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Title
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
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02. UNISA | Gaetano Lamberti | Read More
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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:
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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
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}
}
2016
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}
}
2015
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}
}
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}
}
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}
}
2014
Barba, Anna Angela; Lamberti, Gaetano; Rabbia, Luca; Grassi, Mario; Larobina, Domenico; Grassi, Gabriele
Modeling of the reticulation kinetics of alginate/pluronic blends for biomedