178-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/158/},
doi = {10.2174/1567201813666160602230550},
year = {2017},
date = {2017-02-08},
issuetitle = {NEW TRENDS IN GENE THERAPY: MULTIDISCIPLINARY APPROACHES TO SIRNAS CONTROLLED DELIVERY},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {158 - 178},
abstract = {Modern Chemical Engineering was born around the end of the 19th century in Great Britain, Germany, and the USA, the most industrialized countries at that time. Milton C. Whitaker, in 1914, affirmed that the difference between Chemistry and Chemical Engineering lies in the capability of chemical engineers to transfer laboratory findings to the industrial level. Since then, Chemical Engineering underwent huge transformations determining the detachment from the original Chemistry nest. The beginning of the sixties of the 20th century saw the development of a new branch of Chemical Engineering baptized Biomedical Engineering by Peppas and Langer and that now we can name Biological Engineering. Interestingly, although Biological Engineering focused on completely different topics from Chemical Engineering ones, it resorted to the same theoretical tools such as, for instance, mass, energy and momentum balances. Thus, the birth of Biological Engineering may be considered as a Darwinian evolution of Chemical Engineering similar to that experienced by mammals which, returning to water, used legs and arms to swim. From 1960 on, Biological Engineering underwent a considerable evolution as witnessed by the great variety of topics covered such as hemodialysis, release of synthetic drugs, artificial organs and, more recently, delivery of small interfering RNAs (siRNA). This review, based on the activities developed in the frame of our PRIN 2010-11 (20109PLMH2) project, tries to recount origins and evolution of Chemical Engineering illustrating several examples of recent and successful applications in the biological field. This, in turn, may stimulate the discussion about the Chemical Engineering students curriculum studiorum update.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Modern Chemical Engineering was born around the end of the 19th century in Great Britain, Germany, and the USA, the most industrialized countries at that time. Milton C. Whitaker, in 1914, affirmed that the difference between Chemistry and Chemical Engineering lies in the capability of chemical engineers to transfer laboratory findings to the industrial level. Since then, Chemical Engineering underwent huge transformations determining the detachment from the original Chemistry nest. The beginning of the sixties of the 20th century saw the development of a new branch of Chemical Engineering baptized Biomedical Engineering by Peppas and Langer and that now we can name Biological Engineering. Interestingly, although Biological Engineering focused on completely different topics from Chemical Engineering ones, it resorted to the same theoretical tools such as, for instance, mass, energy and momentum balances. Thus, the birth of Biological Engineering may be considered as a Darwinian evolution of Chemical Engineering similar to that experienced by mammals which, returning to water, used legs and arms to swim. From 1960 on, Biological Engineering underwent a considerable evolution as witnessed by the great variety of topics covered such as hemodialysis, release of synthetic drugs, artificial organs and, more recently, delivery of small interfering RNAs (siRNA). This review, based on the activities developed in the frame of our PRIN 2010-11 (20109PLMH2) project, tries to recount origins and evolution of Chemical Engineering illustrating several examples of recent and successful applications in the biological field. This, in turn, may stimulate the discussion about the Chemical Engineering students curriculum studiorum update.
Caccavo, Diego; Cascone, Sara; Lamberti, Gaetano; Barba, Anna Angela; Larsson, Anette
Drug delivery from hydrogels: a general framework for the release modeling Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 179 - 189, 2017.
Abstract | Links | BibTeX | Tags: Hydrogel Modeling
@article{Caccavo2016b,
title = {Drug delivery from hydrogels: a general framework for the release modeling},
author = {Diego Caccavo and Sara Cascone and Gaetano Lamberti and Anna Angela Barba and Anette Larsson },
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/03.-Caccavo-et-al-CDD-142-179-189-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/179/},
doi = {10.2174/1567201813666160808102106},
year = {2017},
date = {2017-02-08},
issuetitle = {NEW TRENDS IN GENE THERAPY: MULTIDISCIPLINARY APPROACHES TO SIRNAS CONTROLLED DELIVERY},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {179 - 189},
abstract = {The controlled delivery of drugs, including siRNAs, can be effectively obtained using Hydrogel-Based Drugs Delivery Systems (HB-DDSs). Successful design of HB-DDSs requires the knowledge of the mechanisms that influence drug release. The modeling of the physical phenomena involved could help in the development and optimization of HB-DDS, sensibly reducing the time and costs required by a trial-and-error procedures. The modeling is rather complex because of the presence of several, synergistic and competing, transport phenomena. In this work a general framework useful for modeling the HB-DDS has been derived and it is proposed, coupling and homogenizing the literature models. It is shown that all of them can be traced back to two different approaches: multiphasic models and multicomponent mixture models. In the first one the hydrogel is seen as constituted by different phases, the behavior of each one being described by their own mass and momentum conservation equations. In the second approach, the hydrogel is considered as made of one phase composed by several components.},
keywords = {Hydrogel Modeling},
pubstate = {published},
tppubtype = {article}
}
The controlled delivery of drugs, including siRNAs, can be effectively obtained using Hydrogel-Based Drugs Delivery Systems (HB-DDSs). Successful design of HB-DDSs requires the knowledge of the mechanisms that influence drug release. The modeling of the physical phenomena involved could help in the development and optimization of HB-DDS, sensibly reducing the time and costs required by a trial-and-error procedures. The modeling is rather complex because of the presence of several, synergistic and competing, transport phenomena. In this work a general framework useful for modeling the HB-DDS has been derived and it is proposed, coupling and homogenizing the literature models. It is shown that all of them can be traced back to two different approaches: multiphasic models and multicomponent mixture models. In the first one the hydrogel is seen as constituted by different phases, the behavior of each one being described by their own mass and momentum conservation equations. In the second approach, the hydrogel is considered as made of one phase composed by several components.
Abbiati, Roberto Andrea; Manca, Davide
Innovations and improvements in pharmacokinetic models based on physiology Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 190 - 202, 2017.
Abstract | Links | BibTeX | Tags:
@article{Abbiati2016,
title = {Innovations and improvements in pharmacokinetic models based on physiology},
author = {Roberto Andrea Abbiati and Davide Manca},
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/04.-Abbiati-and-Manca-CDD-142-190-202-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/190/},
doi = {10.2174/1567201813666160524142031},
year = {2017},
date = {2017-02-08},
issuetitle = {NEW TRENDS IN GENE THERAPY: MULTIDISCIPLINARY APPROACHES TO SIRNAS CONTROLLED DELIVERY},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {190 - 202},
abstract = {Background
Accompanied by significant improvements of modeling techniques and computational methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic (PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of aspects with possible applications in patient care and new drugs development, as in the case of siRNA therapies.
Method
This article summarizes the features we recently introduced in PBPK modeling within a three-year research project funded by Italian Research Ministry. Four major points are detailed: (i) the mathematical formulation of the model, which allows modulating its complexity as a function of the administration route and active principle; (ii) a dedicated parameter of the PBPK model quantifies the drug-protein binding, which affects the active principle distribution; (iii) the gall bladder compartment and the bile enterohepatic circulation process; (iv) the coupling of the pharmacokinetic and pharmacodynamic models to produce an overall understanding of the drug effects on mammalian body.
Results
The proposed model is applied to two separate endovenous (remifentanil) and oral (sorafenib) drug administrations. The resulting PBPK simulations are consistent with the literature experimental data. Blood concentration predictability is confirmed in multiple reference subjects. Furthermore, in case of sorafenib administration in mice, it is possible to evaluate the drug concentration in the liver and reproduce the effects of the enterohepatic circulation. Finally, a preliminary application of the coupling of the pharmacokinetic/pharmacodynamic models is presented and discussed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background
Accompanied by significant improvements of modeling techniques and computational methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic (PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of aspects with possible applications in patient care and new drugs development, as in the case of siRNA therapies.
Method
This article summarizes the features we recently introduced in PBPK modeling within a three-year research project funded by Italian Research Ministry. Four major points are detailed: (i) the mathematical formulation of the model, which allows modulating its complexity as a function of the administration route and active principle; (ii) a dedicated parameter of the PBPK model quantifies the drug-protein binding, which affects the active principle distribution; (iii) the gall bladder compartment and the bile enterohepatic circulation process; (iv) the coupling of the pharmacokinetic and pharmacodynamic models to produce an overall understanding of the drug effects on mammalian body.
Results
The proposed model is applied to two separate endovenous (remifentanil) and oral (sorafenib) drug administrations. The resulting PBPK simulations are consistent with the literature experimental data. Blood concentration predictability is confirmed in multiple reference subjects. Furthermore, in case of sorafenib administration in mice, it is possible to evaluate the drug concentration in the liver and reproduce the effects of the enterohepatic circulation. Finally, a preliminary application of the coupling of the pharmacokinetic/pharmacodynamic models is presented and discussed.
Accompanied by significant improvements of modeling techniques and computational methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic (PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of aspects with possible applications in patient care and new drugs development, as in the case of siRNA therapies.
Method
This article summarizes the features we recently introduced in PBPK modeling within a three-year research project funded by Italian Research Ministry. Four major points are detailed: (i) the mathematical formulation of the model, which allows modulating its complexity as a function of the administration route and active principle; (ii) a dedicated parameter of the PBPK model quantifies the drug-protein binding, which affects the active principle distribution; (iii) the gall bladder compartment and the bile enterohepatic circulation process; (iv) the coupling of the pharmacokinetic and pharmacodynamic models to produce an overall understanding of the drug effects on mammalian body.
Results
The proposed model is applied to two separate endovenous (remifentanil) and oral (sorafenib) drug administrations. The resulting PBPK simulations are consistent with the literature experimental data. Blood concentration predictability is confirmed in multiple reference subjects. Furthermore, in case of sorafenib administration in mice, it is possible to evaluate the drug concentration in the liver and reproduce the effects of the enterohepatic circulation. Finally, a preliminary application of the coupling of the pharmacokinetic/pharmacodynamic models is presented and discussed.
Bochicchio, Sabrina; Dalmoro, Annalisa; Barba, Anna Angela; D'Amore, Matteo; Lamberti, Gaetano
New preparative approaches for micro and nano drug delivery carriers Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 203 - 215, 2017.
Abstract | Links | BibTeX | Tags: Micro and Nano Vectors
@article{Bochicchio2016b,
title = {New preparative approaches for micro and nano drug delivery carriers},
author = {Sabrina Bochicchio and Annalisa Dalmoro and Anna Angela Barba and Matteo D'Amore and Gaetano Lamberti},
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/05.-Bochicchio-et-al-CDD-142-203-215-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/203/},
doi = {10.2174/1567201813666160628093724},
year = {2017},
date = {2017-02-08},
issuetitle = {NEW TRENDS IN GENE THERAPY: MULTIDISCIPLINARY APPROACHES TO SIRNAS CONTROLLED DELIVERY},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {203 - 215},
abstract = {The full success of pharmacological therapies is strongly depending from the use of suitable, efficient and smart drug delivery systems (DDSs). Thus DDSs development is one of the main challenges in pharmaceutical industry both to achieve tailored carrier systems based on drug features and to promote manufacturing innovations to reduce energetic resources, emissions, wastes and risks. Main functions of an ideal DDS are: to protect loaded active molecules from degradation in physiological environments; to deliver them in a controlled manner and towards a specific organ or tissue, to allow the maintenance of the drug level in the body within therapeutic window. Smart features, such as those able to induce active molecule release upon the occurrence of specific physiological stimuli, are also desirable. Under the manufacturing point of view, the current industrial scenery is obliged to respond to the increasing market requirements and to the mandatory rules in sustainable productions such as raw material and energy savings.
In this work a general framework on drug delivery systems preparation techniques is presented. In particular two sections on innovation in preparative approaches carried out are detailed. These latter involve the use of microwave and ultrasonic energy applied in the production of polymeric and lipidic delivery systems on micro- and nanometric scale. The novelties of these preparative approaches are emphasized and examples of developed drug delivery carriers, loaded with vitamins and drug mimicking siRNA, are shown.},
keywords = {Micro and Nano Vectors},
pubstate = {published},
tppubtype = {article}
}
The full success of pharmacological therapies is strongly depending from the use of suitable, efficient and smart drug delivery systems (DDSs). Thus DDSs development is one of the main challenges in pharmaceutical industry both to achieve tailored carrier systems based on drug features and to promote manufacturing innovations to reduce energetic resources, emissions, wastes and risks. Main functions of an ideal DDS are: to protect loaded active molecules from degradation in physiological environments; to deliver them in a controlled manner and towards a specific organ or tissue, to allow the maintenance of the drug level in the body within therapeutic window. Smart features, such as those able to induce active molecule release upon the occurrence of specific physiological stimuli, are also desirable. Under the manufacturing point of view, the current industrial scenery is obliged to respond to the increasing market requirements and to the mandatory rules in sustainable productions such as raw material and energy savings.
In this work a general framework on drug delivery systems preparation techniques is presented. In particular two sections on innovation in preparative approaches carried out are detailed. These latter involve the use of microwave and ultrasonic energy applied in the production of polymeric and lipidic delivery systems on micro- and nanometric scale. The novelties of these preparative approaches are emphasized and examples of developed drug delivery carriers, loaded with vitamins and drug mimicking siRNA, are shown.
In this work a general framework on drug delivery systems preparation techniques is presented. In particular two sections on innovation in preparative approaches carried out are detailed. These latter involve the use of microwave and ultrasonic energy applied in the production of polymeric and lipidic delivery systems on micro- and nanometric scale. The novelties of these preparative approaches are emphasized and examples of developed drug delivery carriers, loaded with vitamins and drug mimicking siRNA, are shown.
Dalmoro, Annalisa; Abrami, Michela; Galzerano, Barbara; Bochicchio, Sabrina; Barba, Anna Angela; Grassi, Mario; Larobina, Domenico
Injectable chitosan/b-glycerophosphate system for sustained release: gelation study, structural investigation and erosion tests Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 216 - 223, 2017.
Abstract | Links | BibTeX | Tags: Hydrogel Characterization
@article{Dalmoro2016b,
title = { Injectable chitosan/b-glycerophosphate system for sustained release: gelation study, structural investigation and erosion tests},
author = {Annalisa Dalmoro and Michela Abrami and Barbara Galzerano and Sabrina Bochicchio and Anna Angela Barba and Mario Grassi and Domenico Larobina},
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/06.-Dalmoro-et-al-CDD-142-216-223-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/216/
},
doi = {10.2174/1567201813666160721142202},
year = {2017},
date = {2017-02-08},
issuetitle = {NEW TRENDS IN GENE THERAPY: MULTIDISCIPLINARY APPROACHES TO SIRNAS CONTROLLED DELIVERY},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {216 - 223},
abstract = {Hydrogels can constitute reliable delivery systems of drugs, including those based on nucleic acids (NABDs) such as small interfering ribonucleic acid (siRNA). Their nature, structure, and response to physiological or external stimuli strongly influence the delivery mechanisms of entrapped active molecules, and, in turns, their possible uses in pharmacological and biomedical applications. In this study a thermo-gelling chitosan/β-glycero-phosphate system has been optimized in order to assess its use as injectable system able to: i) gelling at physiological pH and temperature, and ii) modulate the release of included active ingredients. To this aim we first analyzed the effect of acetic acid concentration on the gelation temperature. We then found the “optimized composition”, namely, the one in which the Tgel is equal to the physiological temperature. The resulting gel was tested, by low field nuclear magnetic resonance (LF-NMR), to evaluate its average mesh-size, which can affect release kinetics of loaded drug. Finally, films of gelled chitosan, loaded with a model drug, have been tested in vitro to monitor their characteristic times, i.e. diffusion and erosion time, when they are exposed to a medium mimicking a physiological environment (buffer solution at pH 7.4). Results display that the optimized system is deemed to be an ideal candidate as injectable gelling material for a sustained release.},
keywords = {Hydrogel Characterization},
pubstate = {published},
tppubtype = {article}
}
Hydrogels can constitute reliable delivery systems of drugs, including those based on nucleic acids (NABDs) such as small interfering ribonucleic acid (siRNA). Their nature, structure, and response to physiological or external stimuli strongly influence the delivery mechanisms of entrapped active molecules, and, in turns, their possible uses in pharmacological and biomedical applications. In this study a thermo-gelling chitosan/β-glycero-phosphate system has been optimized in order to assess its use as injectable system able to: i) gelling at physiological pH and temperature, and ii) modulate the release of included active ingredients. To this aim we first analyzed the effect of acetic acid concentration on the gelation temperature. We then found the “optimized composition”, namely, the one in which the Tgel is equal to the physiological temperature. The resulting gel was tested, by low field nuclear magnetic resonance (LF-NMR), to evaluate its average mesh-size, which can affect release kinetics of loaded drug. Finally, films of gelled chitosan, loaded with a model drug, have been tested in vitro to monitor their characteristic times, i.e. diffusion and erosion time, when they are exposed to a medium mimicking a physiological environment (buffer solution at pH 7.4). Results display that the optimized system is deemed to be an ideal candidate as injectable gelling material for a sustained release.
Cavallaro, Gennara; Sardo, Carla; Scialabba, Cinzia; Licciardi, Mariano; Giammona, Gaetano
Smart inulin-based polycationic nanodevices for sirna delivery Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 224 - 230, 2017.
Abstract | Links | BibTeX | Tags:
@article{Cavallaro2016,
title = {Smart inulin-based polycationic nanodevices for sirna delivery},
author = {Gennara Cavallaro and Carla Sardo and Cinzia Scialabba and Mariano Licciardi and Gaetano Giammona},
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/07.-Cavallaro-et-al-CDD-142-224-230-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/224/},
doi = {10.2174/1567201813666160811145855},
year = {2017},
date = {2017-02-08},
issuetitle = {NEW TRENDS IN GENE THERAPY: MULTIDISCIPLINARY APPROACHES TO SIRNAS CONTROLLED DELIVERY},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {224 - 230},
abstract = {The advances of short interfering RNA (siRNA) mediated therapy provide a powerful option for treatment of many diseased by silencing the expression of targeted genes including cancer development and progression. Inulin is a very simple and biocompatible polysaccharide proposed by our groups to produce interesting delivery systems for Nucleic acid based drugs (NABDs), such as siRNA, either as polycations able to give polyplexes and polymeric coatings for nanosystems having a metallic core. In this research field different functionalizing groups were linked to the inulin backbone with specific aims including oligo amine such as Ethylendiammine (EDA), Diethylediamine (DETA), Spermine, (SPM) etc... In this contribution the main Inulin-based nanodevices for the delivery of siRNA have been reported, analysed and compared with particular reference to their chemical design and structure, biocompatibility, siRNA complexing ability, silencing ability. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The advances of short interfering RNA (siRNA) mediated therapy provide a powerful option for treatment of many diseased by silencing the expression of targeted genes including cancer development and progression. Inulin is a very simple and biocompatible polysaccharide proposed by our groups to produce interesting delivery systems for Nucleic acid based drugs (NABDs), such as siRNA, either as polycations able to give polyplexes and polymeric coatings for nanosystems having a metallic core. In this research field different functionalizing groups were linked to the inulin backbone with specific aims including oligo amine such as Ethylendiammine (EDA), Diethylediamine (DETA), Spermine, (SPM) etc... In this contribution the main Inulin-based nanodevices for the delivery of siRNA have been reported, analysed and compared with particular reference to their chemical design and structure, biocompatibility, siRNA complexing ability, silencing ability.
D'Apolito, Rosa; Bochicchio, Sabrina; Dalmoro, Annalisa; Barba, Anna Angela; Guido, Stefano; Tomaiuolo, Giovanna
Microfluidic investigation of the effect of liposome surface charge on drug delivery in microcirculation Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 231 - 238, 2017.
Abstract | Links | BibTeX | Tags:
@article{D'Apolito2016,
title = {Microfluidic investigation of the effect of liposome surface charge on drug delivery in microcirculation},
author = {Rosa D'Apolito and Sabrina Bochicchio and Annalisa Dalmoro and Anna Angela Barba and Stefano Guido and Giovanna Tomaiuolo},
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/08.-DApolito-et-al-CDD-142-231-238-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/231/},
doi = {10.2174/1567201813666160813172047},
year = {2017},
date = {2017-02-08},
issuetitle = {NEW TRENDS IN GENE THERAPY: MULTIDISCIPLINARY APPROACHES TO SIRNAS CONTROLLED DELIVERY},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {231 - 238},
abstract = {Nano-carrier drug transport in blood microcirculation is one of the hotspots of current research in drug development due to many advantages over traditional therapies, such as reduced side-effects, target delivery, controlled release, improved pharmacokinetics and therapeutic index. Despite the substantial efforts made in the design of nanotherapeutics, the big majority of the used strategies failed to overcome the biological barriers to drug transport encountered in human microvasculature, such as transport by blood flow via the microcirculatory network and margination, the mechanism according to which particles migrate along vessel radius to the wall. In fact, drug transport efficiency in microvasculature is affected by both the particulate nature of blood and drug carrier properties, such as size, shape and surface charge.
In this work, the effect of the surface charge of liposomes on their margination in blood flow in microcapillaries was experimentally evaluated. By high-speed video microscopy and image analysis it was found that the two custom-made liposomes (one neuter and the other positively charged) tend to drift laterally, moving towards the wall and accumulating in the cell-free layer. In particular, neuter and cationic liposomes showed a comparable margination propensity, suggesting that the presence of blood cells governs the flow behavior independently on liposome surface charge.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Nano-carrier drug transport in blood microcirculation is one of the hotspots of current research in drug development due to many advantages over traditional therapies, such as reduced side-effects, target delivery, controlled release, improved pharmacokinetics and therapeutic index. Despite the substantial efforts made in the design of nanotherapeutics, the big majority of the used strategies failed to overcome the biological barriers to drug transport encountered in human microvasculature, such as transport by blood flow via the microcirculatory network and margination, the mechanism according to which particles migrate along vessel radius to the wall. In fact, drug transport efficiency in microvasculature is affected by both the particulate nature of blood and drug carrier properties, such as size, shape and surface charge.
In this work, the effect of the surface charge of liposomes on their margination in blood flow in microcapillaries was experimentally evaluated. By high-speed video microscopy and image analysis it was found that the two custom-made liposomes (one neuter and the other positively charged) tend to drift laterally, moving towards the wall and accumulating in the cell-free layer. In particular, neuter and cationic liposomes showed a comparable margination propensity, suggesting that the presence of blood cells governs the flow behavior independently on liposome surface charge.
In this work, the effect of the surface charge of liposomes on their margination in blood flow in microcapillaries was experimentally evaluated. By high-speed video microscopy and image analysis it was found that the two custom-made liposomes (one neuter and the other positively charged) tend to drift laterally, moving towards the wall and accumulating in the cell-free layer. In particular, neuter and cationic liposomes showed a comparable margination propensity, suggesting that the presence of blood cells governs the flow behavior independently on liposome surface charge.
Piazza, Ornella; Russo, Ilaria; Bochicchio, Sabrina; Barba, Anna Angela; Lamberti, Gaetano; Zeppa, Pio; Crescenzo, Vincenzo Di; Carrizzo, Albino; Vecchione, Carmine; Ciacci, Carolina
Cyclin D1 gene silencing by siRNA in ex vivo human tissues cultures Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 246 - 252, 2017.
Abstract | Links | BibTeX | Tags:
@article{Piazza2016,
title = {Cyclin D1 gene silencing by siRNA in ex vivo human tissues cultures},
author = {Ornella Piazza and Ilaria Russo and Sabrina Bochicchio and Anna Angela Barba and Gaetano Lamberti and Pio Zeppa and Vincenzo {Di Crescenzo} and Albino Carrizzo and Carmine Vecchione and Carolina Ciacci},
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/10.-Piazza-et-al-CDD-142-246-252-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/246/},
doi = {10.2174/1567201813666160512150710},
year = {2017},
date = {2017-02-08},
issuetitle = {NEW TRENDS IN GENE THERAPY: MULTIDISCIPLINARY APPROACHES TO SIRNAS CONTROLLED DELIVERY},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {246 - 252},
abstract = {Background. Short interfering RNAs (siRNAs) are double-stranded RNA molecules able to specifically targeting genes products responsible for human diseases. Cyclin D1 (CyD1) is a cell cycle-regulatory molecule, up-regulated at sites of inflammation in several tissues. CyD1 is a very interesting potential target in lung and colon inflammatory diseases.
Objective. The aim of this paper was testing CyD1 expression in human lung and colon tissues after the application of an inflammatory stimulus, and verifying its gene silencing by using siRNA for CyD1 (siCyD1).
Method. Colon and pulmonary biopsies were treated with siCyD1 by using two different transfection carriers: a) invivofectamine and b) ad hoc produced nanoliposomes. After 24 hours of incubation with nanoliposomes encapsulating siRNA or invivofectamine-CyD1siRNA, in presence or absence of EC-LPS, we analysed the protein expression of CyD1 through Western-Blotting.
Results. After EC-LPS treatment, in both colon and pulmonary biopsies, an overexpression of CyD1was found (about 64% and 40% respectively). Invivofectamine-CyD1 siRNA reduced the expression of CyD1 approximately by 46% compared to the basal condition, and by around 65% compared to EC-LPS treated colon samples. In lung, following invivofectamine siRNA silencing in the presence of EC-LPS, no reduction was observed.
Ad hoc nanoliposomes were able to enter colon and lung tissues, but CyD1 silencing was reported in 2 colon samples out of 4 and no efficacy was demonstrated in the only lung sample we studied.
Conclusion. It is possible to silencing Cyclin D1 expression in vitro “organ culture” model. Our preliminary results encourage further investigations, using different siRNA concentrations delivered by nanoliposomes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background. Short interfering RNAs (siRNAs) are double-stranded RNA molecules able to specifically targeting genes products responsible for human diseases. Cyclin D1 (CyD1) is a cell cycle-regulatory molecule, up-regulated at sites of inflammation in several tissues. CyD1 is a very interesting potential target in lung and colon inflammatory diseases.
Objective. The aim of this paper was testing CyD1 expression in human lung and colon tissues after the application of an inflammatory stimulus, and verifying its gene silencing by using siRNA for CyD1 (siCyD1).
Method. Colon and pulmonary biopsies were treated with siCyD1 by using two different transfection carriers: a) invivofectamine and b) ad hoc produced nanoliposomes. After 24 hours of incubation with nanoliposomes encapsulating siRNA or invivofectamine-CyD1siRNA, in presence or absence of EC-LPS, we analysed the protein expression of CyD1 through Western-Blotting.
Results. After EC-LPS treatment, in both colon and pulmonary biopsies, an overexpression of CyD1was found (about 64% and 40% respectively). Invivofectamine-CyD1 siRNA reduced the expression of CyD1 approximately by 46% compared to the basal condition, and by around 65% compared to EC-LPS treated colon samples. In lung, following invivofectamine siRNA silencing in the presence of EC-LPS, no reduction was observed.
Ad hoc nanoliposomes were able to enter colon and lung tissues, but CyD1 silencing was reported in 2 colon samples out of 4 and no efficacy was demonstrated in the only lung sample we studied.
Conclusion. It is possible to silencing Cyclin D1 expression in vitro “organ culture” model. Our preliminary results encourage further investigations, using different siRNA concentrations delivered by nanoliposomes.
Objective. The aim of this paper was testing CyD1 expression in human lung and colon tissues after the application of an inflammatory stimulus, and verifying its gene silencing by using siRNA for CyD1 (siCyD1).
Method. Colon and pulmonary biopsies were treated with siCyD1 by using two different transfection carriers: a) invivofectamine and b) ad hoc produced nanoliposomes. After 24 hours of incubation with nanoliposomes encapsulating siRNA or invivofectamine-CyD1siRNA, in presence or absence of EC-LPS, we analysed the protein expression of CyD1 through Western-Blotting.
Results. After EC-LPS treatment, in both colon and pulmonary biopsies, an overexpression of CyD1was found (about 64% and 40% respectively). Invivofectamine-CyD1 siRNA reduced the expression of CyD1 approximately by 46% compared to the basal condition, and by around 65% compared to EC-LPS treated colon samples. In lung, following invivofectamine siRNA silencing in the presence of EC-LPS, no reduction was observed.
Ad hoc nanoliposomes were able to enter colon and lung tissues, but CyD1 silencing was reported in 2 colon samples out of 4 and no efficacy was demonstrated in the only lung sample we studied.
Conclusion. It is possible to silencing Cyclin D1 expression in vitro “organ culture” model. Our preliminary results encourage further investigations, using different siRNA concentrations delivered by nanoliposomes.
Gioia, Sante Di; Sardo, Carla; Castellani, Stefano; Porsio, Barbara; Belgiovine, Giuliana; Carbone, Annalucia; Giammona, Gaetano; Cavallaro, Gennara; Conese, Massimo
From genesis to revelation: the role of inflammatory mediators in chronic respiratory diseases and their control by nucleic acid-based drugs Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 253 - 271, 2017.
Abstract | Links | BibTeX | Tags:
@article{Gioia}2016,
title = {From genesis to revelation: the role of inflammatory mediators in chronic respiratory diseases and their control by nucleic acid-based drugs},
author = {Sante {Di Gioia} and Carla Sardo and Stefano Castellani and Barbara Porsio and Giuliana Belgiovine and Annalucia Carbone and Gaetano Giammona and Gennara Cavallaro and Massimo Conese},
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/11.-Di-Gioia-et-al-CDD-142-253-271-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/253/},
doi = {10.2174/1567201813666160824142843},
year = {2017},
date = {2017-02-08},
issuetitle = {NEW TRENDS IN GENE THERAPY: MULTIDISCIPLINARY APPROACHES TO SIRNAS CONTROLLED DELIVERY},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {253 - 271},
abstract = {Asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis, are among the most common chronic diseases and their prevalence is increasing. Each of these diseases is characterized by the secretion of cytokines and pro-inflammatory molecules which are thought to play a critical role in their pathogenesis. Moreover, immune cells, particularly neutrophils, macrophages and dendritic cells as well structural cell such as epithelial and airway smooth muscle cells also are involved in the pathogenic cycle of these diseases. There is a pressing need for the development of new therapies for these pulmonary diseases, particularly as no existing treatment has been shown to reduce disease progression. HMGB1 (high-mobility group box 1), originally identified as a nuclear nonhistone protein with DNA-binding domains can be secreted by living and dying cells and it is now regarded as an important endogenous danger signaling molecule. Besides as a signal of tissue injury, HMGB1 is considered a powerful mediator of inflammation and high levels of HMGB1 are found in chronic lung diseases. However, the role of HMGB1 in respiratory diseases is still elusive but nevertheless these studies suggest an involvement of this cytokine in their pathogenesis. Nucleic acid-based drugs (NABDs) are a novel class of pharmaceuticals including antisense oligonucleotides, DNA-zymes, and RNA interference as mediated by small interfering RNA (siRNA), which are used to dampen the expression of disease-causing genes having therapeutic potential for controlling chronic airway diseases. Due to their inherent difficulties, such as for example sensitivity to endonucleases, their delivery in vivo should be assured by vectors. Non-viral lipid- and polymer-based nanosystems have acquired much importance in this context. In this review, we will discuss these emerging tools in gene therapy of chronic lung diseases, in particular the use of siRNA in the down-regulation of critical molecules in the pathogenesis of chronic lung diseases, with particular emphasis on HMGB1 as therapeutic target.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis, are among the most common chronic diseases and their prevalence is increasing. Each of these diseases is characterized by the secretion of cytokines and pro-inflammatory molecules which are thought to play a critical role in their pathogenesis. Moreover, immune cells, particularly neutrophils, macrophages and dendritic cells as well structural cell such as epithelial and airway smooth muscle cells also are involved in the pathogenic cycle of these diseases. There is a pressing need for the development of new therapies for these pulmonary diseases, particularly as no existing treatment has been shown to reduce disease progression. HMGB1 (high-mobility group box 1), originally identified as a nuclear nonhistone protein with DNA-binding domains can be secreted by living and dying cells and it is now regarded as an important endogenous danger signaling molecule. Besides as a signal of tissue injury, HMGB1 is considered a powerful mediator of inflammation and high levels of HMGB1 are found in chronic lung diseases. However, the role of HMGB1 in respiratory diseases is still elusive but nevertheless these studies suggest an involvement of this cytokine in their pathogenesis. Nucleic acid-based drugs (NABDs) are a novel class of pharmaceuticals including antisense oligonucleotides, DNA-zymes, and RNA interference as mediated by small interfering RNA (siRNA), which are used to dampen the expression of disease-causing genes having therapeutic potential for controlling chronic airway diseases. Due to their inherent difficulties, such as for example sensitivity to endonucleases, their delivery in vivo should be assured by vectors. Non-viral lipid- and polymer-based nanosystems have acquired much importance in this context. In this review, we will discuss these emerging tools in gene therapy of chronic lung diseases, in particular the use of siRNA in the down-regulation of critical molecules in the pathogenesis of chronic lung diseases, with particular emphasis on HMGB1 as therapeutic target.
Farra, Rossella; Grassi, Gabriele; Tonon, Federica; Abrami, Michela; Grassi, Mario; Pozzato, Gabriele; Fiotti, Nicola; Forte, Giancarlo; Dapas, Barbara
The role of the transcription factor E2F1 in hepatocellular carcinoma Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 272 - 281, 2017.
Abstract | Links | BibTeX | Tags:
@article{Farra2016,
title = {The role of the transcription factor E2F1 in hepatocellular carcinoma},
author = {Rossella Farra and Gabriele Grassi and Federica Tonon and Michela Abrami and Mario Grassi and Gabriele Pozzato and Nicola Fiotti and Giancarlo Forte and Barbara Dapas},
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/12.-Farra-et-al-CDD-142-272-281-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/272/},
doi = {10.2174/1567201813666160527141742},
year = {2017},
date = {2017-02-08},
issuetitle = {NEW TRENDS IN GENE THERAPY: MULTIDISCIPLINARY APPROACHES TO SIRNAS CONTROLLED DELIVERY},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {272 - 281},
abstract = {Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Because of the fast growth, early hepatic metastasis and the multidrug resistance, the five-year survival rate is very low. Thus, the understanding of its biology can significantly contribute in identifying valuable targets for novel therapeutic approaches. In this regard, E2F1 may represent an interesting candidate. E2F1 is a transcription factor implicated in the regulation of many cellular processes including cell proliferation and apoptosis. Whereas the involvement of E2F1 in HCC has been recognized, its ability to act as a proliferative and/or apoptotic factor in HCC has not yet been clarified and, in this regard, an active debate is ongoing. The definition of E2F1 role in HCC is not a trivial aspect as it can have significant consequences for the development of novel therapeutic options with E2F1 as target. In this review, we present data about the reported proliferative/apoptotic effects as well as the dual (combined proliferation and apoptosis) functions of E2F1 in HCC discussing the molecular basis for this behavior. The data available so far indicate that the proliferative and apoptotic functions of E2F1 in HCC may coexist but the proliferative effect seems to be more pronounced than the apoptotic one.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Because of the fast growth, early hepatic metastasis and the multidrug resistance, the five-year survival rate is very low. Thus, the understanding of its biology can significantly contribute in identifying valuable targets for novel therapeutic approaches. In this regard, E2F1 may represent an interesting candidate. E2F1 is a transcription factor implicated in the regulation of many cellular processes including cell proliferation and apoptosis. Whereas the involvement of E2F1 in HCC has been recognized, its ability to act as a proliferative and/or apoptotic factor in HCC has not yet been clarified and, in this regard, an active debate is ongoing. The definition of E2F1 role in HCC is not a trivial aspect as it can have significant consequences for the development of novel therapeutic options with E2F1 as target. In this review, we present data about the reported proliferative/apoptotic effects as well as the dual (combined proliferation and apoptosis) functions of E2F1 in HCC discussing the molecular basis for this behavior. The data available so far indicate that the proliferative and apoptotic functions of E2F1 in HCC may coexist but the proliferative effect seems to be more pronounced than the apoptotic one.
Pavia, Francesco Carfì; Carrubba, Vincenzo La; Ghersi, Giulio; Greco, Silvia; Brucato, Valerio
Double Flow Bioreactor for In Vitro Test of Drug Delivery Journal Article
In: Current Drug Delivery, vol. 14, no. 2, pp. 239-245, 2017.
Abstract | Links | BibTeX | Tags:
@article{Pavia}2017,
title = {Double Flow Bioreactor for In Vitro Test of Drug Delivery},
author = {Francesco {Carf\`{i} Pavia} and Vincenzo {La Carrubba} and Giulio Ghersi and Silvia Greco and Valerio Brucato},
url = {https://www.gruppotpp.it/wp-content/uploads/2017/03/09.-Carf\`{i}-Pavia-et-al-CDD-142-239-245-2017.pdf
http://benthamscience.com/journals/current-drug-delivery/volume/14/issue/2/page/239/},
doi = {10.2174/1567201813666160527141538},
year = {2017},
date = {2017-02-08},
journal = {Current Drug Delivery},
volume = {14},
number = {2},
pages = {239-245},
abstract = {In this work, double-structured polymeric scaffolds were produced, and a double flow bioreactor was designed and set up in order to create a novel system to carry out advanced in vitro drug delivery tests. The scaffolds consists of a cylindrical porous matrix, are able to host cells, thus mimicking a three-dimensional tumor mass: moreover, a "pseudo-vascular" structure was embedded into the matrix, with the aim of allowing a flow circulation. The structure that emulates a blood vessel is a porous tubular-shaped scaffold prepared by Diffusion Induced Phase Separation (DIPS), with an internal lumen of 2 mm and a wall thickness of 200 micrometers. The as-prepared vessel was incorporated into a three-dimensional matrix, prepared by Thermally Induced Phase Separation (TIPS), characterized by a high porosity (about 95%) and pore size adequate to accommodate tumor cells and/or mesenchymal cells. The morphology of the multifunctional scaffolds is easy-tunable in terms of pore size, porosity and thickness and therefore adaptable to various cell or tissue types. At the same time, a double flow bioreactor was designed and built up, in order to be able to carry out biological tests on the scaffold under dynamic conditions. The device allows a separate control of the two flows (one for the tubular scaffold, one for the porous matrix) through the scaffolds. Preliminary characterizations and tests carried out suggest the presented system as a candidate to suitably "in vitro" assess the effects of different drugs on various cell populations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In this work, double-structured polymeric scaffolds were produced, and a double flow bioreactor was designed and set up in order to create a novel system to carry out advanced in vitro drug delivery tests. The scaffolds consists of a cylindrical porous matrix, are able to host cells, thus mimicking a three-dimensional tumor mass: moreover, a "pseudo-vascular" structure was embedded into the matrix, with the aim of allowing a flow circulation. The structure that emulates a blood vessel is a porous tubular-shaped scaffold prepared by Diffusion Induced Phase Separation (DIPS), with an internal lumen of 2 mm and a wall thickness of 200 micrometers. The as-prepared vessel was incorporated into a three-dimensional matrix, prepared by Thermally Induced Phase Separation (TIPS), characterized by a high porosity (about 95%) and pore size adequate to accommodate tumor cells and/or mesenchymal cells. The morphology of the multifunctional scaffolds is easy-tunable in terms of pore size, porosity and thickness and therefore adaptable to various cell or tissue types. At the same time, a double flow bioreactor was designed and built up, in order to be able to carry out biological tests on the scaffold under dynamic conditions. The device allows a separate control of the two flows (one for the tubular scaffold, one for the porous matrix) through the scaffolds. Preliminary characterizations and tests carried out suggest the presented system as a candidate to suitably "in vitro" assess the effects of different drugs on various cell populations.
2016
Scaggiante, Bruna; Farra, Rossella; Dapas, Barbara; Baj, Gabriele; Pozzato, Gabriele; Grassi, Mario; Zanconati, Fabrizio; Grassi, Gabriele
Aptamer targeting of the elongation factor 1A impairs hepatocarcinoma cells viability and potentiates bortezomib and idarubicin effects Journal Article
In: International Journal of Pharmaceutics, vol. 506, no. 1-2, pp. 268–279, 2016.
Abstract | Links | BibTeX | Tags:
@article{Scaggiante2016,
title = {Aptamer targeting of the elongation factor 1A impairs hepatocarcinoma cells viability and potentiates bortezomib and idarubicin effects},
author = {Bruna Scaggiante and Rossella Farra and Barbara Dapas and Gabriele Baj and Gabriele Pozzato and Mario Grassi and Fabrizio Zanconati and Gabriele Grassi},
url = {http://www.sciencedirect.com/science/article/pii/S0378517316303155},
doi = {10.1016/j.ijpharm.2016.04.031},
year = {2016},
date = {2016-06-15},
journal = {International Journal of Pharmaceutics},
volume = {506},
number = {1-2},
pages = {268\textendash279},
abstract = {The high morbidity and mortality of hepatocellular carcinoma (HCC) is mostly due to the limited efficacy of the available therapeutic approaches. Here we explore the anti-HCC potential of an aptamer targeting the elongation factor 1A (eEF1A), a protein implicated in the promotion of HCC. As delivery methods, we have compared the effectiveness of cationic liposome and cholesterol-mediated approaches.
A75 nucleotide long aptamer containing GT repetition (GT75) was tested in three HCC cell lines, HepG2, HuH7 and JHH6. When delivered by liposomes, GT75 was able to effectively reducing HCC cells viability in a dose and time dependent fashion. Particular sensitive were JHH6 where increased apoptosis with no effects on cell cycle were observed. GT75 effect was likely due to the interference with eEF1A activity as neither the mRNA nor the protein levels were significantly affected. Notably, cholesterol-mediated delivery of GT75 abrogated its efficacy due to cellular mis-localization as proven by fluorescence and confocal microscopic analysis. Finally, liposome-mediated delivery of GT75 improved the therapeutic index of the anticancer drugs bortezomib and idarubicin.
In conclusion, liposome but not cholesterol-mediated delivery of GT75 resulted in an effective delivery of GT75, causing the impairment of the vitality of a panel of HCC derived cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The high morbidity and mortality of hepatocellular carcinoma (HCC) is mostly due to the limited efficacy of the available therapeutic approaches. Here we explore the anti-HCC potential of an aptamer targeting the elongation factor 1A (eEF1A), a protein implicated in the promotion of HCC. As delivery methods, we have compared the effectiveness of cationic liposome and cholesterol-mediated approaches.
A75 nucleotide long aptamer containing GT repetition (GT75) was tested in three HCC cell lines, HepG2, HuH7 and JHH6. When delivered by liposomes, GT75 was able to effectively reducing HCC cells viability in a dose and time dependent fashion. Particular sensitive were JHH6 where increased apoptosis with no effects on cell cycle were observed. GT75 effect was likely due to the interference with eEF1A activity as neither the mRNA nor the protein levels were significantly affected. Notably, cholesterol-mediated delivery of GT75 abrogated its efficacy due to cellular mis-localization as proven by fluorescence and confocal microscopic analysis. Finally, liposome-mediated delivery of GT75 improved the therapeutic index of the anticancer drugs bortezomib and idarubicin.
In conclusion, liposome but not cholesterol-mediated delivery of GT75 resulted in an effective delivery of GT75, causing the impairment of the vitality of a panel of HCC derived cells.
A75 nucleotide long aptamer containing GT repetition (GT75) was tested in three HCC cell lines, HepG2, HuH7 and JHH6. When delivered by liposomes, GT75 was able to effectively reducing HCC cells viability in a dose and time dependent fashion. Particular sensitive were JHH6 where increased apoptosis with no effects on cell cycle were observed. GT75 effect was likely due to the interference with eEF1A activity as neither the mRNA nor the protein levels were significantly affected. Notably, cholesterol-mediated delivery of GT75 abrogated its efficacy due to cellular mis-localization as proven by fluorescence and confocal microscopic analysis. Finally, liposome-mediated delivery of GT75 improved the therapeutic index of the anticancer drugs bortezomib and idarubicin.
In conclusion, liposome but not cholesterol-mediated delivery of GT75 resulted in an effective delivery of GT75, causing the impairment of the vitality of a panel of HCC derived cells.
Abbiati, Roberto Andrea; Depetri, Valentina; Scotti, Federico; Manca, Davide
A NEW APPROACH FOR PHARMACOKINETIC MODEL APPLICATION TOWARDS PERSONALIZED MEDICINE Journal Article
In: Computer Aided Chemical Engineering, vol. submitted, 2016.
BibTeX | Tags:
@article{Abbiati2016b,
title = {A NEW APPROACH FOR PHARMACOKINETIC MODEL APPLICATION TOWARDS PERSONALIZED MEDICINE},
author = {Roberto Andrea Abbiati and Valentina Depetri and Federico Scotti and Davide Manca},
year = {2016},
date = {2016-06-15},
journal = {Computer Aided Chemical Engineering},
volume = {submitted},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Marizza, Paolo; Abrami, Michela; Keller, Stephan Sylvest; Posocco, Paola; Laurini, Erik; Goswami, Kaustav; Skov, Anne Ladegaard; Boisen, Anja; Larobina, Domenico; Grassi, Gabriele; Grassi, Mario
In: International Journal of Polymeric Materials and Polymeric Biomaterials, vol. 65, no. 10, pp. 516-525, 2016.
Abstract | Links | BibTeX | Tags:
@article{Marizza2016,
title = {Synthesis and characterization of UV photocrosslinkable hydrogels with poly(N-vinyl-2-pyrrolidone): determination of the network mesh size distribution},
author = {Paolo Marizza and Michela Abrami and Stephan Sylvest Keller and Paola Posocco and Erik Laurini and Kaustav Goswami and Anne Ladegaard Skov and Anja Boisen and Domenico Larobina and Gabriele Grassi and Mario Grassi},
url = {http://www.tandfonline.com/doi/abs/10.1080/00914037.2015.1129964},
doi = {10.1080/00914037.2015.1129964},
year = {2016},
date = {2016-04-06},
journal = {International Journal of Polymeric Materials and Polymeric Biomaterials},
volume = {65},
number = {10},
pages = {516-525},
abstract = {Hydrogels of poly(n-vinyl-2-pyrrolidone) were produced by UV irradiation of aqueous solutions of the polymer in presence of hydrogen peroxide, used as initiator. The mechanical and the nanostructural properties of the gels were characterized by a combination of experimental techniques including rheology, low field nuclear magnetic resonance spectroscopy (LF-NMR), and small angle X-ray scattering. Different irradiation doses as well as polymer and initiator concentrations were tested in the characterization. The study elucidates the relationship between different methods to estimate the mesh size of the gel polymeric network. Moreover, a novel correlation model was developed based on Chui and Scherer theories for the interpretation of LF-NMR dataset of polymer solutions and networks.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hydrogels of poly(n-vinyl-2-pyrrolidone) were produced by UV irradiation of aqueous solutions of the polymer in presence of hydrogen peroxide, used as initiator. The mechanical and the nanostructural properties of the gels were characterized by a combination of experimental techniques including rheology, low field nuclear magnetic resonance spectroscopy (LF-NMR), and small angle X-ray scattering. Different irradiation doses as well as polymer and initiator concentrations were tested in the characterization. The study elucidates the relationship between different methods to estimate the mesh size of the gel polymeric network. Moreover, a novel correlation model was developed based on Chui and Scherer theories for the interpretation of LF-NMR dataset of polymer solutions and networks.
Abbiati, Roberto Andrea; Manca, Davide
A modeling tool for the personalization of pharmacokinetic predictions Journal Article
In: Computers & Chemical Engineering, vol. in press, 2016.
Abstract | Links | BibTeX | Tags:
@article{Abbiati2016b,
title = {A modeling tool for the personalization of pharmacokinetic predictions},
author = {Roberto Andrea Abbiati and Davide Manca},
url = {http://www.sciencedirect.com/science/article/pii/S0098135416300618},
doi = {10.1016/j.compchemeng.2016.03.008},
year = {2016},
date = {2016-03-23},
journal = {Computers \& Chemical Engineering},
volume = {in press},
abstract = {A method to apply pharmacokinetic models to assist physicians in therapeutic drug monitoring is proposed. The practice of therapeutic drug monitoring is required for drugs characterized by a narrow therapeutic index, which consequently present toxicity concerns. The proposed method employs a physiologically based pharmacokinetic (PBPK) model to determine an initial assessment of the pharmacokinetics (PK) of a specific patient. To further increase the precision of this prediction, the method uses two experimental datasets: (i) the PK data from a group of reference subjects, and (ii) limited drug blood concentration measures of the specific patient under study.
By combining the available information, it is possible to assess the precision of the initial model prediction and determine a correction factor to improve it. The resulting patient-specific PBPK model produces encouraging results as there is a concrete reduction in prediction errors of the individualized PK with respect to experimental data.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
A method to apply pharmacokinetic models to assist physicians in therapeutic drug monitoring is proposed. The practice of therapeutic drug monitoring is required for drugs characterized by a narrow therapeutic index, which consequently present toxicity concerns. The proposed method employs a physiologically based pharmacokinetic (PBPK) model to determine an initial assessment of the pharmacokinetics (PK) of a specific patient. To further increase the precision of this prediction, the method uses two experimental datasets: (i) the PK data from a group of reference subjects, and (ii) limited drug blood concentration measures of the specific patient under study.
By combining the available information, it is possible to assess the precision of the initial model prediction and determine a correction factor to improve it. The resulting patient-specific PBPK model produces encouraging results as there is a concrete reduction in prediction errors of the individualized PK with respect to experimental data.
By combining the available information, it is possible to assess the precision of the initial model prediction and determine a correction factor to improve it. The resulting patient-specific PBPK model produces encouraging results as there is a concrete reduction in prediction errors of the individualized PK with respect to experimental data.
D'Apolito, Rosa; Taraballi, Francesca; Minardi, Silvia; Liu, Xuewu; Caserta, Sergio; Cevenini, Armando; Tasciotti, Ennio; Tomaiuolo, Giovanna; Guido, Stefano
Microfluidic interactions between red blood cells and drug carriers by image analysis techniques Journal Article
In: Medical Engineering & Physics, vol. 38, no. 1, pp. 17-23, 2016.
Abstract | Links | BibTeX | Tags:
@article{D'Apolito2016,
title = {Microfluidic interactions between red blood cells and drug carriers by image analysis techniques},
author = {Rosa D'Apolito and Francesca Taraballi and Silvia Minardi and Xuewu Liu and Sergio Caserta and Armando Cevenini and Ennio Tasciotti and Giovanna Tomaiuolo and Stefano Guido },
url = {http://www.sciencedirect.com/science/article/pii/S1350453315002465},
doi = {10.1016/j.medengphy.2015.10.005},
year = {2016},
date = {2016-02-01},
journal = {Medical Engineering \& Physics},
volume = {38},
number = {1},
pages = {17-23},
abstract = {Blood is a complex biological fluid composed of deformable cells and platelets suspended in plasma, a protein-rich liquid. The peculiar nature of blood needs to be considered when designing a drug delivery strategy based on systemically administered carriers. Here, we report on an in vitro fluid dynamic investigation of the influence of the microcapillary flow of red blood cells (RBCs) on micron-sized carriers by high-speed imaging methods. The experiments were carried out in a 50 µm diameter glass capillary that mimicked the hydrodynamic conditions of human microcirculation. Spherical μ-particles (μ-Ps), with sizes ranging between 0.5 and 3 µm, were tested. Images of the flowing RBCs and μ-Ps were acquired by a high- speed/high-magnification microscopy. The transport and distribution of rigid particles in a suspension of RBCs under shear flow were investigated by analyzing: (i) the velocity profile of both μ-Ps and RBCs in the capillary; (ii) the radial distribution of μ-Ps in the presence of RBCs; (iii) the migration of μ-Ps towards the vessel wall due to their hydrodynamic interactions with RBCs. This study suggests that the therapeutic efficacy of μ-Ps could be ultimately affected by their interactions with the flowing RBCs in the vasculature.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Blood is a complex biological fluid composed of deformable cells and platelets suspended in plasma, a protein-rich liquid. The peculiar nature of blood needs to be considered when designing a drug delivery strategy based on systemically administered carriers. Here, we report on an in vitro fluid dynamic investigation of the influence of the microcapillary flow of red blood cells (RBCs) on micron-sized carriers by high-speed imaging methods. The experiments were carried out in a 50 µm diameter glass capillary that mimicked the hydrodynamic conditions of human microcirculation. Spherical μ-particles (μ-Ps), with sizes ranging between 0.5 and 3 µm, were tested. Images of the flowing RBCs and μ-Ps were acquired by a high- speed/high-magnification microscopy. The transport and distribution of rigid particles in a suspension of RBCs under shear flow were investigated by analyzing: (i) the velocity profile of both μ-Ps and RBCs in the capillary; (ii) the radial distribution of μ-Ps in the presence of RBCs; (iii) the migration of μ-Ps towards the vessel wall due to their hydrodynamic interactions with RBCs. This study suggests that the therapeutic efficacy of μ-Ps could be ultimately affected by their interactions with the flowing RBCs in the vasculature.
Abbiati, Roberto Andrea; Lamberti, Gaetano; Grassi, Mario; Trotta, Francesco; Manca, Davide
Definition and validation of a patient-individualized physiologically-based pharmacokinetic model Journal Article
In: Computers & Chemical Engineering, vol. 84 , pp. 394-408, 2016, ISSN: 00981354.
Abstract | Links | BibTeX | Tags: Biodistribution, In silico, Model reduction and lumping, Personalized parameters, Pharmacokinetic models, Pharmacokinetics, Physiologically based modeling, Remifentanil.
@article{Abbiati2015,
title = {Definition and validation of a patient-individualized physiologically-based pharmacokinetic model},
author = { Roberto Andrea Abbiati and Gaetano Lamberti and Mario Grassi and Francesco Trotta and Davide Manca},
url = {http://www.sciencedirect.com/science/article/pii/S0098135415003130},
doi = {10.1016/j.compchemeng.2015.09.018},
issn = {00981354},
year = {2016},
date = {2016-01-04},
journal = {Computers \& Chemical Engineering},
volume = {84 },
pages = {394-408},
abstract = {Pharmacokinetic modeling based on a mechanistic approach is a promising tool for drug concentration prediction in living beings. The development of a reduced physiologically-based pharmacokinetic model (PBPK model), is performed by lumping organs and tissues with comparable characteristics respect to drug distribution phenomena. The proposed reduced model comprises eight differential equations and 18 adaptive parameters. To improve the quality of the PBPK model these adaptive parameters are alternatively: (i) individualized according to literature correlations on the physiological features of each patient; (ii) assigned as constants based on the features of either human body or drug properties; (iii) regressed respect to experimental data. The model predictive capability is validated with experimental blood concentrations of remifentanil, an analgesic drug, administered via bolus injection with four doses (2, 5, 15, 30$mu$g/kg) to mixed groups of patients. Concentration profiles for the four simulated doses reveal a rather good consistency with experimental data.},
keywords = {Biodistribution, In silico, Model reduction and lumping, Personalized parameters, Pharmacokinetic models, Pharmacokinetics, Physiologically based modeling, Remifentanil.},
pubstate = {published},
tppubtype = {article}
}
Pharmacokinetic modeling based on a mechanistic approach is a promising tool for drug concentration prediction in living beings. The development of a reduced physiologically-based pharmacokinetic model (PBPK model), is performed by lumping organs and tissues with comparable characteristics respect to drug distribution phenomena. The proposed reduced model comprises eight differential equations and 18 adaptive parameters. To improve the quality of the PBPK model these adaptive parameters are alternatively: (i) individualized according to literature correlations on the physiological features of each patient; (ii) assigned as constants based on the features of either human body or drug properties; (iii) regressed respect to experimental data. The model predictive capability is validated with experimental blood concentrations of remifentanil, an analgesic drug, administered via bolus injection with four doses (2, 5, 15, 30$mu$g/kg) to mixed groups of patients. Concentration profiles for the four simulated doses reveal a rather good consistency with experimental data.
Caccavo, Diego; Ström, Anna; Larsson, Anette; Lamberti, Gaetano
Modeling capillary formation in calcium and copper alginate gels Journal Article
In: Materials Science and Engineering: C, vol. 58, pp. 442–449, 2016, ISSN: 09284931.
Abstract | Links | BibTeX | Tags: Alginate, Gel capillaries, Hydrogel Characterization, Hydrogel Modeling, Ionotropic gelation, Modeling
@article{Caccavo2016,
title = {Modeling capillary formation in calcium and copper alginate gels},
author = { Diego Caccavo and Anna Str\"{o}m and Anette Larsson and Gaetano Lamberti},
url = {http://www.sciencedirect.com/science/article/pii/S0928493115302940},
doi = {10.1016/j.msec.2015.08.040},
issn = {09284931},
year = {2016},
date = {2016-01-01},
journal = {Materials Science and Engineering: C},
volume = {58},
pages = {442--449},
abstract = {Alginate solutions in the presence of bivalent ions can form ionic cross-linked gels. In particular gelation conditions the gel structure can be characterized by great anisotropy with the presence of straight capillaries along a preferential direction. These materials can find applications mainly in high-tech sectors, like tissue engineering, where the gel characteristics play a crucial role. Despite the need of mastering the capillary formation and properties, the process remains a poorly known problem, and its development is left to trial and error procedures. In this work a quantitative approach to the description of the capillary formation process has been developed. The theory proposed by Treml et al. (2003) has been implemented and extended to an alginate different from the one used in that study and two different ions (calcium and copper). Some of the model parameters have been derived through simple measurements; others have been scaled using proper scaling equations. Experiments have been performed in different gelation conditions, varying alginate and ionic solution concentrations, to highlight the effects of these parameters on the anisotropic structure and to validate the model. In all the analyses done, the model has performed nicely showing a good reliability in the prediction of gel characteristics like capillary formation, capillary length and process time.},
keywords = {Alginate, Gel capillaries, Hydrogel Characterization, Hydrogel Modeling, Ionotropic gelation, Modeling},
pubstate = {published},
tppubtype = {article}
}
Alginate solutions in the presence of bivalent ions can form ionic cross-linked gels. In particular gelation conditions the gel structure can be characterized by great anisotropy with the presence of straight capillaries along a preferential direction. These materials can find applications mainly in high-tech sectors, like tissue engineering, where the gel characteristics play a crucial role. Despite the need of mastering the capillary formation and properties, the process remains a poorly known problem, and its development is left to trial and error procedures. In this work a quantitative approach to the description of the capillary formation process has been developed. The theory proposed by Treml et al. (2003) has been implemented and extended to an alginate different from the one used in that study and two different ions (calcium and copper). Some of the model parameters have been derived through simple measurements; others have been scaled using proper scaling equations. Experiments have been performed in different gelation conditions, varying alginate and ionic solution concentrations, to highlight the effects of these parameters on the anisotropic structure and to validate the model. In all the analyses done, the model has performed nicely showing a good reliability in the prediction of gel characteristics like capillary formation, capillary length and process time.
Tomaiuolo, Giovanna; Lanotte, Luca; D'Apolito, Rosa; Cassinese, Antonio; Guido, Stefano
Microconfined flow behavior of red blood cells Journal Article
In: Medical Engineering and Physics, vol. 38, no. 1, pp. 11–16, 2016.
Abstract | Links | BibTeX | Tags:
@article{Tomaiuolo2016,
title = {Microconfined flow behavior of red blood cells},
author = {Giovanna Tomaiuolo and Luca Lanotte and Rosa D'Apolito and Antonio Cassinese and Stefano Guido },
url = {http://www.medengphys.com/article/S1350-4533%2815%2900125-3/abstract},
doi = {10.1016/j.medengphy.2015.05.007},
year = {2016},
date = {2016-01-01},
journal = {Medical Engineering and Physics},
volume = {38},
number = {1},
pages = {11\textendash16},
abstract = {Red blood cells (RBCs) perform essential functions in human body, such as gas exchange between blood and tissues, thanks to their ability to deform and flow in the microvascular network. The high RBC deformability is mainly due to the viscoelastic properties of the cell membrane. Since an impaired RBC deformability could be found in some diseases, such as malaria, sickle cell anemia, diabetes and hereditary disorders, there is the need to provide further insight into measurement of RBC deformability in a physiologically relevant flow field. Here, RBCs deformability has been studied in terms of the minimum apparent plasma-layer thickness by using high-speed video microscopy of RBCs flowing in cylindrical glass capillaries. An in vitro systematic microfluidic investigation of RBCs in micro-confined conditions has been performed, resulting in the determination of the RBCs time recovery constant, RBC volume and surface area and RBC membrane shear elastic modulus and surface viscosity. It has been noticed that the deformability of RBCs induces cells aggregation during flow in microcapillaries, allowing the formation of clusters of cells. Overall, our results provide a novel technique to estimate RBC deformability and also RBCs collective behavior, which can be used for the analysis of pathological RBCs, for which reliable quantitative methods are still lacking.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Red blood cells (RBCs) perform essential functions in human body, such as gas exchange between blood and tissues, thanks to their ability to deform and flow in the microvascular network. The high RBC deformability is mainly due to the viscoelastic properties of the cell membrane. Since an impaired RBC deformability could be found in some diseases, such as malaria, sickle cell anemia, diabetes and hereditary disorders, there is the need to provide further insight into measurement of RBC deformability in a physiologically relevant flow field. Here, RBCs deformability has been studied in terms of the minimum apparent plasma-layer thickness by using high-speed video microscopy of RBCs flowing in cylindrical glass capillaries. An in vitro systematic microfluidic investigation of RBCs in micro-confined conditions has been performed, resulting in the determination of the RBCs time recovery constant, RBC volume and surface area and RBC membrane shear elastic modulus and surface viscosity. It has been noticed that the deformability of RBCs induces cells aggregation during flow in microcapillaries, allowing the formation of clusters of cells. Overall, our results provide a novel technique to estimate RBC deformability and also RBCs collective behavior, which can be used for the analysis of pathological RBCs, for which reliable quantitative methods are still lacking.
Coviello, Tommasina; Margheritelli, Silvia; Matricardi, Pietro; Meo, Chiara Di; Cerreto, Felice; Alhaique, Franco; Abrami, Michela; Grassi, Mario
Influence of borate amount on the swelling and rheological properties of the Scleroglucan/borax system Journal Article
In: Journal of Applied Polymer Science, vol. 133, no. 3, pp. 42860 (1-10), 2016.
Abstract | Links | BibTeX | Tags:
@article{Coviello2016,
title = {Influence of borate amount on the swelling and rheological properties of the Scleroglucan/borax system},
author = {Tommasina Coviello and Silvia Margheritelli and Pietro Matricardi and Chiara {Di Meo} and Felice Cerreto and Franco Alhaique and Michela Abrami and Mario Grassi },
url = {http://onlinelibrary.wiley.com/doi/10.1002/app.42860/abstract},
doi = {10.1002/app.42860},
year = {2016},
date = {2016-01-01},
journal = {Journal of Applied Polymer Science},
volume = {133},
number = {3},
pages = {42860 (1-10)},
abstract = {Scleroglucan is a fungal polysaccharide that, when dispersed in water, assumes a very stable triple helix structure. It has numerous industrial applications in different fields, such as food industry, cosmetics, and pharmaceutics. In the presence of borate ions, this polymer forms weak gels that, after freeze-drying and compaction, show an anisotropic swelling behavior, related to the borate/polymer ratio. By monitoring the evolution of the elastic and viscous moduli it was possible to follow the gel formation kinetics. The rheological properties of the network were studied as a function of crosslinking agent concentration and the corresponding flow curves and mechanical spectra were recorded. The kinetics of the crosslinking reaction was monitored by following the time evolution of the storage and loss moduli, after the addition of borate ions to the Scleroglucan system. Creep-recovery experiments allowed acquiring recoverable strain values and those of the critical stress above which a very high compliance of the sample is reached. Obtained results are to be related to the specific type of bonds between the polysaccharide chains and the crosslinking agent.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Scleroglucan is a fungal polysaccharide that, when dispersed in water, assumes a very stable triple helix structure. It has numerous industrial applications in different fields, such as food industry, cosmetics, and pharmaceutics. In the presence of borate ions, this polymer forms weak gels that, after freeze-drying and compaction, show an anisotropic swelling behavior, related to the borate/polymer ratio. By monitoring the evolution of the elastic and viscous moduli it was possible to follow the gel formation kinetics. The rheological properties of the network were studied as a function of crosslinking agent concentration and the corresponding flow curves and mechanical spectra were recorded. The kinetics of the crosslinking reaction was monitored by following the time evolution of the storage and loss moduli, after the addition of borate ions to the Scleroglucan system. Creep-recovery experiments allowed acquiring recoverable strain values and those of the critical stress above which a very high compliance of the sample is reached. Obtained results are to be related to the specific type of bonds between the polysaccharide chains and the crosslinking agent.
2015
Tomaiuolo, Giovanna; Carciati, Antonio; Caserta, Sergio; Guido, Stefano
Blood linear viscoelasticity by small amplitude oscillatory flow Journal Article
In: Rheologica Acta, vol. in press, 2015.
Abstract | Links | BibTeX | Tags:
@article{Tomaiuolo2015,
title = {Blood linear viscoelasticity by small amplitude oscillatory flow},
author = {Giovanna Tomaiuolo and Antonio Carciati and Sergio Caserta and Stefano Guido},
url = {http://link.springer.com/article/10.1007/s00397-015-0894-3},
doi = {10.1007/s00397-015-0894-3},
year = {2015},
date = {2015-12-05},
journal = {Rheologica Acta},
volume = {in press},
abstract = {Blood is a complex fluid with non-Newtonian characteristics and consists primarily of a concentrated suspension of red blood cells (RBCs) characterized by high deformability and aggregability. The majority of both research and clinical investigations on blood rheology is based on steady shear measurements aimed at determining blood viscosity as a function of shear rate. On the other hand, investigations of blood rheology in the linear viscoelastic regime are sparse in the literature and currently limited. In principle, small amplitude oscillatory flow is best suited to study blood microstructure and rheology under quasi-static conditions, which are relevant in a range of applications, from blood storage to blood aggregability testing. Here, we present the first systematic experimental investigation of blood rheological behavior in the linear viscoelastic regime, by performing oscillatory shear measurements by conventional bulk rheology. The storage (G′) and loss (G″) moduli of whole human blood have been measured over an extended range of frequencies [0.1\textendash30 rad/s]. Data show that G″ predominates over G′ across the entire tested range of frequency. By comparing steady and oscillatory shear viscosity, it was found that the Cox-Merz rule is followed to a good approximation, with higher deviations at small shear rate/frequencies. The effects of RBC volume fraction and of aggregating media (i.e., dextran solution at two different concentrations) have been also investigated. Overall, our results are consistent with the behavior of a weakly attractive suspension, where RBCs form reversible aggregates that can be broken by the action of flow.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Blood is a complex fluid with non-Newtonian characteristics and consists primarily of a concentrated suspension of red blood cells (RBCs) characterized by high deformability and aggregability. The majority of both research and clinical investigations on blood rheology is based on steady shear measurements aimed at determining blood viscosity as a function of shear rate. On the other hand, investigations of blood rheology in the linear viscoelastic regime are sparse in the literature and currently limited. In principle, small amplitude oscillatory flow is best suited to study blood microstructure and rheology under quasi-static conditions, which are relevant in a range of applications, from blood storage to blood aggregability testing. Here, we present the first systematic experimental investigation of blood rheological behavior in the linear viscoelastic regime, by performing oscillatory shear measurements by conventional bulk rheology. The storage (G′) and loss (G″) moduli of whole human blood have been measured over an extended range of frequencies [0.1–30 rad/s]. Data show that G″ predominates over G′ across the entire tested range of frequency. By comparing steady and oscillatory shear viscosity, it was found that the Cox-Merz rule is followed to a good approximation, with higher deviations at small shear rate/frequencies. The effects of RBC volume fraction and of aggregating media (i.e., dextran solution at two different concentrations) have been also investigated. Overall, our results are consistent with the behavior of a weakly attractive suspension, where RBCs form reversible aggregates that can be broken by the action of flow.
D'Apolito, Rosa; Tomaiuolo, Giovanna; Taraballi, Francesca; Minardi, Silvia; Kirui, Dickson; Liu, Xuewu; Cevenini, Armando; Palomba, Roberto; Ferrari, Mauro; Salvatore, Francesco; Tasciotti, Ennio; Guido, Stefano
In: Journal of Controlled Release, vol. 217, pp. 263–272, 2015.
Abstract | Links | BibTeX | Tags:
@article{D'Apolito2015,
title = {Red blood cells affect the margination of microparticles in synthetic microcapillaries and intravital microcirculation as a function of their size and shape},
author = {Rosa D'Apolito and Giovanna Tomaiuolo and Francesca Taraballi and Silvia Minardi and Dickson Kirui and Xuewu Liu and Armando Cevenini and Roberto Palomba and Mauro Ferrari and Francesco Salvatore and Ennio Tasciotti and Stefano Guido},
url = {http://www.sciencedirect.com/science/article/pii/S0168365915301152},
doi = {10.1016/j.jconrel.2015.09.013},
year = {2015},
date = {2015-11-10},
journal = {Journal of Controlled Release},
volume = {217},
pages = {263\textendash272},
abstract = {A key step in particle-based drug delivery through microcirculation is particle migration from blood flow to vessel walls, also known as “margination”, which promotes particle contact and adhesion to the vessel wall. Margination and adhesion should be independently addressed as two distinct phenomena, considering that the former is a fundamental prerequisite to achieve particle adhesion and subsequent extravasation. Although margination has been modeled by numerical simulations and investigated in model systems in vitro, experimental studies including red blood cells (RBCs) are lacking. Here, we evaluate the effect of RBCs on margination through microfluidic studies in vitro and by intravital microscopy in vivo. We show that margination, which is almost absent when particles are suspended in a cell-free medium, is drastically enhanced by RBCs. This effect is size- and shape-dependent, larger spherical/discoid particles being more effectively marginated both in vitro and in vivo. Our findings can be explained by the collision of particles with RBCs that induces the drifting of the particles towards the vessel walls where they become trapped in the cell-free layer. These results are relevant for the design of drug delivery strategies based on systemically administered carriers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
A key step in particle-based drug delivery through microcirculation is particle migration from blood flow to vessel walls, also known as “margination”, which promotes particle contact and adhesion to the vessel wall. Margination and adhesion should be independently addressed as two distinct phenomena, considering that the former is a fundamental prerequisite to achieve particle adhesion and subsequent extravasation. Although margination has been modeled by numerical simulations and investigated in model systems in vitro, experimental studies including red blood cells (RBCs) are lacking. Here, we evaluate the effect of RBCs on margination through microfluidic studies in vitro and by intravital microscopy in vivo. We show that margination, which is almost absent when particles are suspended in a cell-free medium, is drastically enhanced by RBCs. This effect is size- and shape-dependent, larger spherical/discoid particles being more effectively marginated both in vitro and in vivo. Our findings can be explained by the collision of particles with RBCs that induces the drifting of the particles towards the vessel walls where they become trapped in the cell-free layer. These results are relevant for the design of drug delivery strategies based on systemically administered carriers.
Licciardi, Mariano; Volsi, Anna Li; Sardo, Carla; Mauro, Nicolò; Cavallaro, Gennara; Giammona, Gaetano
Inulin-Ethylenediamine Coated SPIONs Magnetoplexes: A Promising Tool for Improving siRNA Delivery Journal Article
In: Pharmaceutical Research, vol. 32, no. 11, pp. 3674-3687, 2015.
Abstract | Links | BibTeX | Tags:
@article{Licciardi2015,
title = {Inulin-Ethylenediamine Coated SPIONs Magnetoplexes: A Promising Tool for Improving siRNA Delivery},
author = {Mariano Licciardi and Anna Li Volsi and Carla Sardo and Nicol\`{o} Mauro and Gennara Cavallaro and Gaetano Giammona},
url = {http://link.springer.com/article/10.1007/s11095-015-1726-y},
doi = {10.1007/s11095-015-1726-y},
year = {2015},
date = {2015-11-01},
journal = {Pharmaceutical Research},
volume = {32},
number = {11},
pages = {3674-3687},
abstract = {PURPOSE: An inulin based polycation (Inu-EDA) has been synthesized by the grafting of ethylenediamine molecules onto inulin backbone. The obtained inulin copolymer has been though to coat SPIONs (IC-SPIONs) and obtain stable magnetoplexes by complexation of IC-SPIONs with a model duplexed siRNA, for improving oligonucleotide transfection efficiency.
METHODS: The physical-chemical characteristics of IC-SPIONs and IC-SPIONs/siRNA magnetoplexes have been investigated by scanning and transmission electron microscopies, dynamic light scattering, FT-IR and qualitative surface elementary analysis. Cell compatibility and internalization in vitro of IC-SPIONs have been evaluated by MTS and fluorescence microscopy respectively on cancer (HCT116) and normal human (16HBE) cells. The efficiency of gene silencing effect of magnetoplexes was studied on both tumoral (JHH6) and non tumoral (16HBE) cell lines also by applying an external magnet.
RESULTS: IC-SPIONs showed dimension of 30 nm and resulted cytocompatible on the tested cell lines; in the presence of an external magnet, the magnetic force enhanced the IC-SPIONs uptake inside cells. Magnetically improved transfection was observed in 16HBE cells under magnetofective conditions, in accordance with the IC-SPIONs uptake enhancement in the presence of an external magnet.
CONCLUSIONS: These findings support the potential application of this system as a magnetically targeted drug delivery system. Graphical Abstract Magnetically improved siRNA transfection in cells under magnetofective conditions upon uptake enhancement of IC-SPIONs in the presence of an external magnet.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
PURPOSE: An inulin based polycation (Inu-EDA) has been synthesized by the grafting of ethylenediamine molecules onto inulin backbone. The obtained inulin copolymer has been though to coat SPIONs (IC-SPIONs) and obtain stable magnetoplexes by complexation of IC-SPIONs with a model duplexed siRNA, for improving oligonucleotide transfection efficiency.
METHODS: The physical-chemical characteristics of IC-SPIONs and IC-SPIONs/siRNA magnetoplexes have been investigated by scanning and transmission electron microscopies, dynamic light scattering, FT-IR and qualitative surface elementary analysis. Cell compatibility and internalization in vitro of IC-SPIONs have been evaluated by MTS and fluorescence microscopy respectively on cancer (HCT116) and normal human (16HBE) cells. The efficiency of gene silencing effect of magnetoplexes was studied on both tumoral (JHH6) and non tumoral (16HBE) cell lines also by applying an external magnet.
RESULTS: IC-SPIONs showed dimension of 30 nm and resulted cytocompatible on the tested cell lines; in the presence of an external magnet, the magnetic force enhanced the IC-SPIONs uptake inside cells. Magnetically improved transfection was observed in 16HBE cells under magnetofective conditions, in accordance with the IC-SPIONs uptake enhancement in the presence of an external magnet.
CONCLUSIONS: These findings support the potential application of this system as a magnetically targeted drug delivery system. Graphical Abstract Magnetically improved siRNA transfection in cells under magnetofective conditions upon uptake enhancement of IC-SPIONs in the presence of an external magnet.
METHODS: The physical-chemical characteristics of IC-SPIONs and IC-SPIONs/siRNA magnetoplexes have been investigated by scanning and transmission electron microscopies, dynamic light scattering, FT-IR and qualitative surface elementary analysis. Cell compatibility and internalization in vitro of IC-SPIONs have been evaluated by MTS and fluorescence microscopy respectively on cancer (HCT116) and normal human (16HBE) cells. The efficiency of gene silencing effect of magnetoplexes was studied on both tumoral (JHH6) and non tumoral (16HBE) cell lines also by applying an external magnet.
RESULTS: IC-SPIONs showed dimension of 30 nm and resulted cytocompatible on the tested cell lines; in the presence of an external magnet, the magnetic force enhanced the IC-SPIONs uptake inside cells. Magnetically improved transfection was observed in 16HBE cells under magnetofective conditions, in accordance with the IC-SPIONs uptake enhancement in the presence of an external magnet.
CONCLUSIONS: These findings support the potential application of this system as a magnetically targeted drug delivery system. Graphical Abstract Magnetically improved siRNA transfection in cells under magnetofective conditions upon uptake enhancement of IC-SPIONs in the presence of an external magnet.
Sardo, Carla; Craparo, Emanuela Fabiola; Fiorica, Calogero; Giammona, Gaetano; Cavallaro, Gennara
Inulin Derivatives Obtained Via Enhanced Microwave Synthesis for Nucleic Acid Based Drug Delivery Journal Article
In: Current Drug Targets, vol. 16, no. 14, pp. 1650 - 1659, 2015.
Abstract | Links | BibTeX | Tags:
@article{Sardo2015b,
title = {Inulin Derivatives Obtained Via Enhanced Microwave Synthesis for Nucleic Acid Based Drug Delivery},
author = {Carla Sardo and Emanuela Fabiola Craparo and Calogero Fiorica and Gaetano Giammona and Gennara Cavallaro},
url = {http://www.eurekaselect.com/137079/article},
doi = {10.2174/138945011614151119130426},
year = {2015},
date = {2015-11-01},
journal = {Current Drug Targets},
volume = {16},
number = {14},
pages = {1650 - 1659},
abstract = {A new class of therapeutic agents with a high potential for the treatment of different socially relevant human diseases is represented by Nucleic Acid Based Drugs (NABD), including small interfering RNAs (siRNA), decoy oligodeoxynucleotides (decoy ODN) and antisense oligonucleotides (ASOs). Although NABD can be engineered to be specifically directed against virtually any target, their susceptibility to nuclease degradation and the difficulty of delivery into target tissues severely limit their use in clinical practice and require the development of an appropriate nanostructured delivery system. For delivery of NABD, Inulin (Inu), a natural, water soluble and biocompatible polysaccharide, was derivatized by Spermine (Spm), a flexible molecule with four amine groups that, having pKa values in the range between 8-11, is mainly in the protonated form at pH 7.4. The synthesis of related copolymers (Inu-Spm) was performed by a two step reaction, using a method termed Enhanced Microwave Synthesis (EMS) which has the advantage, compared to conventional microwave reaction, that high amount of energy can be applied to the reaction system, by administering microwave irradiation and simultaneously controlling the temperature in the reaction vessel with cooled air. The synthesized inulin derivatives were characterized by FT-IR spectra and 1H-NMR. INU-Spm derivatives with a degree of derivatization of about 14 % mol/mol were obtained. These polycations were tested to evaluate their ability to form non covalent complexes with genetic material (polyplexes). Agarose gel retardation assays showed that the obtained copolymers are able to electrostatically interact with DNA duplex to form polyplexes at different c/p weight ratios. Moreover, light scattering studies, performed to analyze size and z-potential of polyplexes, evidenced that copolymers are able to interact with genetic material leading to the formation of nanoscaled systems. In addition, biocompatibility of polyplexes was demonstrated by performing cytotoxicity assays on a 16HBE cell line. Transfection studies, performed by using siRNA able to silence luciferase expression, demonstrate the efficiency of polyplexes to transfect the same cell line, with a reduction of luciferase expression to about 70%. These results encourage us to work with these copolymers to obtain an efficient and feasible inulin based NABD delivery system. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
A new class of therapeutic agents with a high potential for the treatment of different socially relevant human diseases is represented by Nucleic Acid Based Drugs (NABD), including small interfering RNAs (siRNA), decoy oligodeoxynucleotides (decoy ODN) and antisense oligonucleotides (ASOs). Although NABD can be engineered to be specifically directed against virtually any target, their susceptibility to nuclease degradation and the difficulty of delivery into target tissues severely limit their use in clinical practice and require the development of an appropriate nanostructured delivery system. For delivery of NABD, Inulin (Inu), a natural, water soluble and biocompatible polysaccharide, was derivatized by Spermine (Spm), a flexible molecule with four amine groups that, having pKa values in the range between 8-11, is mainly in the protonated form at pH 7.4. The synthesis of related copolymers (Inu-Spm) was performed by a two step reaction, using a method termed Enhanced Microwave Synthesis (EMS) which has the advantage, compared to conventional microwave reaction, that high amount of energy can be applied to the reaction system, by administering microwave irradiation and simultaneously controlling the temperature in the reaction vessel with cooled air. The synthesized inulin derivatives were characterized by FT-IR spectra and 1H-NMR. INU-Spm derivatives with a degree of derivatization of about 14 % mol/mol were obtained. These polycations were tested to evaluate their ability to form non covalent complexes with genetic material (polyplexes). Agarose gel retardation assays showed that the obtained copolymers are able to electrostatically interact with DNA duplex to form polyplexes at different c/p weight ratios. Moreover, light scattering studies, performed to analyze size and z-potential of polyplexes, evidenced that copolymers are able to interact with genetic material leading to the formation of nanoscaled systems. In addition, biocompatibility of polyplexes was demonstrated by performing cytotoxicity assays on a 16HBE cell line. Transfection studies, performed by using siRNA able to silence luciferase expression, demonstrate the efficiency of polyplexes to transfect the same cell line, with a reduction of luciferase expression to about 70%. These results encourage us to work with these copolymers to obtain an efficient and feasible inulin based NABD delivery system.
De’Nobili, Maria D.; Rojas, Ana M.; Abrami, Michela; Lapasin, Romano; Grassi, Mario
In: Journal of Food Engineering, vol. 165, pp. 82–92, 2015.
Abstract | Links | BibTeX | Tags:
@article{De’Nobili2015,
title = {Structure characterization by means of rheological and NMR experiments as a first necessary approach to study the l-(+)-ascorbic acid diffusion from pectin and pectin/alginate films to agar hydrogels that mimic food materials},
author = {Maria D. De’Nobili and Ana M. Rojas and Michela Abrami and Romano Lapasin and Mario Grassi},
url = {http://www.sciencedirect.com/science/article/pii/S0260877415002253},
doi = {10.1016/j.jfoodeng.2015.05.014},
year = {2015},
date = {2015-11-01},
journal = {Journal of Food Engineering},
volume = {165},
pages = {82\textendash92},
abstract = {Pectin (P) and pectin\textendashalginate (PAL) edible films, developed for antioxidant preservation, were placed on agar cylinders, mimicking food materials, in order to understand the release of l-(+)-ascorbic acid (AA) from the films. To improve the release properties of polymeric systems, it is crucial to describe and understand the macro- and microscopic properties of the matrices. Rheological studies performed within linear and non linear frames permitted to select, among different polymer concentrations (0.50\textendash2.00% w/w), a 2.00% w/w agar gel as food model as this system shows the higher pure elastic contribution. Rheological and Low Field NMR (LFNMR) tests performed on 0.50\textendash2.00% w/w agar gels as well as on P- and PAL-films after exposure (up to 6 h) to 2.00%-agar gels, showed that in spite of the higher glycerol (plasticizer) content, P-network is characterized by more numerous calcium-junction zones than PAL-matrix. The determined average network mesh size (View the MathML sourceξ¯) for both of P- and PAL-films did not significantly change during 6 h of contact with 2.00%-agar gel. However, due to a higher swelling degree, PAL-film leads to higher View the MathML sourceξ¯ value and water mobility inside the polymeric network. These results are of paramount importance as “View the MathML sourceξ¯” is the main parameter affecting the release kinetics of AA from film networks to agar gels and also the diffusion of AA into the agar gel or food.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pectin (P) and pectin–alginate (PAL) edible films, developed for antioxidant preservation, were placed on agar cylinders, mimicking food materials, in order to understand the release of l-(+)-ascorbic acid (AA) from the films. To improve the release properties of polymeric systems, it is crucial to describe and understand the macro- and microscopic properties of the matrices. Rheological studies performed within linear and non linear frames permitted to select, among different polymer concentrations (0.50–2.00% w/w), a 2.00% w/w agar gel as food model as this system shows the higher pure elastic contribution. Rheological and Low Field NMR (LFNMR) tests performed on 0.50–2.00% w/w agar gels as well as on P- and PAL-films after exposure (up to 6 h) to 2.00%-agar gels, showed that in spite of the higher glycerol (plasticizer) content, P-network is characterized by more numerous calcium-junction zones than PAL-matrix. The determined average network mesh size (View the MathML sourceξ¯) for both of P- and PAL-films did not significantly change during 6 h of contact with 2.00%-agar gel. However, due to a higher swelling degree, PAL-film leads to higher View the MathML sourceξ¯ value and water mobility inside the polymeric network. These results are of paramount importance as “View the MathML sourceξ¯” is the main parameter affecting the release kinetics of AA from film networks to agar gels and also the diffusion of AA into the agar gel or food.
Caccavo, Diego; Lamberti, Gaetano; Cascone, Sara; Barba, Anna Angela; Larsson, Anette
Understanding the adhesion phenomena in carbohydrate-hydrogel-based systems: Water up-take, swelling and elastic detachment Journal Article
In: Carbohydrate Polymers, vol. 131, pp. 41–49, 2015, ISSN: 01448617.
Abstract | Links | BibTeX | Tags: Bio-adhesion, Carbopol, Elastic behavior, Hydrogel Characterization, Hydrogel Modeling, Modeling, Water transport
@article{Caccavo2015b,
title = {Understanding the adhesion phenomena in carbohydrate-hydrogel-based systems: Water up-take, swelling and elastic detachment},
author = { Diego Caccavo and Gaetano Lamberti and Sara Cascone and Anna Angela Barba and Anette Larsson},
url = {http://www.sciencedirect.com/science/article/pii/S0144861715004476},
doi = {10.1016/j.carbpol.2015.05.041},
issn = {01448617},
year = {2015},
date = {2015-10-01},
journal = {Carbohydrate Polymers},
volume = {131},
pages = {41--49},
abstract = {The bio-adhesion is a complex phenomenon which takes place when two materials (at least one of biological nature, the other usually is a polymeric one) are held together for extended periods of time, usually for local drug delivery purposes. Despite bio-adhesion is widely exploited in commercial pharmaceuticals such as the buccal patches, the underlying phenomena of the process are not completely clarified yet. In this study experimental tests, in which the role of biological membranes is played by a water-rich agarose gel whereas patches are mimicked by hydrogel tablets (made of Carbopol or of Carbopol added with NaCl), have been used to analyze the behavior of the model system above described. Tablets have been forced to adhere on the agarose gel, and after a given contact time they have been detached, recording the required forces. Furthermore weight gain of the tablets (the water transported from the agarose gel toward the tablet) has been quantified. Water transport (during the time in which the contact between tablet and agarose gel is held) and elastic part of mechanical response during the detachment are modelled to achieve a better understanding of the adhesion process. Both the two sub-models nicely reproduce, respectively, the weight gain as well as the swelling of the Carbopol tablets, and the point at which the mechanical response ceases to be purely elastic.},
keywords = {Bio-adhesion, Carbopol, Elastic behavior, Hydrogel Characterization, Hydrogel Modeling, Modeling, Water transport},
pubstate = {published},
tppubtype = {article}
}
The bio-adhesion is a complex phenomenon which takes place when two materials (at least one of biological nature, the other usually is a polymeric one) are held together for extended periods of time, usually for local drug delivery purposes. Despite bio-adhesion is widely exploited in commercial pharmaceuticals such as the buccal patches, the underlying phenomena of the process are not completely clarified yet. In this study experimental tests, in which the role of biological membranes is played by a water-rich agarose gel whereas patches are mimicked by hydrogel tablets (made of Carbopol or of Carbopol added with NaCl), have been used to analyze the behavior of the model system above described. Tablets have been forced to adhere on the agarose gel, and after a given contact time they have been detached, recording the required forces. Furthermore weight gain of the tablets (the water transported from the agarose gel toward the tablet) has been quantified. Water transport (during the time in which the contact between tablet and agarose gel is held) and elastic part of mechanical response during the detachment are modelled to achieve a better understanding of the adhesion process. Both the two sub-models nicely reproduce, respectively, the weight gain as well as the swelling of the Carbopol tablets, and the point at which the mechanical response ceases to be purely elastic.
Pallavicini, Piersandro; Cabrini, Elisa; Cavallaro, Gennara; Chirico, Giuseppe; Collini, Maddalena; D'Alfonso, Laura; Dacarro, Giacomo; Donà, Alice; Marchesi, Nicoletta; Milanese, Chiara; Pascale, Alessia; Sironi, Laura; Taglietti, Angelo
In: Journal of Inorganic Biochemistry, vol. 151, pp. 123–131, 2015.
Abstract | Links | BibTeX | Tags:
@article{Pallavicini2015,
title = {Gold nanostars coated with neutral and charged polyethylene glycols: A comparative study of in-vitro biocompatibility and of their interaction with SH-SY5Y neuroblastoma cells},
author = {Piersandro Pallavicini and Elisa Cabrini and Gennara Cavallaro and Giuseppe Chirico and Maddalena Collini and Laura D'Alfonso and Giacomo Dacarro and Alice Don\`{a} and Nicoletta Marchesi and Chiara Milanese and Alessia Pascale and Laura Sironi and Angelo Taglietti},
url = {http://www.sciencedirect.com/science/article/pii/S0162013415001191},
doi = {10.1016/j.jinorgbio.2015.05.002},
year = {2015},
date = {2015-10-01},
journal = {Journal of Inorganic Biochemistry},
volume = {151},
pages = {123\textendash131},
abstract = {Gold nanostars (GNS) have been coated with four different polyethylene glycols (PEGs) equipped with a -SH function for grafting on the gold surface. These PEGs have different chain lengths with average MW=2000, 3000, 5000 and average number of -O-CH2-CH2 - units 44, 66, and 111, respectively. Two are neutral and two are terminated with -COOH and -NH2 functions, thus bearing negative and positive charges at physiological pH, thanks to the formation of carboxylate and ammonium groups. The negative charge of the GNS coated with PEG carboxylate has also been exploited to further coat the GNS with the PAH (polyallylamine hydrochloride) cationic polymer. Vitality tests have been carried out on SH-SY5Y cells treated with the five differently coated GNS for 4, 24, and 48h, at Au concentrations ranging from 1.25 to 100μg/mL. The same tests have been repeated with the pure PEGs and PAH. Excellent biocompatibility was found for all PEGs, independently on charge and chain length, both for coated GNS and for the pure polymers. On the contrary, poor biocompatibility was found for PAH overcoated GNS and for pure PAH, although the latter only at high concentrations. Exploiting the two-photon luminescence of GNS, we have found by confocal laser scanning microscopy that when GNS are coated with PEGs they do not enter SH-SY5Y cells, while when overcoated with PAH they massively penetrate into the cytoplasm. This causes cell death by dramatically changing cell morphology, as demonstrated also by atomic force microscopy. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Gold nanostars (GNS) have been coated with four different polyethylene glycols (PEGs) equipped with a -SH function for grafting on the gold surface. These PEGs have different chain lengths with average MW=2000, 3000, 5000 and average number of -O-CH2-CH2 - units 44, 66, and 111, respectively. Two are neutral and two are terminated with -COOH and -NH2 functions, thus bearing negative and positive charges at physiological pH, thanks to the formation of carboxylate and ammonium groups. The negative charge of the GNS coated with PEG carboxylate has also been exploited to further coat the GNS with the PAH (polyallylamine hydrochloride) cationic polymer. Vitality tests have been carried out on SH-SY5Y cells treated with the five differently coated GNS for 4, 24, and 48h, at Au concentrations ranging from 1.25 to 100μg/mL. The same tests have been repeated with the pure PEGs and PAH. Excellent biocompatibility was found for all PEGs, independently on charge and chain length, both for coated GNS and for the pure polymers. On the contrary, poor biocompatibility was found for PAH overcoated GNS and for pure PAH, although the latter only at high concentrations. Exploiting the two-photon luminescence of GNS, we have found by confocal laser scanning microscopy that when GNS are coated with PEGs they do not enter SH-SY5Y cells, while when overcoated with PAH they massively penetrate into the cytoplasm. This causes cell death by dramatically changing cell morphology, as demonstrated also by atomic force microscopy.
Gioia, Sante Di; Trapani, Adriana; Castellani, Stefano; Carbone, Annalucia; Belgiovine, Giuliana; Craparo, Emanuela Fabiola; Puglisi, Giovanni; Cavallaro, Gennara; Trapani, Giuseppe; Conese, Massimo
Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier Journal Article
In: Pulmonary Pharmacology & Therapeutics, vol. 34, pp. 8–24, 2015.
Abstract | Links | BibTeX | Tags:
@article{Gioia2015,
title = {Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier},
author = {Sante Di Gioia and Adriana Trapani and Stefano Castellani and Annalucia Carbone and Giuliana Belgiovine and Emanuela Fabiola Craparo and Giovanni Puglisi and Gennara Cavallaro and Giuseppe Trapani and Massimo Conese},
url = {http://www.sciencedirect.com/science/article/pii/S1094553915000760},
doi = {10.1016/j.pupt.2015.07.003},
year = {2015},
date = {2015-10-01},
journal = {Pulmonary Pharmacology \& Therapeutics},
volume = {34},
pages = {8\textendash24},
abstract = {Gene therapy, i.e. the delivery and expression of therapeutic genes, holds great promise for congenital and acquired respiratory diseases. Non-viral vectors are less toxic and immunogenic than viral vectors, although they are characterized by lower efficiency. However, they have to overcome many barriers, including inflammatory and immune mediators and cells. The respiratory and airway epithelial cells, the main target of these vectors, are coated with a layer of mucus, which hampers the effective reaching of gene therapy vectors carrying either plasmid DNA or small interfering RNA. This barrier is thicker in many lung diseases, such as cystic fibrosis. This review summarizes the most important advancements in the field of non-viral vectors that have been achieved with the use of nanoparticulate (NP) systems, composed either of polymers or lipids, in the lung gene delivery. In particular, different strategies of targeting of respiratory and airway lung cells will be described. Then, we will focus on the two approaches that attempt to overcome the mucus barrier: coating of the nanoparticulate system with poly(ethylene glycol) and treatment with mucolytics. Our conclusions are: 1) Ligand and physical targeting can direct therapeutic gene expression in specific cell types in the respiratory tract; 2) Mucopenetrating NPs are endowed with promising features to be useful in treating respiratory diseases and should be now advanced in pre-clinical trials. Finally, we discuss the development of such polymer- and lipid-based NPs in the context of in vitro and in vivo disease models, such as lung cancer, as well as in clinical trials.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Gene therapy, i.e. the delivery and expression of therapeutic genes, holds great promise for congenital and acquired respiratory diseases. Non-viral vectors are less toxic and immunogenic than viral vectors, although they are characterized by lower efficiency. However, they have to overcome many barriers, including inflammatory and immune mediators and cells. The respiratory and airway epithelial cells, the main target of these vectors, are coated with a layer of mucus, which hampers the effective reaching of gene therapy vectors carrying either plasmid DNA or small interfering RNA. This barrier is thicker in many lung diseases, such as cystic fibrosis. This review summarizes the most important advancements in the field of non-viral vectors that have been achieved with the use of nanoparticulate (NP) systems, composed either of polymers or lipids, in the lung gene delivery. In particular, different strategies of targeting of respiratory and airway lung cells will be described. Then, we will focus on the two approaches that attempt to overcome the mucus barrier: coating of the nanoparticulate system with poly(ethylene glycol) and treatment with mucolytics. Our conclusions are: 1) Ligand and physical targeting can direct therapeutic gene expression in specific cell types in the respiratory tract; 2) Mucopenetrating NPs are endowed with promising features to be useful in treating respiratory diseases and should be now advanced in pre-clinical trials. Finally, we discuss the development of such polymer- and lipid-based NPs in the context of in vitro and in vivo disease models, such as lung cancer, as well as in clinical trials.
Cavallaro, Gennara; Craparo, Emanuela Fabiola; Sardo, Carla; Lamberti, Gaetano; Barba, Anna Angela; Dalmoro, Annalisa
PHEA-PLA biocompatible nanoparticles by technique of solvent evaporation from multiple emulsions. Journal Article
In: International journal of pharmaceutics, vol. 495, no. 2, pp. 719-727, 2015, ISSN: 1873-3476.
Abstract | Links | BibTeX | Tags: Biopolymer, Micro and Nano Vectors, multiple emulsions, nanoparticles, solvent evaporation
@article{Cavallaro2015,
title = {PHEA-PLA biocompatible nanoparticles by technique of solvent evaporation from multiple emulsions.},
author = { Gennara Cavallaro and Emanuela Fabiola Craparo and Carla Sardo and Gaetano Lamberti and Anna Angela Barba and Annalisa Dalmoro},
url = {http://www.sciencedirect.com/science/article/pii/S0378517315302519},
doi = {10.1016/j.ijpharm.2015.09.050},
issn = {1873-3476},
year = {2015},
date = {2015-09-01},
journal = {International journal of pharmaceutics},
volume = {495},
number = {2},
pages = {719-727},
abstract = {Nanocarriers of amphiphilic polymeric materials represent versatile delivery systems for poorly water soluble drugs. In this work the technique of solvent evaporation from multiple emulsions was applied to produce nanovectors based on new amphiphilic copolymer, the $alpha$,$beta$-poly(N-2-hydroxyethyl)-DL-aspartamide - polylactic acid (PHEA - PLA), purposely synthesized to be used in the controlled release of active molecules poorly soluble in water. To this aim an amphiphilic derivative of PHEA, a hydrophilic polymer, was synthesized by derivatization of the polymeric backbone with hydrophobic grafts of polylactic acid (PLA). The achieved copolymer was thus used to produce nanoparticles loaded with $alpha$ tocopherol (vitamin E) adopted as lipophilic model molecule. Applying a protocol based on solvent evaporation from multiple emulsions assisted by ultrasonic energy and optimizing the emulsification process (solvent selection/separation stages), PHEA-PLA nanostructured particles with total $alpha$ tocopherol entrapment efficiency (100%), were obtained. The drug release is expected to take place in lower times with respect to PLA due to the presence of the hydrophilic PHEA, therefore the produced nanoparticles can be used for semi- long term release drug delivery systems.},
keywords = {Biopolymer, Micro and Nano Vectors, multiple emulsions, nanoparticles, solvent evaporation},
pubstate = {published},
tppubtype = {article}
}
Nanocarriers of amphiphilic polymeric materials represent versatile delivery systems for poorly water soluble drugs. In this work the technique of solvent evaporation from multiple emulsions was applied to produce nanovectors based on new amphiphilic copolymer, the $alpha$,$beta$-poly(N-2-hydroxyethyl)-DL-aspartamide - polylactic acid (PHEA - PLA), purposely synthesized to be used in the controlled release of active molecules poorly soluble in water. To this aim an amphiphilic derivative of PHEA, a hydrophilic polymer, was synthesized by derivatization of the polymeric backbone with hydrophobic grafts of polylactic acid (PLA). The achieved copolymer was thus used to produce nanoparticles loaded with $alpha$ tocopherol (vitamin E) adopted as lipophilic model molecule. Applying a protocol based on solvent evaporation from multiple emulsions assisted by ultrasonic energy and optimizing the emulsification process (solvent selection/separation stages), PHEA-PLA nanostructured particles with total $alpha$ tocopherol entrapment efficiency (100%), were obtained. The drug release is expected to take place in lower times with respect to PLA due to the presence of the hydrophilic PHEA, therefore the produced nanoparticles can be used for semi- long term release drug delivery systems.
Craparo, Emanuela Fabiola; Porsio, Barbara; Bondì, Maria Luisa; Giammona, Gaetano; Cavallaro, Gennara
Evaluation of biodegradability on polyaspartamide-polylactic acid based nanoparticles by chemical hydrolysis studies Journal Article
In: Polymer Degradation and Stability, vol. 119, pp. 56–67, 2015.
Abstract | Links | BibTeX | Tags:
@article{Craparo2015b,
title = {Evaluation of biodegradability on polyaspartamide-polylactic acid based nanoparticles by chemical hydrolysis studies},
author = {Emanuela Fabiola Craparo and Barbara Porsio and Maria Luisa Bond\`{i} and Gaetano Giammona and Gennara Cavallaro},
url = {http://www.sciencedirect.com/science/article/pii/S0141391015001718},
doi = {10.1016/j.polymdegradstab.2015.05.003},
year = {2015},
date = {2015-09-01},
journal = {Polymer Degradation and Stability},
volume = {119},
pages = {56\textendash67},
abstract = {Here, the synthesis of two graft copolymers based on α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) and poly(lactic acid) (PLA), the O-(2-aminoethyl)-O′-galactosyl polyethylene glycol (GAL-PEG-NH2) or the methoxypolyethylene glycol amine (H2N-PEG-OCH3) is described. Starting from the obtained PHEA-PLA-PEG-GAL and PHEA-PLA-PEG copolymers, polymeric nanoparticles were prepared by high pressure homogenization\textendashsolvent evaporation method.
To demonstrate their biodegradability as a function of the matrix composition, a chemical stability study was carried out until 21 days by incubating systems in two media mimicking physiological compartments (pH 7.4 and pH 5.5). The degradability of both nanosystems was firstly confirmed by the reduction of the pH of the incubation medium. Moreover, the percentage yield of recovered nanoparticles show a gradual reduction while mean size increases as a function of incubation time. Degradation seems to be mainly attributed to the loss of water-soluble portions of PLA, and proceeds with greater speed at pH 5.5, than at pH 7.4 and as a function of matrix composition.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Here, the synthesis of two graft copolymers based on α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) and poly(lactic acid) (PLA), the O-(2-aminoethyl)-O′-galactosyl polyethylene glycol (GAL-PEG-NH2) or the methoxypolyethylene glycol amine (H2N-PEG-OCH3) is described. Starting from the obtained PHEA-PLA-PEG-GAL and PHEA-PLA-PEG copolymers, polymeric nanoparticles were prepared by high pressure homogenization–solvent evaporation method.
To demonstrate their biodegradability as a function of the matrix composition, a chemical stability study was carried out until 21 days by incubating systems in two media mimicking physiological compartments (pH 7.4 and pH 5.5). The degradability of both nanosystems was firstly confirmed by the reduction of the pH of the incubation medium. Moreover, the percentage yield of recovered nanoparticles show a gradual reduction while mean size increases as a function of incubation time. Degradation seems to be mainly attributed to the loss of water-soluble portions of PLA, and proceeds with greater speed at pH 5.5, than at pH 7.4 and as a function of matrix composition.
To demonstrate their biodegradability as a function of the matrix composition, a chemical stability study was carried out until 21 days by incubating systems in two media mimicking physiological compartments (pH 7.4 and pH 5.5). The degradability of both nanosystems was firstly confirmed by the reduction of the pH of the incubation medium. Moreover, the percentage yield of recovered nanoparticles show a gradual reduction while mean size increases as a function of incubation time. Degradation seems to be mainly attributed to the loss of water-soluble portions of PLA, and proceeds with greater speed at pH 5.5, than at pH 7.4 and as a function of matrix composition.
Farra, Rossella; Grassi, Mario; Grassi, Gabriele; Dapas, Barbara
Therapeutic potential of small interfering RNAs/micro interfering RNA in hepatocellular carcinoma Journal Article
In: World Journal of Gastroenterology, vol. 21, no. 30, pp. 8994-9001, 2015.
Abstract | Links | BibTeX | Tags:
@article{Farra2015b,
title = {Therapeutic potential of small interfering RNAs/micro interfering RNA in hepatocellular carcinoma },
author = {Rossella Farra and Mario Grassi and Gabriele Grassi and Barbara Dapas},
url = {http://www.wjgnet.com/1007-9327/full/v21/i30/8994.htm},
doi = {10.3748/wjg.v21.i30.8994},
year = {2015},
date = {2015-08-14},
journal = {World Journal of Gastroenterology},
volume = {21},
number = {30},
pages = {8994-9001},
abstract = {Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and represents the third leading cause of cancer-related death worldwide. Current available therapeutic approaches are poorly effective, especially for the advanced forms of the disease. In the last year, short double stranded RNA molecules termed small interfering RNAs (siRNAs) and micro interfering RNAs (miRNA), emerged as interesting molecules with potential therapeutic value for HCC. The practical use of these molecules is however limited by the identification of optimal molecular targets and especially by the lack of effective and targeted HCC delivery systems. Here we focus our discussion on the most recent advances in the identification of siRNAs/miRNAs molecular targets and on the development of suitable siRNA/miRNAs delivery systems. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and represents the third leading cause of cancer-related death worldwide. Current available therapeutic approaches are poorly effective, especially for the advanced forms of the disease. In the last year, short double stranded RNA molecules termed small interfering RNAs (siRNAs) and micro interfering RNAs (miRNA), emerged as interesting molecules with potential therapeutic value for HCC. The practical use of these molecules is however limited by the identification of optimal molecular targets and especially by the lack of effective and targeted HCC delivery systems. Here we focus our discussion on the most recent advances in the identification of siRNAs/miRNAs molecular targets and on the development of suitable siRNA/miRNAs delivery systems.
Gioia, Sante Di; Sardo, Carla; Belgiovine, Giuliana; Triolo, Daniela; d’Apolito, Maria; Castellani, Stefano; Carbone, Annalucia; Giardino, Ida; Giammona, Gaetano; Cavallaro, Gennara; Conese, Massimo
In: International Journal of Pharmaceutics, vol. 491, no. 1-2, pp. 359–366, 2015.
Abstract | Links | BibTeX | Tags:
@article{DiGioia2015,
title = {Cationic polyaspartamide-based nanocomplexes mediate siRNA entry and down-regulation of the pro-inflammatory mediator high mobility group box 1 in airway epithelial cells},
author = {Sante {Di Gioia} and Carla Sardo and Giuliana Belgiovine and Daniela Triolo and Maria d’Apolito and Stefano Castellani and Annalucia Carbone and Ida Giardino and Gaetano Giammona and Gennara Cavallaro and Massimo Conese },
url = {http://www.sciencedirect.com/science/article/pii/S0378517315005372},
doi = {10.1016/j.ijpharm.2015.06.017},
year = {2015},
date = {2015-08-01},
journal = {International Journal of Pharmaceutics},
volume = {491},
number = {1-2},
pages = {359\textendash366},
abstract = {High-mobility group box 1 (HMGB1) is a nonhistone protein secreted by airway epithelial cells in hyperinflammatory diseases such as asthma. In order to down-regulate HMGB1 expression in airway epithelial cells, siRNA directed against HMGB1 was delivered through nanocomplexes based on a cationic copolymer of poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) by using H441 cells. Two copolymers were used in these experiments bearing respectively spermine side chains (PHEA-Spm) and both spermine and PEG2000 chains (PHEA-PEG-Spm).
PHEA-Spm and PHEA-PEG-Spm derivatives complexed dsDNA oligonucleotides with a w/w ratio of 1 and higher as shown by a gel retardation assay. PHEA-Spm and PHEA-PEG-Spm siRNA polyplexes were sized 350\textendash650 nm and 100\textendash400 nm respectively and ranged from negativity/neutrality (at 0.5 ratio) to positivity (at 5 ratio) as ζ potential. Polyplexes formed either at a ratio of 0.5 (partially complexing) or at the ratio of 5 (fully complexing) were tested in subsequent experiments. Epifluorescence revealed that nanocomplexes favored siRNA entry into H441 cells in comparison with naked siRNA. As determined by flow cytometry and a trypan blue assay, PHEA-Spm and PHEA-PEG-Spm allowed siRNA uptake in 42\textendash47% and 30% of cells respectively, however only with PHEA-Spm at w/w ratio of 5 these percentages were significantly higher than those obtained with naked siRNA (20%). Naked siRNA or complexed scrambled siRNA did not exert any effect on HMGB1mRNA levels, whereas PHEA-Spm/siRNA at the w/w ratio of 5 down-regulated HMGB1 mRNA up to 58% of control levels (untransfected cells). PEGylated PHEA-Spm/siRNA nanocomplexes were able to down-regulate HMGB1 mRNA levels up to 61% of control cells. MTT assay revealed excellent biocompatibility of copolymer/siRNA polyplexes with cells.
In conclusion, we have found optimal conditions for down-regulation of HMGB1 by siRNA delivery mediated by polyaminoacidic polymers in airway epithelial cells in the absence of cytotoxicity. Functional and in-vivo studies are warranted.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
High-mobility group box 1 (HMGB1) is a nonhistone protein secreted by airway epithelial cells in hyperinflammatory diseases such as asthma. In order to down-regulate HMGB1 expression in airway epithelial cells, siRNA directed against HMGB1 was delivered through nanocomplexes based on a cationic copolymer of poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) by using H441 cells. Two copolymers were used in these experiments bearing respectively spermine side chains (PHEA-Spm) and both spermine and PEG2000 chains (PHEA-PEG-Spm).
PHEA-Spm and PHEA-PEG-Spm derivatives complexed dsDNA oligonucleotides with a w/w ratio of 1 and higher as shown by a gel retardation assay. PHEA-Spm and PHEA-PEG-Spm siRNA polyplexes were sized 350–650 nm and 100–400 nm respectively and ranged from negativity/neutrality (at 0.5 ratio) to positivity (at 5 ratio) as ζ potential. Polyplexes formed either at a ratio of 0.5 (partially complexing) or at the ratio of 5 (fully complexing) were tested in subsequent experiments. Epifluorescence revealed that nanocomplexes favored siRNA entry into H441 cells in comparison with naked siRNA. As determined by flow cytometry and a trypan blue assay, PHEA-Spm and PHEA-PEG-Spm allowed siRNA uptake in 42–47% and 30% of cells respectively, however only with PHEA-Spm at w/w ratio of 5 these percentages were significantly higher than those obtained with naked siRNA (20%). Naked siRNA or complexed scrambled siRNA did not exert any effect on HMGB1mRNA levels, whereas PHEA-Spm/siRNA at the w/w ratio of 5 down-regulated HMGB1 mRNA up to 58% of control levels (untransfected cells). PEGylated PHEA-Spm/siRNA nanocomplexes were able to down-regulate HMGB1 mRNA levels up to 61% of control cells. MTT assay revealed excellent biocompatibility of copolymer/siRNA polyplexes with cells.
In conclusion, we have found optimal conditions for down-regulation of HMGB1 by siRNA delivery mediated by polyaminoacidic polymers in airway epithelial cells in the absence of cytotoxicity. Functional and in-vivo studies are warranted.
PHEA-Spm and PHEA-PEG-Spm derivatives complexed dsDNA oligonucleotides with a w/w ratio of 1 and higher as shown by a gel retardation assay. PHEA-Spm and PHEA-PEG-Spm siRNA polyplexes were sized 350–650 nm and 100–400 nm respectively and ranged from negativity/neutrality (at 0.5 ratio) to positivity (at 5 ratio) as ζ potential. Polyplexes formed either at a ratio of 0.5 (partially complexing) or at the ratio of 5 (fully complexing) were tested in subsequent experiments. Epifluorescence revealed that nanocomplexes favored siRNA entry into H441 cells in comparison with naked siRNA. As determined by flow cytometry and a trypan blue assay, PHEA-Spm and PHEA-PEG-Spm allowed siRNA uptake in 42–47% and 30% of cells respectively, however only with PHEA-Spm at w/w ratio of 5 these percentages were significantly higher than those obtained with naked siRNA (20%). Naked siRNA or complexed scrambled siRNA did not exert any effect on HMGB1mRNA levels, whereas PHEA-Spm/siRNA at the w/w ratio of 5 down-regulated HMGB1 mRNA up to 58% of control levels (untransfected cells). PEGylated PHEA-Spm/siRNA nanocomplexes were able to down-regulate HMGB1 mRNA levels up to 61% of control cells. MTT assay revealed excellent biocompatibility of copolymer/siRNA polyplexes with cells.
In conclusion, we have found optimal conditions for down-regulation of HMGB1 by siRNA delivery mediated by polyaminoacidic polymers in airway epithelial cells in the absence of cytotoxicity. Functional and in-vivo studies are warranted.
Craparo, Emanuela Fabiola; Porsio, Barbara; Mauro, Nicolò; Giammona, Gaetano; Cavallaro, Gennara
Polyaspartamide-Polylactide Graft Copolymers with Tunable Properties for the Realization of Fluorescent Nanoparticles for Imaging Journal Article
In: Macromolecular Rapid Communications, vol. 36, no. 15, pp. 1409–1415, 2015.
Abstract | Links | BibTeX | Tags:
@article{Craparo2015b,
title = {Polyaspartamide-Polylactide Graft Copolymers with Tunable Properties for the Realization of Fluorescent Nanoparticles for Imaging},
author = {Emanuela Fabiola Craparo and Barbara Porsio and Nicol\`{o} Mauro and Gaetano Giammona and Gennara Cavallaro},
url = {http://onlinelibrary.wiley.com/doi/10.1002/marc.201500154/abstract;jsessionid=4772692D1D8AA8B4D0B65C62E286B829.f04t02},
doi = {10.1002/marc.201500154},
year = {2015},
date = {2015-08-01},
journal = {Macromolecular Rapid Communications},
volume = {36},
number = {15},
pages = {1409\textendash1415},
abstract = {Here, the synthesis and the characterization of novel amphiphilic graft copolymers with tunable properties, useful in obtaining polymeric fluorescent nanoparticles for application in imaging, are described. These copolymers are obtained by chemical conjugation of rhodamine B (RhB) moieties, polylactic acid (PLA), and O-(2-aminoethyl)-O′-methyl poly(ethylene glycol) (PEG) on α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA). In particular, PHEA is first functionalized with RhB to obtain PHEA\textendashRhB with a derivatization degree in RhB (DDRhB) equal to 0.55 mol%. By varying the reaction conditions, different amounts of PLA are grafted on PHEA\textendashRhB to obtain PHEA-RhB-PLA with DDPLA equal to 1.9, 4.0, and 6.2 mol%. Then, PEG chains are grafted on PHEA-RhB-PLA derivatives to obtain PHEA-RhB-PLA-PEG graft copolymers. The preparation of polymeric fluorescent nanoparticles with tunable properties and spherical shape is described by using PHEA-RhB-PLA-PEG with DD in PLA and PEG equal to 4.0 and 4.9 mol%, by following easily scaling up processes, such as emulsion-solvent evaporation and high pressure homogenization (HPH)-solvent evaporation techniques. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Here, the synthesis and the characterization of novel amphiphilic graft copolymers with tunable properties, useful in obtaining polymeric fluorescent nanoparticles for application in imaging, are described. These copolymers are obtained by chemical conjugation of rhodamine B (RhB) moieties, polylactic acid (PLA), and O-(2-aminoethyl)-O′-methyl poly(ethylene glycol) (PEG) on α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA). In particular, PHEA is first functionalized with RhB to obtain PHEA–RhB with a derivatization degree in RhB (DDRhB) equal to 0.55 mol%. By varying the reaction conditions, different amounts of PLA are grafted on PHEA–RhB to obtain PHEA-RhB-PLA with DDPLA equal to 1.9, 4.0, and 6.2 mol%. Then, PEG chains are grafted on PHEA-RhB-PLA derivatives to obtain PHEA-RhB-PLA-PEG graft copolymers. The preparation of polymeric fluorescent nanoparticles with tunable properties and spherical shape is described by using PHEA-RhB-PLA-PEG with DD in PLA and PEG equal to 4.0 and 4.9 mol%, by following easily scaling up processes, such as emulsion-solvent evaporation and high pressure homogenization (HPH)-solvent evaporation techniques.
Gioia, Sante Di; Trapani, Adriana; Mandracchia, Delia; Giglio, Elvira De; Cometa, Stefania; Mangini, Vincenzo; Arnesano, Fabio; Belgiovine, Giuliana; Castellani, Stefano; Pace, Lorenzo; Lavecchia, Michele Angelo; Trapani, Giuseppe; Conese, Massimo; Puglisi, Giovanni; Cassano, Tommaso
Intranasal delivery of dopamine to the striatum using glycol chitosan/sulfobutylether-β-cyclodextrin based nanoparticles Journal Article
In: European Journal of Pharmaceutics and Biopharmaceutics, vol. 94, pp. 180–193, 2015.
Abstract | Links | BibTeX | Tags:
@article{Gioia2015b,
title = {Intranasal delivery of dopamine to the striatum using glycol chitosan/sulfobutylether-β-cyclodextrin based nanoparticles},
author = {Sante Di Gioia and Adriana Trapani and Delia Mandracchia and Elvira {De Giglio} and Stefania Cometa and Vincenzo Mangini and Fabio Arnesano and Giuliana Belgiovine and Stefano Castellani and Lorenzo Pace and Michele Angelo Lavecchia and Giuseppe Trapani and Massimo Conese and Giovanni Puglisi and Tommaso Cassano},
url = {http://www.sciencedirect.com/science/article/pii/S0939641115002519},
doi = {10.1016/j.ejpb.2015.05.019},
year = {2015},
date = {2015-08-01},
journal = {European Journal of Pharmaceutics and Biopharmaceutics},
volume = {94},
pages = {180\textendash193},
abstract = {The aim of this study was to evaluate chitosan (CS)-, glycol chitosan (GCS)- and corresponding thiomer-based nanoparticles (NPs) for delivering dopamine (DA) to the brain by nasal route. Thus, the polyanions tripolyphosphate and sulfobutylether-β-cyclodextrin (SBE-β-CD), respectively, were used as polycation crosslinking agents and SBE-β-CD also in order to enhance the DA stability. The most interesting formulation, containing GCS and SBE-β-CD, was denoted as DA GCS/DA-CD NPs. NMR spectroscopy demonstrated an inclusion complex formation between SBE-β-CD and DA. X-ray photoelectron spectroscopy analysis revealed the presence of DA on the external surface of NPs. DA GCS/DA-CD NPs showed cytotoxic effect toward Olfactory Ensheathing Cells only at higher dosage. Acute administration of DA GCS/DA-CD NPs into the right nostril of rats did not modify the levels of the neurotransmitter in both right and left striatum. Conversely, repeated intranasal administration of DA GCS/DA-CD NPs into the right nostril significantly increased DA in the ipsilateral striatum. Fluorescent microscopy of olfactory bulb after acute administration of DA fluorescent-labeled GCS/DA-CD NPs into the right nostril showed the presence of NPs only in the right olfactory bulb and no morphological tissue damage occurred. Thus, these GCS based NPs could be potentially used as carriers for nose-to-brain DA delivery for the Parkinson’s disease treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The aim of this study was to evaluate chitosan (CS)-, glycol chitosan (GCS)- and corresponding thiomer-based nanoparticles (NPs) for delivering dopamine (DA) to the brain by nasal route. Thus, the polyanions tripolyphosphate and sulfobutylether-β-cyclodextrin (SBE-β-CD), respectively, were used as polycation crosslinking agents and SBE-β-CD also in order to enhance the DA stability. The most interesting formulation, containing GCS and SBE-β-CD, was denoted as DA GCS/DA-CD NPs. NMR spectroscopy demonstrated an inclusion complex formation between SBE-β-CD and DA. X-ray photoelectron spectroscopy analysis revealed the presence of DA on the external surface of NPs. DA GCS/DA-CD NPs showed cytotoxic effect toward Olfactory Ensheathing Cells only at higher dosage. Acute administration of DA GCS/DA-CD NPs into the right nostril of rats did not modify the levels of the neurotransmitter in both right and left striatum. Conversely, repeated intranasal administration of DA GCS/DA-CD NPs into the right nostril significantly increased DA in the ipsilateral striatum. Fluorescent microscopy of olfactory bulb after acute administration of DA fluorescent-labeled GCS/DA-CD NPs into the right nostril showed the presence of NPs only in the right olfactory bulb and no morphological tissue damage occurred. Thus, these GCS based NPs could be potentially used as carriers for nose-to-brain DA delivery for the Parkinson’s disease treatment.
Kirchhof, Susanne; Abrami, Michela; Messmann, Viktoria; Hammer, Nadine; Goepferich, Achim M.; Grassi, Mario; Brandl, Ferdinand P.
Diels–Alder Hydrogels for Controlled Antibody Release: Correlation between Mesh Size and Release Rate Journal Article
In: Molecular Pharmaceutics, vol. 12, no. 9, pp. 3358–3368, 2015.
Abstract | Links | BibTeX | Tags:
@article{Kirchhof2015,
title = {Diels\textendashAlder Hydrogels for Controlled Antibody Release: Correlation between Mesh Size and Release Rate},
author = {Susanne Kirchhof and Michela Abrami and Viktoria Messmann and Nadine Hammer and Achim M. Goepferich and Mario Grassi and Ferdinand P. Brandl},
url = {http://pubs.acs.org/doi/full/10.1021/acs.molpharmaceut.5b00375},
doi = {10.1021/acs.molpharmaceut.5b00375},
year = {2015},
date = {2015-08-01},
journal = {Molecular Pharmaceutics},
volume = {12},
number = {9},
pages = {3358\textendash3368},
abstract = {Eight-armed PEG, molecular mass 10 kDa, was functionalized with furyl and maleimide groups, respectively; the obtained macromonomers were cross-linked via Diels\textendashAlder chemistry. The mesh size (ξ) of the prepared hydrogels was determined by swelling studies, rheology, and low field NMR spectroscopy. The in vitro release of fluorescein isothiocyanate labeled dextrans (FDs) and bevacizumab was investigated. The average mesh size (ξavg) increased from 5.8 ± 0.1 nm to 56 ± 13 nm during degradation, as determined by swelling studies. The result of the rheological measurements (8.0 nm) matched the initial value of ξavg. Low field NMR spectroscopy enabled the determination of the mesh size distribution; the most abundant mesh size was found to be 9.2 nm. In combination with the hydrodynamic radius of the molecule (Rh), the time-dependent increase of ξavg was used to predict the release profiles of incorporated FDs applying an obstruction-scaling model. The predicted release profiles matched the experimentally determined release profiles when Rh \< ξavg. However, significant deviations from the theoretical predictions were observed when Rh ≥ ξavg, most likely due to the statistical distribution of ξ in real polymer networks. The release profile of bevacizumab differed from those of equivalently sized FDs. The delayed release of bevacizumab was most likely a result of the globular structure and rigidity of the protein. The observed correlation between ξ and the release rate could facilitate the design of controlled release systems for antibodies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Eight-armed PEG, molecular mass 10 kDa, was functionalized with furyl and maleimide groups, respectively; the obtained macromonomers were cross-linked via Diels–Alder chemistry. The mesh size (ξ) of the prepared hydrogels was determined by swelling studies, rheology, and low field NMR spectroscopy. The in vitro release of fluorescein isothiocyanate labeled dextrans (FDs) and bevacizumab was investigated. The average mesh size (ξavg) increased from 5.8 ± 0.1 nm to 56 ± 13 nm during degradation, as determined by swelling studies. The result of the rheological measurements (8.0 nm) matched the initial value of ξavg. Low field NMR spectroscopy enabled the determination of the mesh size distribution; the most abundant mesh size was found to be 9.2 nm. In combination with the hydrodynamic radius of the molecule (Rh), the time-dependent increase of ξavg was used to predict the release profiles of incorporated FDs applying an obstruction-scaling model. The predicted release profiles matched the experimentally determined release profiles when Rh < ξavg. However, significant deviations from the theoretical predictions were observed when Rh ≥ ξavg, most likely due to the statistical distribution of ξ in real polymer networks. The release profile of bevacizumab differed from those of equivalently sized FDs. The delayed release of bevacizumab was most likely a result of the globular structure and rigidity of the protein. The observed correlation between ξ and the release rate could facilitate the design of controlled release systems for antibodies.
Travan, Andrea; Fiorentino, Simona; Grassi, Mario; Borgogna, Massimiliano; Marsich, Eleonora; Paoletti, Sergio; Donati, Ivan
Rheology of mixed alginate-hyaluronan aqueous solutions Journal Article
In: International Journal of Biological Macromolecules, vol. 78, pp. 363–369, 2015.
Abstract | Links | BibTeX | Tags:
@article{Travan2015,
title = {Rheology of mixed alginate-hyaluronan aqueous solutions},
author = {Andrea Travan and Simona Fiorentino and Mario Grassi and Massimiliano Borgogna and Eleonora Marsich and Sergio Paoletti and Ivan Donati },
url = {http://www.sciencedirect.com/science/article/pii/S0141813015002470},
doi = {10.1016/j.ijbiomac.2015.04.009},
year = {2015},
date = {2015-07-25},
journal = {International Journal of Biological Macromolecules},
volume = {78},
pages = {363\textendash369},
abstract = {The present manuscript addresses the description of binary systems of hyaluronan (HA) and alginate (Alg) in semi-concentrated solution. The two polysaccharides were completely miscible in the entire range of relative weight fraction explored at a total polymer concentration of up to 3% (w/V). The rheological study encompassed steady flow and mechanical spectra for HA/Alg systems at different weight fractions with hyaluronan at different molecular weights. These extensive analyses allowed us to propose a model for the molecular arrangement in solution that envisages a mutual exclusion between the two polysaccharides even though a clear phase separation does not occur. This result may have profound implications when combinations of alginate and hyaluronan are proposed in the field of biomedical materials.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The present manuscript addresses the description of binary systems of hyaluronan (HA) and alginate (Alg) in semi-concentrated solution. The two polysaccharides were completely miscible in the entire range of relative weight fraction explored at a total polymer concentration of up to 3% (w/V). The rheological study encompassed steady flow and mechanical spectra for HA/Alg systems at different weight fractions with hyaluronan at different molecular weights. These extensive analyses allowed us to propose a model for the molecular arrangement in solution that envisages a mutual exclusion between the two polysaccharides even though a clear phase separation does not occur. This result may have profound implications when combinations of alginate and hyaluronan are proposed in the field of biomedical materials.
Craparo, Emanuela Fabiola; Licciardi, Mariano; Conigliaro, Alice; Palumbo, Fabio Salvatore; Giammona, Gaetano; Alessandro, Riccardo; Leo, Giacomo De; Cavallaro, Gennara
Hepatocyte-targeted fluorescent nanoparticles based on a polyaspartamide for potential theranostic applications Journal Article
In: Polymer, vol. 70, pp. 257–270, 2015.
Abstract | Links | BibTeX | Tags:
@article{Craparo2015,
title = {Hepatocyte-targeted fluorescent nanoparticles based on a polyaspartamide for potential theranostic applications},
author = {Emanuela Fabiola Craparo and Mariano Licciardi and Alice Conigliaro and Fabio Salvatore Palumbo and Gaetano Giammona and Riccardo Alessandro and Giacomo De Leo and Gennara Cavallaro },
url = {http://www.sciencedirect.com/science/article/pii/S0032386115300306},
doi = {10.1016/j.polymer.2015.06.009},
year = {2015},
date = {2015-07-23},
journal = {Polymer},
volume = {70},
pages = {257\textendash270},
abstract = {Here, the synthesis of a galactosylated amphiphilic copolymer bearing rhodamine (RhB) moieties and its use for the preparation of polymeric fluorescent nanoparticles for potential applications in therapy and diagnosis are described.
To do this, firstly, a fluorescent derivative of α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) was synthesized by chemical reaction with RhB, and with polylactic acid (PLA), to obtain PHEA-RhB-PLA. Then, the derivatization of PHEA-RhB-PLA with GAL-PEG-NH2 allows obtaining PHEA-RhB-PLA-PEG-GAL copolymer, with derivatization degrees in -PLA and -PEG-GAL equal to 1.9 mol% and 4.5 mol%, respectively. Starting from this copolymer, liver-targeted fluorescent nanoparticles were prepared by high pressure homogenization\textendashsolvent evaporation method, and showed nanoscaled size, slightly negative zeta potential and spherical shape. Chemical and enzymatic stability of fluorescent dye covalently linked to the copolymer backbone by ester linkage was demonstrated until 4 days of incubation. Finally, thanks to the covalently-linked fluorescent RhB, it was demonstrated that these galactosylated nanoparticles interact with HepG2 cells that are positive for the asialoglycoprotein receptor (ASGPR), while these do not interact with HeLa cells that are negative for the same receptor, demonstrating the contributor of ASGPR to the internalization process.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Here, the synthesis of a galactosylated amphiphilic copolymer bearing rhodamine (RhB) moieties and its use for the preparation of polymeric fluorescent nanoparticles for potential applications in therapy and diagnosis are described.
To do this, firstly, a fluorescent derivative of α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) was synthesized by chemical reaction with RhB, and with polylactic acid (PLA), to obtain PHEA-RhB-PLA. Then, the derivatization of PHEA-RhB-PLA with GAL-PEG-NH2 allows obtaining PHEA-RhB-PLA-PEG-GAL copolymer, with derivatization degrees in -PLA and -PEG-GAL equal to 1.9 mol% and 4.5 mol%, respectively. Starting from this copolymer, liver-targeted fluorescent nanoparticles were prepared by high pressure homogenization–solvent evaporation method, and showed nanoscaled size, slightly negative zeta potential and spherical shape. Chemical and enzymatic stability of fluorescent dye covalently linked to the copolymer backbone by ester linkage was demonstrated until 4 days of incubation. Finally, thanks to the covalently-linked fluorescent RhB, it was demonstrated that these galactosylated nanoparticles interact with HepG2 cells that are positive for the asialoglycoprotein receptor (ASGPR), while these do not interact with HeLa cells that are negative for the same receptor, demonstrating the contributor of ASGPR to the internalization process.
To do this, firstly, a fluorescent derivative of α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) was synthesized by chemical reaction with RhB, and with polylactic acid (PLA), to obtain PHEA-RhB-PLA. Then, the derivatization of PHEA-RhB-PLA with GAL-PEG-NH2 allows obtaining PHEA-RhB-PLA-PEG-GAL copolymer, with derivatization degrees in -PLA and -PEG-GAL equal to 1.9 mol% and 4.5 mol%, respectively. Starting from this copolymer, liver-targeted fluorescent nanoparticles were prepared by high pressure homogenization–solvent evaporation method, and showed nanoscaled size, slightly negative zeta potential and spherical shape. Chemical and enzymatic stability of fluorescent dye covalently linked to the copolymer backbone by ester linkage was demonstrated until 4 days of incubation. Finally, thanks to the covalently-linked fluorescent RhB, it was demonstrated that these galactosylated nanoparticles interact with HepG2 cells that are positive for the asialoglycoprotein receptor (ASGPR), while these do not interact with HeLa cells that are negative for the same receptor, demonstrating the contributor of ASGPR to the internalization process.
Sardo, Carla; Farra, Rossella; Licciardi, Mariano; Dapas, Barbara; Scialabba, Cinzia; Giammona, Gaetano; Grassi, Mario; Grassi, Gabriele; Cavallaro, Gennara
Development of a simple, biocompatible and cost-effective Inulin-Diethylenetriamine based siRNA delivery system Journal Article
In: European Journal of Pharmaceutical Sciences, vol. 70, pp. 60-71, 2015.
Abstract | Links | BibTeX | Tags:
@article{Sardo2015,
title = {Development of a simple, biocompatible and cost-effective Inulin-Diethylenetriamine based siRNA delivery system},
author = {Carla Sardo and Rossella Farra and Mariano Licciardi and Barbara Dapas and Cinzia Scialabba and Gaetano Giammona and Mario Grassi and Gabriele Grassi and Gennara Cavallaro},
url = {http://www.sciencedirect.com/science/article/pii/S0928098715001219},
doi = {10.1016/j.ejps.2015.03.021},
year = {2015},
date = {2015-07-01},
journal = {European Journal of Pharmaceutical Sciences},
volume = {70},
pages = {60-71},
abstract = {Small interfering RNAs (siRNAs) have the potential to be of therapeutic value for many human diseases. So far, however, a serious obstacle to their therapeutic use is represented by the absence of appropriate delivery systems able to protect them from degradation and to allow an efficient cellular uptake.
In this work we developed a siRNA delivery system based on inulin (Inu), an abundant and natural polysaccharide. Inu was functionalized via the conjugation with diethylenetriamine (DETA) residues to form the complex Inu-DETA. We studied the size, surface charge and the shape of the Inu-DETA/siRNA complexes; additionally, the cytotoxicity, the silencing efficacy and the cell uptake-mechanisms were studied in the human bronchial epithelial cells (16HBE) and in the hepatocellular carcinoma derived cells (JHH6).
The results presented here indicate that Inu-DETA copolymers can effectively bind siRNAs, are highly cytocompatible and, in JHH6, can effectively deliver functional siRNAs. Optimal delivery is observed using a weight ratio Inu-DETA/siRNA of 4 that corresponds to polyplexes with an average size of 600 nm and a slightly negative surface charge. Moreover, the uptake and trafficking mechanisms, mainly based on micropinocytosis and clatrin mediated endocytosis, allow the homogeneous diffusion of siRNA within the cytoplasm of JHH6. Notably, in 16 HBE where the trafficking mechanism (caveolae mediated endocytosis) does not allow an even distribution of siRNA within the cell cytoplasm, no significant siRNA activity is observed.
In conclusion, we developed a novel inulin-based siRNA delivery system able to efficiently release siRNA in JHH6 with negligible cytotoxicity thus opening the way for further testing in more complex in vivo models.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Small interfering RNAs (siRNAs) have the potential to be of therapeutic value for many human diseases. So far, however, a serious obstacle to their therapeutic use is represented by the absence of appropriate delivery systems able to protect them from degradation and to allow an efficient cellular uptake.
In this work we developed a siRNA delivery system based on inulin (Inu), an abundant and natural polysaccharide. Inu was functionalized via the conjugation with diethylenetriamine (DETA) residues to form the complex Inu-DETA. We studied the size, surface charge and the shape of the Inu-DETA/siRNA complexes; additionally, the cytotoxicity, the silencing efficacy and the cell uptake-mechanisms were studied in the human bronchial epithelial cells (16HBE) and in the hepatocellular carcinoma derived cells (JHH6).
The results presented here indicate that Inu-DETA copolymers can effectively bind siRNAs, are highly cytocompatible and, in JHH6, can effectively deliver functional siRNAs. Optimal delivery is observed using a weight ratio Inu-DETA/siRNA of 4 that corresponds to polyplexes with an average size of 600 nm and a slightly negative surface charge. Moreover, the uptake and trafficking mechanisms, mainly based on micropinocytosis and clatrin mediated endocytosis, allow the homogeneous diffusion of siRNA within the cytoplasm of JHH6. Notably, in 16 HBE where the trafficking mechanism (caveolae mediated endocytosis) does not allow an even distribution of siRNA within the cell cytoplasm, no significant siRNA activity is observed.
In conclusion, we developed a novel inulin-based siRNA delivery system able to efficiently release siRNA in JHH6 with negligible cytotoxicity thus opening the way for further testing in more complex in vivo models.
In this work we developed a siRNA delivery system based on inulin (Inu), an abundant and natural polysaccharide. Inu was functionalized via the conjugation with diethylenetriamine (DETA) residues to form the complex Inu-DETA. We studied the size, surface charge and the shape of the Inu-DETA/siRNA complexes; additionally, the cytotoxicity, the silencing efficacy and the cell uptake-mechanisms were studied in the human bronchial epithelial cells (16HBE) and in the hepatocellular carcinoma derived cells (JHH6).
The results presented here indicate that Inu-DETA copolymers can effectively bind siRNAs, are highly cytocompatible and, in JHH6, can effectively deliver functional siRNAs. Optimal delivery is observed using a weight ratio Inu-DETA/siRNA of 4 that corresponds to polyplexes with an average size of 600 nm and a slightly negative surface charge. Moreover, the uptake and trafficking mechanisms, mainly based on micropinocytosis and clatrin mediated endocytosis, allow the homogeneous diffusion of siRNA within the cytoplasm of JHH6. Notably, in 16 HBE where the trafficking mechanism (caveolae mediated endocytosis) does not allow an even distribution of siRNA within the cell cytoplasm, no significant siRNA activity is observed.
In conclusion, we developed a novel inulin-based siRNA delivery system able to efficiently release siRNA in JHH6 with negligible cytotoxicity thus opening the way for further testing in more complex in vivo models.
Posocco, Bianca; Dreussi, Eva; de Santa, Jacopo; Toffoli, Giuseppe; Abrami, Michela; Musiani, Francesco; Grassi, Mario; Farra, Rossella; Tonon, Federica; Grassi, Gabriele; Dapas, Barbara
Polysaccharides for the Delivery of Antitumor Drugs Journal Article
In: Materials, vol. 8, no. 5, pp. 2569-2615, 2015.
Abstract | Links | BibTeX | Tags:
@article{Posocco2015,
title = {Polysaccharides for the Delivery of Antitumor Drugs},
author = {Bianca Posocco and Eva Dreussi and Jacopo {de Santa} and Giuseppe Toffoli and Michela Abrami and Francesco Musiani and Mario Grassi and Rossella Farra and Federica Tonon and Gabriele Grassi and Barbara Dapas
},
url = {http://www.mdpi.com/1996-1944/8/5/2569},
doi = {10.3390/ma8052569},
year = {2015},
date = {2015-05-13},
journal = {Materials},
volume = {8},
number = {5},
pages = {2569-2615},
abstract = {Among the several delivery materials available so far, polysaccharides represent very attractive molecules as they can undergo a wide range of chemical modifications, are biocompatible, biodegradable, and have low immunogenic properties. Thus, polysaccharides can contribute to significantly overcome the limitation in the use of many types of drugs, including anti-cancer drugs. The use of conventional anti-cancer drugs is hampered by their high toxicity, mostly depending on the indiscriminate targeting of both cancer and normal cells. Additionally, for nucleic acid based drugs (NABDs), an emerging class of drugs with potential anti-cancer value, the practical use is problematic. This mostly depends on their fast degradation in biological fluids and the difficulties to cross cell membranes. Thus, for both classes of drugs, the development of optimal delivery materials is crucial. Here we discuss the possibility of using different kinds of polysaccharides, such as chitosan, hyaluronic acid, dextran, and pullulan, as smart drug delivery materials. We first describe the main features of polysaccharides, then a general overview about the aspects ruling drug release mechanisms and the pharmacokinetic are reported. Finally, notable examples of polysaccharide-based delivery of conventional anti-cancer drugs and NABDs are reported. Whereas additional research is required, the promising results obtained so far, fully justify further efforts, both in terms of economic support and investigations in the field of polysaccharides as drug delivery materials. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Among the several delivery materials available so far, polysaccharides represent very attractive molecules as they can undergo a wide range of chemical modifications, are biocompatible, biodegradable, and have low immunogenic properties. Thus, polysaccharides can contribute to significantly overcome the limitation in the use of many types of drugs, including anti-cancer drugs. The use of conventional anti-cancer drugs is hampered by their high toxicity, mostly depending on the indiscriminate targeting of both cancer and normal cells. Additionally, for nucleic acid based drugs (NABDs), an emerging class of drugs with potential anti-cancer value, the practical use is problematic. This mostly depends on their fast degradation in biological fluids and the difficulties to cross cell membranes. Thus, for both classes of drugs, the development of optimal delivery materials is crucial. Here we discuss the possibility of using different kinds of polysaccharides, such as chitosan, hyaluronic acid, dextran, and pullulan, as smart drug delivery materials. We first describe the main features of polysaccharides, then a general overview about the aspects ruling drug release mechanisms and the pharmacokinetic are reported. Finally, notable examples of polysaccharide-based delivery of conventional anti-cancer drugs and NABDs are reported. Whereas additional research is required, the promising results obtained so far, fully justify further efforts, both in terms of economic support and investigations in the field of polysaccharides as drug delivery materials.
Farra, Rossella; Dapas, Barbara; Baiz, Daniele; Tonon, Federica; Chiaretti, Sara; Sal, Giannino Del; Rustighi, Alessandra; Elvassore, Nicola; Pozzato, Gabriele; Grassi, Mario; Grassi, Gabriele
Impairment of the Pin1/E2F1 axis in the anti-proliferative effect of bortezomib in hepatocellular carcinoma cells Journal Article
In: Biochimie, vol. 112, pp. 85–95, 2015.
Abstract | Links | BibTeX | Tags:
@article{Farra2015,
title = {Impairment of the Pin1/E2F1 axis in the anti-proliferative effect of bortezomib in hepatocellular carcinoma cells},
author = {Rossella Farra and Barbara Dapas and Daniele Baiz and Federica Tonon and Sara Chiaretti and Giannino {Del Sal} and Alessandra Rustighi and Nicola Elvassore and Gabriele Pozzato and Mario Grassi and Gabriele Grassi},
url = {http://www.sciencedirect.com/science/article/pii/S0300908415000504},
doi = {10.1016/j.biochi.2015.02.015},
year = {2015},
date = {2015-05-01},
journal = {Biochimie},
volume = {112},
pages = {85\textendash95},
abstract = {Background
The modest efficacy of available therapies for Hepatocellular carcinoma (HCC) indicates the need to develop novel therapeutic approaches. For the proteasome inhibitor Bortezomib (BZB), potentially attractive for HCC treatment, the mechanism of action is largely unknown. The BZB effect on E2Fs and the E2Fs control on the peptidylproline cis-trans isomerase (Pin1), prompted us to explore the BZB effect on the Pin1-E2F1 axis.
Methods
The tumorigenic cell line HuH7 together with the non-tumorigenic cells IHH and the human pluripotent stem cell derived hepatocytes (hPSC-H), were used as cellular models of HCC and normal liver cells, respectively.
Results
BZB reduces HuH7 growth as shown by cell counting, cell vitality test and cell cycle analysis; this is paralleled by the decrease of Pin1, E2F1, cyclin A2 and of the hyper-phosphorylated pRB. Pin1-E2F1 axis impairment justifies the anti-proliferative effect since Pin-E2F1 depletion decreases HuH7 growth while the over-expression rescues BZB-induced inhibition of proliferation. Moreover, Pin1-E2F1 promote HuH7 growth via the up-regulation of cyclin D1, cyclin E, cyclin A2, E2F2 and in part E2F3. Finally, in the control cells IHH and hPSC-H, BZB effect on cell vitality is not irrelevant, a fact correlated to the cellular proliferation rate. Thus, BZB effect on healthy liver tissue may not be entirely negligible hence caution should be exercised in its use in liver regeneration processes.
Conclusion
For the first time we prove the functional involvement of the Pin1-E2F1 axis in the anti-proliferative effect of BZB indicating Pin1-E2F as an attractive target to control HCC cell growth.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background
The modest efficacy of available therapies for Hepatocellular carcinoma (HCC) indicates the need to develop novel therapeutic approaches. For the proteasome inhibitor Bortezomib (BZB), potentially attractive for HCC treatment, the mechanism of action is largely unknown. The BZB effect on E2Fs and the E2Fs control on the peptidylproline cis-trans isomerase (Pin1), prompted us to explore the BZB effect on the Pin1-E2F1 axis.
Methods
The tumorigenic cell line HuH7 together with the non-tumorigenic cells IHH and the human pluripotent stem cell derived hepatocytes (hPSC-H), were used as cellular models of HCC and normal liver cells, respectively.
Results
BZB reduces HuH7 growth as shown by cell counting, cell vitality test and cell cycle analysis; this is paralleled by the decrease of Pin1, E2F1, cyclin A2 and of the hyper-phosphorylated pRB. Pin1-E2F1 axis impairment justifies the anti-proliferative effect since Pin-E2F1 depletion decreases HuH7 growth while the over-expression rescues BZB-induced inhibition of proliferation. Moreover, Pin1-E2F1 promote HuH7 growth via the up-regulation of cyclin D1, cyclin E, cyclin A2, E2F2 and in part E2F3. Finally, in the control cells IHH and hPSC-H, BZB effect on cell vitality is not irrelevant, a fact correlated to the cellular proliferation rate. Thus, BZB effect on healthy liver tissue may not be entirely negligible hence caution should be exercised in its use in liver regeneration processes.
Conclusion
For the first time we prove the functional involvement of the Pin1-E2F1 axis in the anti-proliferative effect of BZB indicating Pin1-E2F as an attractive target to control HCC cell growth.
The modest efficacy of available therapies for Hepatocellular carcinoma (HCC) indicates the need to develop novel therapeutic approaches. For the proteasome inhibitor Bortezomib (BZB), potentially attractive for HCC treatment, the mechanism of action is largely unknown. The BZB effect on E2Fs and the E2Fs control on the peptidylproline cis-trans isomerase (Pin1), prompted us to explore the BZB effect on the Pin1-E2F1 axis.
Methods
The tumorigenic cell line HuH7 together with the non-tumorigenic cells IHH and the human pluripotent stem cell derived hepatocytes (hPSC-H), were used as cellular models of HCC and normal liver cells, respectively.
Results
BZB reduces HuH7 growth as shown by cell counting, cell vitality test and cell cycle analysis; this is paralleled by the decrease of Pin1, E2F1, cyclin A2 and of the hyper-phosphorylated pRB. Pin1-E2F1 axis impairment justifies the anti-proliferative effect since Pin-E2F1 depletion decreases HuH7 growth while the over-expression rescues BZB-induced inhibition of proliferation. Moreover, Pin1-E2F1 promote HuH7 growth via the up-regulation of cyclin D1, cyclin E, cyclin A2, E2F2 and in part E2F3. Finally, in the control cells IHH and hPSC-H, BZB effect on cell vitality is not irrelevant, a fact correlated to the cellular proliferation rate. Thus, BZB effect on healthy liver tissue may not be entirely negligible hence caution should be exercised in its use in liver regeneration processes.
Conclusion
For the first time we prove the functional involvement of the Pin1-E2F1 axis in the anti-proliferative effect of BZB indicating Pin1-E2F as an attractive target to control HCC cell growth.
Caccavo, Diego; Cascone, Sara; Lamberti, Gaetano; Barba, Anna Angela
Controlled drug release from hydrogel-based matrices: Experiments and modeling. Journal Article
In: International journal of pharmaceutics, vol. 486, no. 1-2, pp. 144–152, 2015, ISSN: 1873-3476.
Abstract | Links | BibTeX | Tags: Hydrogel Characterization, Hydrogel Modeling, Hydrogels, Modeling, Texture analysis, Transport phenomena, Water uptake
@article{Caccavo2015a,
title = {Controlled drug release from hydrogel-based matrices: Experiments and modeling.},
author = { Diego Caccavo and Sara Cascone and Gaetano Lamberti and Anna Angela Barba},
url = {http://www.sciencedirect.com/science/article/pii/S0378517315002707},
doi = {10.1016/j.ijpharm.2015.03.054},
issn = {1873-3476},
year = {2015},
date = {2015-03-01},
journal = {International journal of pharmaceutics},
volume = {486},
number = {1-2},
pages = {144--152},
abstract = {Controlled release by oral administration is mainly achieved by pharmaceuticals based on hydrogels. Once swallowed, a matrix made of hydrogels experiences water up-take, swelling, drug dissolution and diffusion, polymer erosion. The detailed understanding and quantification of such a complex behavior is a mandatory prerequisite to the design of novel pharmaceuticals for controlled oral delivery. In this work, the behavior of hydrogel-based matrices has been investigated by means of several experimental techniques previously pointed out (gravimetric, and based on texture analysis); and then all the observed features were mathematically described using a physical model, defined and recently improved by our research group (based on balance equations, rate equations and swelling predictions). The agreement between the huge set of experimental data and the detailed calculations by the model is good, confirming the validity of both the experimental and the theoretical approaches.},
keywords = {Hydrogel Characterization, Hydrogel Modeling, Hydrogels, Modeling, Texture analysis, Transport phenomena, Water uptake},
pubstate = {published},
tppubtype = {article}
}
Controlled release by oral administration is mainly achieved by pharmaceuticals based on hydrogels. Once swallowed, a matrix made of hydrogels experiences water up-take, swelling, drug dissolution and diffusion, polymer erosion. The detailed understanding and quantification of such a complex behavior is a mandatory prerequisite to the design of novel pharmaceuticals for controlled oral delivery. In this work, the behavior of hydrogel-based matrices has been investigated by means of several experimental techniques previously pointed out (gravimetric, and based on texture analysis); and then all the observed features were mathematically described using a physical model, defined and recently improved by our research group (based on balance equations, rate equations and swelling predictions). The agreement between the huge set of experimental data and the detailed calculations by the model is good, confirming the validity of both the experimental and the theoretical approaches.
Paolino, Donatella; Licciardi, Mariano; Cella, Christian; Giammona, Gaetano; Fresta, Massimo; Cavallaro, Gennara
Bisphosphonate–polyaspartamide conjugates as bone targeted drug delivery systems Journal Article
In: Journal of Materials Chemistry B, vol. 3, pp. 250-259, 2015.
Abstract | Links | BibTeX | Tags:
@article{Paolino2015,
title = { Bisphosphonate\textendashpolyaspartamide conjugates as bone targeted drug delivery systems},
author = {Donatella Paolino and Mariano Licciardi and Christian Cella and Gaetano Giammona and Massimo Fresta and Gennara Cavallaro},
url = {http://pubs.rsc.org/en/content/articlelanding/tb/2015/c4tb00955j#!divAbstract},
doi = {10.1039/C4TB00955J },
year = {2015},
date = {2015-03-01},
journal = {Journal of Materials Chemistry B},
volume = {3},
pages = {250-259},
abstract = {Poly-hydroxy-aspartamide was used as a backbone to synthesize bisphosphonate derivatives thus achieving macromolecular carriers to be potentially used as targeting agents for bone drug delivery. Molecules bearing bisphosphonate groups, such as aminobisphosphonate (ABP) and neridronate (NRD), have been conjugated to polyaspartamide (α,β-poly(N-2-hydroxyethyl)-DL-aspartamide, PHEA), with or without a spacer (succinic acid or 6-aminocaproic acid) thus obtaining PHEA-succinate-ABP and PHEA-caproylcarbamate-ABP and PHEA-ABP and PHEA-NRD, respectively. Bisphosphonate\textendashpolymer conjugates were physico-chemically characterized using size exclusion chromatography and 1H-NMR; and their in vitro and ex vivo affinity for bone tissue has been further tested using the hydroxylapatite and rabbit bone binding assays, respectively. In vivo studies were carried out using rats to evaluate the biodistribution features of bisphosphonate\textendashpolymer conjugates in comparison with the starting PHEA. In vivo findings evidenced a suitable selectivity of bisphosphonate\textendashpolymer conjugates toward the bone tissues also as a function of time.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Poly-hydroxy-aspartamide was used as a backbone to synthesize bisphosphonate derivatives thus achieving macromolecular carriers to be potentially used as targeting agents for bone drug delivery. Molecules bearing bisphosphonate groups, such as aminobisphosphonate (ABP) and neridronate (NRD), have been conjugated to polyaspartamide (α,β-poly(N-2-hydroxyethyl)-DL-aspartamide, PHEA), with or without a spacer (succinic acid or 6-aminocaproic acid) thus obtaining PHEA-succinate-ABP and PHEA-caproylcarbamate-ABP and PHEA-ABP and PHEA-NRD, respectively. Bisphosphonate–polymer conjugates were physico-chemically characterized using size exclusion chromatography and 1H-NMR; and their in vitro and ex vivo affinity for bone tissue has been further tested using the hydroxylapatite and rabbit bone binding assays, respectively. In vivo studies were carried out using rats to evaluate the biodistribution features of bisphosphonate–polymer conjugates in comparison with the starting PHEA. In vivo findings evidenced a suitable selectivity of bisphosphonate–polymer conjugates toward the bone tissues also as a function of time.
Caccavo, Diego; Cascone, Sara; Lamberti, Gaetano; Barba, Anna Angela
Modeling the Drug Release from Hydrogel-Based Matrices Journal Article
In: Molecular Pharmaceutics, vol. 12, no. 2, pp. 474–483, 2015, ISSN: 1543-8384.
Links | BibTeX | Tags: Hydrogel Modeling
@article{Caccavo2015c,
title = {Modeling the Drug Release from Hydrogel-Based Matrices},
author = { Diego Caccavo and Sara Cascone and Gaetano Lamberti and Anna Angela Barba},
url = {http://pubs.acs.org/doi/abs/10.1021/mp500563n},
doi = {10.1021/mp500563n},
issn = {1543-8384},
year = {2015},
date = {2015-02-01},
journal = {Molecular Pharmaceutics},
volume = {12},
number = {2},
pages = {474--483},
publisher = {American Chemical Society},
chapter = {474},
keywords = {Hydrogel Modeling},
pubstate = {published},
tppubtype = {article}
}
Barba, Anna Angela; Dalmoro, Annalisa; D'Amore, Matteo; Lamberti, Gaetano
Liposoluble vitamin encapsulation in shell–core microparticles produced by ultrasonic atomization and microwave stabilization Journal Article
In: LWT - Food Science and Technology, vol. 64, no. 1, pp. 149–156, 2015, ISSN: 00236438.
Abstract | Links | BibTeX | Tags: drug delivery, Micro and Nano Vectors, Microwave drying, Shell{–}core microparticles, Ultrasonic energy, Vitamins
@article{Barba2015a,
title = {Liposoluble vitamin encapsulation in shell\textendashcore microparticles produced by ultrasonic atomization and microwave stabilization},
author = { Anna Angela Barba and Annalisa Dalmoro and Matteo D'Amore and Gaetano Lamberti},
url = {http://www.sciencedirect.com/science/article/pii/S002364381500403X},
doi = {10.1016/j.lwt.2015.05.040},
issn = {00236438},
year = {2015},
date = {2015-01-01},
journal = {LWT - Food Science and Technology},
volume = {64},
number = {1},
pages = {149--156},
abstract = {Encapsulation may protect unstable, fat soluble vitamins such as vitamin D2 (ergocalciferol). However, encapsulation by the solvent extraction and/or evaporation techniques can require toxic organic solvents, which greatly increase processing costs. The objective of this study was to evaluate the effect on ergocalciferol encapsulation by a combination of the ionic gelation method with the ultrasonic atomization and microwave drying. Optimization of manufacturing parameters included the addition of pluronic-F127 to the core solution at 1.5% w/w to increase the encapsulation efficiency to nearly 92%, greatly improving performance compared to Tween 80 at 0.5% w/w. Microwave treatment at 230 W promoted the recovery of 100% of the ergocalciferol and reduced drying times to about 30 min, while 690 W degraded 40% of the D2. In contrast, the conventional heating degraded 17% of the ergocalciferol during 12 h of processing. By all the applied methods, microparticles were produced with similar gastoresistance properties of less than 10% release at pH of 1.0, to nearly 100% release at pH of 6.8 and 240 min of dissolution. Analysis showed limited ergocalciferol degradation after 5 months of storage.},
keywords = {drug delivery, Micro and Nano Vectors, Microwave drying, Shell{\textendash}core microparticles, Ultrasonic energy, Vitamins},
pubstate = {published},
tppubtype = {article}
}
Encapsulation may protect unstable, fat soluble vitamins such as vitamin D2 (ergocalciferol). However, encapsulation by the solvent extraction and/or evaporation techniques can require toxic organic solvents, which greatly increase processing costs. The objective of this study was to evaluate the effect on ergocalciferol encapsulation by a combination of the ionic gelation method with the ultrasonic atomization and microwave drying. Optimization of manufacturing parameters included the addition of pluronic-F127 to the core solution at 1.5% w/w to increase the encapsulation efficiency to nearly 92%, greatly improving performance compared to Tween 80 at 0.5% w/w. Microwave treatment at 230 W promoted the recovery of 100% of the ergocalciferol and reduced drying times to about 30 min, while 690 W degraded 40% of the D2. In contrast, the conventional heating degraded 17% of the ergocalciferol during 12 h of processing. By all the applied methods, microparticles were produced with similar gastoresistance properties of less than 10% release at pH of 1.0, to nearly 100% release at pH of 6.8 and 240 min of dissolution. Analysis showed limited ergocalciferol degradation after 5 months of storage.
Abbiati, Roberto Andrea; Cavallaro, Gennara; Craparo, Emanuela Fabiola; Manca, Davide
Sorafenib in mice - A Pharmacokinetic study Journal Article
In: Chemical Engineering Transactions, vol. 43, pp. 283-288, 2015, ISBN: 978-88-95608-34-1.
Abstract | Links | BibTeX | Tags: Pharmacokinetics
@article{Abbiati2015283,
title = {Sorafenib in mice - A Pharmacokinetic study},
author = {Roberto Andrea Abbiati and Gennara Cavallaro and Emanuela Fabiola Craparo and Davide Manca },
url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-84945909799\&partnerID=40\&md5=b585516a5e98e400072d7e0bd03a95b0},
doi = {10.3303/CET1543048},
isbn = {978-88-95608-34-1},
year = {2015},
date = {2015-01-01},
journal = {Chemical Engineering Transactions},
volume = {43},
pages = {283-288},
abstract = {Pharmacokinetic models are applied to determine the drug distribution in the organism with respect to a given administration. Models based on body anatomy and physiology can provide an accurate description of drug concentrations reached in specific organs and tissues of mammals. This article proposes a model based on mammalian anatomy and physiology to predict the biodistribution in mice of sorafenib, an anti-cancer drug, with specific attention to the concentration reached in the liver, as that is the action site in case of hepatocellular carcinoma treatment. The model reveals a close correspondence respect to experimental concentration data in the organism and also assesses with good fidelity the enterohepatic circulation, a phenomenon occurring at the liver-intestine level and that strongly characterizes sorafenib distribution. },
keywords = {Pharmacokinetics},
pubstate = {published},
tppubtype = {article}
}
Pharmacokinetic models are applied to determine the drug distribution in the organism with respect to a given administration. Models based on body anatomy and physiology can provide an accurate description of drug concentrations reached in specific organs and tissues of mammals. This article proposes a model based on mammalian anatomy and physiology to predict the biodistribution in mice of sorafenib, an anti-cancer drug, with specific attention to the concentration reached in the liver, as that is the action site in case of hepatocellular carcinoma treatment. The model reveals a close correspondence respect to experimental concentration data in the organism and also assesses with good fidelity the enterohepatic circulation, a phenomenon occurring at the liver-intestine level and that strongly characterizes sorafenib distribution.
Abbiati, Roberto Andrea; Lamberti, Gaetano; Barba, Anna Angela; Grassi, Mario; Manca, Davide
A PSE approach to patient-individualized physiologically-based pharmacokinetic modeling Journal Article
In: 12th International Symposium on Process Systems Engineering and 25th European Symposium on Computer Aided Process Engineering, vol. 37, pp. 77–84, 2015, ISSN: 15707946.
Abstract | Links | BibTeX | Tags: Complexity reduction, In silico, Lumping, Personalization, Pharmacokinetics, Physiologically-Based modeling, Remifentanil
@article{Abbiati2015a,
title = {A PSE approach to patient-individualized physiologically-based pharmacokinetic modeling},
author = { Roberto Andrea Abbiati and Gaetano Lamberti and Anna Angela Barba and Mario Grassi and Davide Manca},
url = {http://www.sciencedirect.com/science/article/pii/B9780444635785500104},
doi = {10.1016/B978-0-444-63578-5.50010-4},
issn = {15707946},
year = {2015},
date = {2015-01-01},
journal = {12th International Symposium on Process Systems Engineering and 25th European Symposium on Computer Aided Process Engineering},
volume = {37},
pages = {77--84},
publisher = {Elsevier},
series = {Computer Aided Chemical Engineering},
abstract = {Pharmacokinetic modeling allows predicting the drug concentration reached in the blood as a consequence of a specific administration. When such models are based on mammalian anatomy and physiology it is possible to theoretically evaluate the drug concentration in every organ and tissue of the body. This is the case of the so-called physiologically based pharmacokinetic (PBPK) models. This paper proposes and validates a procedure to deploy PBPK models based on a simplified, although highly consistent with human anatomy and physiology, approach. The article aims at reducing the pharmacokinetic variations among subjects due to inter-individual variability, by applying a strategy to individualize some model parameters. The simulation results are validated respect to experimental data on remifentanil.},
keywords = {Complexity reduction, In silico, Lumping, Personalization, Pharmacokinetics, Physiologically-Based modeling, Remifentanil},
pubstate = {published},
tppubtype = {article}
}
Pharmacokinetic modeling allows predicting the drug concentration reached in the blood as a consequence of a specific administration. When such models are based on mammalian anatomy and physiology it is possible to theoretically evaluate the drug concentration in every organ and tissue of the body. This is the case of the so-called physiologically based pharmacokinetic (PBPK) models. This paper proposes and validates a procedure to deploy PBPK models based on a simplified, although highly consistent with human anatomy and physiology, approach. The article aims at reducing the pharmacokinetic variations among subjects due to inter-individual variability, by applying a strategy to individualize some model parameters. The simulation results are validated respect to experimental data on remifentanil.
Gioia, Sante Di; Trapani, Adriana; Carbone, Annalucia; Castellani, Stefano; Colombo, Carla; Trapani, Giuseppe; Conese, Massimo
Cationic polymers for gene delivery into mesenchymal stem cells as a novel approach to regenerative medicine Book Chapter
In: RSC Polymer Chemistry Series No. 12 “Cationic Polymers in Regenerative Medicine”, Chapter 15, pp. 386-437, The Royal Society of Chemistry, London, 2015, ISBN: 978-1-84973-937-5.
Abstract | Links | BibTeX | Tags:
@inbook{Gioia2015b,
title = {Cationic polymers for gene delivery into mesenchymal stem cells as a novel approach to regenerative medicine},
author = {Sante Di Gioia and Adriana Trapani and Annalucia Carbone and Stefano Castellani and Carla Colombo and Giuseppe Trapani and Massimo Conese },
url = {http://pubs.rsc.org/en/content/chapter/bk9781849739375-00386/978-1-84973-937-5#!divabstract},
doi = {10.1039/9781782620105-00386},
isbn = { 978-1-84973-937-5},
year = {2015},
date = {2015-01-01},
booktitle = {RSC Polymer Chemistry Series No. 12 “Cationic Polymers in Regenerative Medicine”},
pages = {386-437},
publisher = {The Royal Society of Chemistry},
address = {London},
chapter = {15},
abstract = {Many studies have demonstrated the importance of mesenchymal stem cells (MSCs) in regenerative medicine and tissue engineering. Indeed, MSCs may be widely used to repair or regenerate mesenchymal tissues, such as bone, cartilage, muscle or tendon. Scientific evidence supports the fact that MSCs can act during tissue repair, not only by simple engraftment and differentiation but also by releasing mediators which can function as paracrine factors, or modulating signaling involving cell\textendashcell contact. Recently, gene delivery approaches have been used to potentiate the ability of MSCs in repairing tissues. Cationic polymers are versatile systems that constitute biomaterials which aid in regenerative medicine and tissue engineering based on MSCs by delivering therapeutic genes to these stem cells and helping them in the adhesion and proliferation processes. In this chapter we revise the current knowledge about cationic polymer-mediated gene transfer into MSCs and pre-clinical applications for angiogenesis, chondrogenesis and osteogenesis. Owing to the development of biodegradable and biocompatible cationic polymers with reduced toxicity, it is envisioned that the combination of cationic polymers and MSCs will open novel avenues in the regeneration of tissues and even complex organs.},
keywords = {},
pubstate = {published},
tppubtype = {inbook}
}
Many studies have demonstrated the importance of mesenchymal stem cells (MSCs) in regenerative medicine and tissue engineering. Indeed, MSCs may be widely used to repair or regenerate mesenchymal tissues, such as bone, cartilage, muscle or tendon. Scientific evidence supports the fact that MSCs can act during tissue repair, not only by simple engraftment and differentiation but also by releasing mediators which can function as paracrine factors, or modulating signaling involving cell–cell contact. Recently, gene delivery approaches have been used to potentiate the ability of MSCs in repairing tissues. Cationic polymers are versatile systems that constitute biomaterials which aid in regenerative medicine and tissue engineering based on MSCs by delivering therapeutic genes to these stem cells and helping them in the adhesion and proliferation processes. In this chapter we revise the current knowledge about cationic polymer-mediated gene transfer into MSCs and pre-clinical applications for angiogenesis, chondrogenesis and osteogenesis. Owing to the development of biodegradable and biocompatible cationic polymers with reduced toxicity, it is envisioned that the combination of cationic polymers and MSCs will open novel avenues in the regeneration of tissues and even complex organs.
Ferreira, J. A.; Grassi, Mario; Gudiño, E.; de Oliveira, P.
A new look to non-Fickian diffusion Journal Article
In: Applied Mathematical Modelling, vol. 39, no. 1, pp. 194–204, 2015.
Abstract | Links | BibTeX | Tags:
@article{Ferreira2015,
title = {A new look to non-Fickian diffusion},
author = {J.A. Ferreira and Mario Grassi and E. Gudi\~{n}o and P. {de Oliveira}},
url = {http://www.sciencedirect.com/science/article/pii/S0307904X14002923},
doi = {10.1016/j.apm.2014.05.030},
year = {2015},
date = {2015-01-01},
journal = {Applied Mathematical Modelling},
volume = {39},
number = {1},
pages = {194\textendash204},
abstract = {In this paper a non linear mathematical model to describe absorption phenomena in polymers is proposed. The model is established assuming that the diffusing penetrant causes a deformation which induces a viscoelastic stress responsible for a convective field. This convective field is defined to represent an opposition of the polymer to the Fickian diffusion. Several numerical examples show the effectiveness of the model.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In this paper a non linear mathematical model to describe absorption phenomena in polymers is proposed. The model is established assuming that the diffusing penetrant causes a deformation which induces a viscoelastic stress responsible for a convective field. This convective field is defined to represent an opposition of the polymer to the Fickian diffusion. Several numerical examples show the effectiveness of the model.
2014
Sardo, Carla; Nottelet, Benjamin; Triolo, Daniela; Giammona, Gaetano; Garric, Xavier; Lavigne, Jean-Philippe; Cavallaro, Gennara; Coudane, Jean
When Functionalization of PLA Surfaces Meets Thiol–Yne Photochemistry: Case Study with Antibacterial Polyaspartamide Derivatives Journal Article
In: Biomacromolecules, vol. 15, no. 11, pp. 4351–4362, 2014.
Abstract | Links | BibTeX | Tags:
@article{Sardo2014,
title = {When Functionalization of PLA Surfaces Meets Thiol\textendashYne Photochemistry: Case Study with Antibacterial Polyaspartamide Derivatives},
author = {Carla Sardo and Benjamin Nottelet and Daniela Triolo and Gaetano Giammona and Xavier Garric and Jean-Philippe Lavigne and Gennara Cavallaro and Jean Coudane},
url = {http://pubs.acs.org/doi/abs/10.1021/bm5013772},
doi = {10.1021/bm5013772},
year = {2014},
date = {2014-10-16},
journal = {Biomacromolecules},
volume = {15},
number = {11},
pages = {4351\textendash4362},
abstract = {In this work we wish to report on the covalent functionalization of polylactide (PLA) surfaces by photoradical thiol\textendashyne to yield antibacterial surfaces. At first, hydrophilic and hydrophobic thiol fluorescent probes are synthesized and used to study and optimize the conditions of ligation on alkyne-PLA surfaces. In a second part, a new antibacterial polyaspartamide copolymer is covalently grafted. The covalent surface modification and the density of surface functionalization are evaluated by SEC and XPS analyses. No degradation of PLA chains is observed, whereas covalent grafting is confirmed by the presence of S2p and N1s signals. Antiadherence and antibiofilm activities are assessed against four bacterial strains, including Gram-negative and Gram-positive bacteria. A strong activity is observed with adherence reduction factors superior to 99.98% and biofilm formation decreased by 80%. Finally, in vitro cytocompatibility tests of the antibacterial surfaces are performed with L929 murine fibroblasts and show cell viability without promoting proliferation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In this work we wish to report on the covalent functionalization of polylactide (PLA) surfaces by photoradical thiol–yne to yield antibacterial surfaces. At first, hydrophilic and hydrophobic thiol fluorescent probes are synthesized and used to study and optimize the conditions of ligation on alkyne-PLA surfaces. In a second part, a new antibacterial polyaspartamide copolymer is covalently grafted. The covalent surface modification and the density of surface functionalization are evaluated by SEC and XPS analyses. No degradation of PLA chains is observed, whereas covalent grafting is confirmed by the presence of S2p and N1s signals. Antiadherence and antibiofilm activities are assessed against four bacterial strains, including Gram-negative and Gram-positive bacteria. A strong activity is observed with adherence reduction factors superior to 99.98% and biofilm formation decreased by 80%. Finally, in vitro cytocompatibility tests of the antibacterial surfaces are performed with L929 murine fibroblasts and show cell viability without promoting proliferation.
Conference Proceedings
Read More2015
Caccavo, Diego; Cascone, Sara; Bochicchio, Sabrina; Lamberti, Gaetano; Dalmoro, Annalisa; Barba, Anna Angela
Hydrogels-based matrices behavior: experimental and modeling description Proceedings Article
In: 42nd Annual Meeting & Exposition of the Controlled Release Society, 2015.
BibTeX | Tags:
@inproceedings{Caccavo:aa,
title = {Hydrogels-based matrices behavior: experimental and modeling description},
author = {Diego Caccavo and Sara Cascone and Sabrina Bochicchio and Gaetano Lamberti and Annalisa Dalmoro and Anna Angela Barba},
year = {2015},
date = {2015-07-26},
booktitle = {42nd Annual Meeting \& Exposition of the Controlled Release Society},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Dalmoro, Annalisa; Bochicchio, Sabrina; Lamberti, Gaetano; Sala, Marina; Campiglia, Pietro
Ultrasonic assisted production of nanoliposomes as peptide delivery vectors Proceedings Article
In: 42nd Annual Meeting & Exposition of the Controlled Release Society, 2015.
BibTeX | Tags:
@inproceedings{Dalmoro:ab,
title = {Ultrasonic assisted production of nanoliposomes as peptide delivery vectors},
author = { Annalisa Dalmoro and Sabrina Bochicchio and Gaetano Lamberti and Marina Sala and Pietro Campiglia},
year = {2015},
date = {2015-07-26},
booktitle = {42nd Annual Meeting \& Exposition of the Controlled Release Society},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Dalmoro, Annalisa; Cavallaro, Gennara; Craparo, Emanuela Fabiola; Sardo, Carla; Lamberti, Gaetano; Barba, Anna Angela
Production of polyaspartamide based nanovectors by the method of solvent evaporation from ultrasound-made multiple emulsions Proceedings Article
In: 42nd Annual Meeting & Exposition of the Controlled Release Society, 2015.
BibTeX | Tags:
@inproceedings{Dalmoro:ac,
title = {Production of polyaspartamide based nanovectors by the method of solvent evaporation from ultrasound-made multiple emulsions},
author = { Annalisa Dalmoro and Gennara Cavallaro and Emanuela Fabiola Craparo and Carla Sardo and Gaetano Lamberti and Anna Angela Barba},
year = {2015},
date = {2015-07-26},
booktitle = {42nd Annual Meeting \& Exposition of the Controlled Release Society},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Grassi, Mario; Abrami, Michela; Abbiati, Roberto Andrea; Posocco, Bianca; Barba, Anna Angela; Lamberti, Gaetano; Manca, Davide; Voinovich, Dario; Grassi, Gabriele
MASS BALANCE: AN OLD CONCEPT FOR THE NEW CHALLENGES PROPOSED BY PERSONALIZED MEDICINE Proceedings Article
In: The 42nd Annual Meeting & Exposition of the Controlled Release Society, 2015.
BibTeX | Tags:
@inproceedings{Grassi:aa,
title = {MASS BALANCE: AN OLD CONCEPT FOR THE NEW CHALLENGES PROPOSED BY PERSONALIZED MEDICINE},
author = { Mario Grassi and Michela Abrami and Roberto Andrea Abbiati and Bianca Posocco and Anna Angela Barba and Gaetano Lamberti and Davide Manca and Dario Voinovich and Gabriele Grassi},
year = {2015},
date = {2015-07-26},
booktitle = {The 42nd Annual Meeting \& Exposition of the Controlled Release Society},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Bochicchio, Sabrina; Dalmoro, Annalisa; Cascone, Sara; Lamberti, Gaetano; Barba, Anna Angela
dsDNA encapsulating in nanoliposomal structures towards gene therapies Proceedings Article
In: 1st International Congress οf Controlled Release Society - Greek Local Chapter, 2015.
BibTeX | Tags:
@inproceedings{Bochicchio:ab,
title = {dsDNA encapsulating in nanoliposomal structures towards gene therapies},
author = { Sabrina Bochicchio and Annalisa Dalmoro and Sara Cascone and Gaetano Lamberti and Anna Angela Barba},
year = {2015},
date = {2015-05-27},
booktitle = {1st International Congress οf Controlled Release Society - Greek Local Chapter},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Cascone, Sara; Piazza, Ornella; Lamberti, Gaetano; Barba, Anna Angela; Abbiati, Roberto Andrea; Manca, Davide
PHARMACOKINETICS OF REMIFENTANIL: METABOLISM AND MODELING Proceedings Article
In: 1st International Congress of Controlled Release Society - Greek Local Chapter, 2015.
BibTeX | Tags: In silico, Pharmacokinetics
@inproceedings{Cascone:aa,
title = {PHARMACOKINETICS OF REMIFENTANIL: METABOLISM AND MODELING},
author = {Sara Cascone and Ornella Piazza and Gaetano Lamberti and Anna Angela Barba and Roberto Andrea Abbiati and Davide Manca},
year = {2015},
date = {2015-05-27},
booktitle = {1st International Congress of Controlled Release Society - Greek Local Chapter},
keywords = {In silico, Pharmacokinetics},
pubstate = {published},
tppubtype = {inproceedings}
}
Dalmoro, Annalisa; Cascone, Sara; Lamberti, Gaetano; Barba, Anna Angela
Enteric dosage systems by ultrasonic atomization of natural biopolymers coupled to polyelectrolyte complexation Proceedings Article
In: 1st International Congress οf Controlled Release Society - Greek Local Chapter, 2015.
BibTeX | Tags:
@inproceedings{Dalmoro:af,
title = {Enteric dosage systems by ultrasonic atomization of natural biopolymers coupled to polyelectrolyte complexation},
author = { Annalisa Dalmoro and Sara Cascone and Gaetano Lamberti and Anna Angela Barba},
year = {2015},
date = {2015-05-27},
booktitle = {1st International Congress οf Controlled Release Society - Greek Local Chapter},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Abbiati, Roberto Andrea; Manca, Davide
A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR SORAFENIB BIODISTRIBUTION IN MAMMALIANS Proceedings Article
In: CAPE Forum 2015, 2015.
BibTeX | Tags:
@inproceedings{Abbiati:ab,
title = {A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR SORAFENIB BIODISTRIBUTION IN MAMMALIANS},
author = { Roberto Andrea Abbiati and Davide Manca},
year = {2015},
date = {2015-04-27},
booktitle = {CAPE Forum 2015},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Cascone, Sara; Barba, Anna Angela; Lamberti, Gaetano; Marra, Francesco; Titomanlio, Giuseppe
Bioaccessibility of active principles: an in-vitro reproduction of human physiology Proceedings Article
In: Proccedings of 4th International Conference on Food Digestion, pp. 1–1, 4th International Conference on Food Digestion, Naples, Italy, 2015.
BibTeX | Tags: In vitro, Pharmacokinetics
@inproceedings{cascone2015b,
title = {Bioaccessibility of active principles: an in-vitro reproduction of human physiology},
author = { Sara Cascone and Anna Angela Barba and Gaetano Lamberti and Francesco Marra and Giuseppe Titomanlio},
year = {2015},
date = {2015-03-01},
booktitle = {Proccedings of 4th International Conference on Food Digestion},
pages = {1--1},
publisher = {4th International Conference on Food Digestion},
address = {Naples, Italy},
keywords = {In vitro, Pharmacokinetics},
pubstate = {published},
tppubtype = {inproceedings}
}
2014
Dalmoro, Annalisa; Bochicchio, Sabrina; Apicella, Pietro; D'Amore, Matteo; Barba, Anna Angela
Micro and nano structured vectors for the drug delivery Proceedings Article
In: 21st International Congress of Chemical and Process Engineering CHISA 2014, 2014.
BibTeX | Tags:
@inproceedings{Dalmoro:ae,
title = {Micro and nano structured vectors for the drug delivery},
author = { Annalisa Dalmoro and Sabrina Bochicchio and Pietro Apicella and Matteo D'Amore and Anna Angela Barba},
year = {2014},
date = {2014-08-23},
booktitle = {21st International Congress of Chemical and Process Engineering CHISA 2014},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Cascone, Sara; Caccavo, Diego; Lamberti, Gaetano; Titomanlio, Giuseppe; Barba, Anna Angela
In-vitro models of the gastro-intestinal tract for pharmaceutical and nutritional purposes Proceedings Article
In: Proceedings of CHISA 2014/PRES 2014, pp. 2–2, CHISA 2014, Prague, Czech Republic, 2014.
BibTeX | Tags: In vitro, Pharmacokinetics
@inproceedings{s.2014-4,
title = {In-vitro models of the gastro-intestinal tract for pharmaceutical and nutritional purposes},
author = { Sara Cascone and Diego Caccavo and Gaetano Lamberti and Giuseppe Titomanlio and Anna Angela Barba},
year = {2014},
date = {2014-08-01},
booktitle = {Proceedings of CHISA 2014/PRES 2014},
pages = {2--2},
publisher = {CHISA 2014},
address = {Prague, Czech Republic},
keywords = {In vitro, Pharmacokinetics},
pubstate = {published},
tppubtype = {inproceedings}
}
Caccavo, Diego; Cascone, Sara; Lamberti, Gaetano; Barba, Anna Angela
Testing and modelling of hydrogels behavior for pharmaceutical and biomedical applications Proceedings Article
In: Proceedings of CHISA 2014, pp. 1–1, CHISA 2014, Prague, Czech Republic, 2014.
BibTeX | Tags: Hydrogel Characterization, Hydrogel Modeling
@inproceedings{d.2014,
title = {Testing and modelling of hydrogels behavior for pharmaceutical and biomedical applications},
author = { Diego Caccavo and Sara Cascone and Gaetano Lamberti and Anna Angela Barba},
year = {2014},
date = {2014-08-01},
booktitle = {Proceedings of CHISA 2014},
pages = {1--1},
publisher = {CHISA 2014},
address = {Prague, Czech Republic},
keywords = {Hydrogel Characterization, Hydrogel Modeling},
pubstate = {published},
tppubtype = {inproceedings}
}
Abbiati, Roberto Andrea; Lamberti, Gaetano; Trotta, Francesco; Grassi, Mario; Manca, Davide
MATHEMATICS APPLIED TO PHARMACOKINETICS A PHYSIOLOGICALLY BASED MODEL Proceedings Article
In: CAPE Forum 2014, 2014.
BibTeX | Tags:
@inproceedings{Abbiati:aa,
title = {MATHEMATICS APPLIED TO PHARMACOKINETICS A PHYSIOLOGICALLY BASED MODEL},
author = {Roberto Andrea Abbiati and Gaetano Lamberti and Francesco Trotta and Mario Grassi and Davide Manca},
year = {2014},
date = {2014-05-12},
booktitle = {CAPE Forum 2014},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Bochicchio, Sabrina; Dalmoro, Annalisa; Grassi, Gabriele; Lamberti, Gaetano; Barba, Anna Angela
Vectors for vitamins delivery: nano liposomes production via utrasonic irradiation Proceedings Article
In: 13th European Symposium on Controlled Drug Delivery, 2014.
BibTeX | Tags:
@inproceedings{Bochicchio:aa,
title = {Vectors for vitamins delivery: nano liposomes production via utrasonic irradiation},
author = { Sabrina Bochicchio and Annalisa Dalmoro and Gabriele Grassi and Gaetano Lamberti and Anna Angela Barba},
year = {2014},
date = {2014-04-16},
booktitle = {13th European Symposium on Controlled Drug Delivery},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Dalmoro, Annalisa; Bochicchio, Sabrina; Lamberti, Gaetano; D'Amore, Matteo; Barba, Anna Angela
Vectors for vitamins delivery: shell-core microparticles production via ultrasonic atomization and microwave stabilization Proceedings Article
In: 13th European Symposium on Controlled Drug Delivery, 2014.
BibTeX | Tags:
@inproceedings{Dalmoro:aa,
title = {Vectors for vitamins delivery: shell-core microparticles production via ultrasonic atomization and microwave stabilization},
author = { Annalisa Dalmoro and Sabrina Bochicchio and Gaetano Lamberti and Matteo D'Amore and Anna Angela Barba},
year = {2014},
date = {2014-04-16},
booktitle = {13th European Symposium on Controlled Drug Delivery},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Cascone, Sara; Lamberti, Gaetano; Marra, Francesco; Titomanlio, Giuseppe; Barba, Anna Angela
AN IN VITRO MODEL TO REPRODUCE THE MECHANICS AND THE ABSORPTION IN THE GASTROINTESTINAL TRACT Proceedings Article
In: 13th European Symposium on Controlled Drug Delivery, pp. 1–2, ESCDD 2014, Egmond aan Zee, The Netherlands, 2014.
BibTeX | Tags: In vitro, Pharmacokinetics
@inproceedings{s.2014-1,
title = {AN IN VITRO MODEL TO REPRODUCE THE MECHANICS AND THE ABSORPTION IN THE GASTROINTESTINAL TRACT},
author = { Sara Cascone and Gaetano Lamberti and Francesco Marra and Giuseppe Titomanlio and Anna Angela Barba},
year = {2014},
date = {2014-04-01},
booktitle = {13th European Symposium on Controlled Drug Delivery},
pages = {1--2},
publisher = {ESCDD 2014},
address = {Egmond aan Zee, The Netherlands},
keywords = {In vitro, Pharmacokinetics},
pubstate = {published},
tppubtype = {inproceedings}
}
Cascone, Sara; Caccavo, Diego; Lamberti, Gaetano; Titomanlio, Giuseppe; D'Amore, Matteo; Barba, Anna Angela
MODELING THE BEHAVIOR OF SWELLABLE HYDROGELS-BASED MATRICES FOR PHARMACEUTICAL APPLICATIONS Proceedings Article
In: 13th European Symposium on Controlled Drug Delivery, pp. 3–4, ESCDD 2014, Egmond aan Zee, The Netherlands, 2014.
BibTeX | Tags: Hydrogel Modeling
@inproceedings{s.2014,
title = {MODELING THE BEHAVIOR OF SWELLABLE HYDROGELS-BASED MATRICES FOR PHARMACEUTICAL APPLICATIONS},
author = { Sara Cascone and Diego Caccavo and Gaetano Lamberti and Giuseppe Titomanlio and Matteo D'Amore and Anna Angela Barba},
year = {2014},
date = {2014-04-01},
booktitle = {13th European Symposium on Controlled Drug Delivery},
pages = {3--4},
publisher = {ESCDD 2014},
address = {Egmond aan Zee, The Netherlands},
keywords = {Hydrogel Modeling},
pubstate = {published},
tppubtype = {inproceedings}
}
Barba, Anna Angela; Bochicchio, Sabrina; Dalmoro, Annalisa; Lamberti, Gaetano
Liposomal SUVs preparation by ultrasonic energy: a new approach based on a conventional technique Proceedings Article
In: 9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, 2014.
BibTeX | Tags:
@inproceedings{Barba:ab,
title = {Liposomal SUVs preparation by ultrasonic energy: a new approach based on a conventional technique},
author = { Anna Angela Barba and Sabrina Bochicchio and Annalisa Dalmoro and Gaetano Lamberti},
year = {2014},
date = {2014-03-31},
booktitle = {9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Barba, Anna Angela; Dalmoro, Annalisa; Orlando, Elena; Galzerano, Barbara; Lamberti, Gaetano; Grassi, Mario; Grassi, Gabriele
Pluronic F127- Alginate blends as gel-paving for coronary drug eluting stent Proceedings Article
In: 9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, 2014.
BibTeX | Tags:
@inproceedings{Barba:aa,
title = {Pluronic F127- Alginate blends as gel-paving for coronary drug eluting stent},
author = { Anna Angela Barba and Annalisa Dalmoro and Elena Orlando and Barbara Galzerano and Gaetano Lamberti and Mario Grassi and Gabriele Grassi},
year = {2014},
date = {2014-03-31},
booktitle = {9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Dalmoro, Annalisa; Feo, Giovanna; Costabile, Margherita; D'Amore, Matteo; Barba, Anna Angela
Microparticles production by a novel apparatus coupling ultrasonic atomization and microwave drying Proceedings Article
In: 9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, 2014.
BibTeX | Tags:
@inproceedings{Dalmoro:ad,
title = {Microparticles production by a novel apparatus coupling ultrasonic atomization and microwave drying},
author = { Annalisa Dalmoro and Giovanna Feo and Margherita Costabile and Matteo D'Amore and Anna Angela Barba},
year = {2014},
date = {2014-03-31},
booktitle = {9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Cascone, Sara; Lamberti, Gaetano; Titomanlio, Giuseppe
Simulation of gastrointestinal tract: mechanics and absorption Proceedings Article
In: Proceedings of PBP 2014, pp. 3–4, PBP 2014, Lisbon, Portugal, 2014.
BibTeX | Tags: In vitro, Pharmacokinetics
@inproceedings{s.2014-2,
title = {Simulation of gastrointestinal tract: mechanics and absorption},
author = { Sara Cascone and Gaetano Lamberti and Giuseppe Titomanlio},
year = {2014},
date = {2014-03-01},
booktitle = {Proceedings of PBP 2014},
pages = {3--4},
publisher = {PBP 2014},
address = {Lisbon, Portugal},
keywords = {In vitro, Pharmacokinetics},
pubstate = {published},
tppubtype = {inproceedings}
}
Cascone, Sara; Lamberti, Gaetano; Titomanlio, Giuseppe; D'Amore, Matteo; Barba, Anna Angela
The use of texture analysis for hydrogel water content measurements Proceedings Article
In: Proceedings of PBP 2014, pp. 1–2, PBP 2014, Lisbon, Portugal, 2014.
BibTeX | Tags:
@inproceedings{s.2014-3,
title = {The use of texture analysis for hydrogel water content measurements},
author = { Sara Cascone and Gaetano Lamberti and Giuseppe Titomanlio and Matteo D'Amore and Anna Angela Barba},
year = {2014},
date = {2014-03-01},
booktitle = {Proceedings of PBP 2014},
pages = {1--2},
publisher = {PBP 2014},
address = {Lisbon, Portugal},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Dissemination
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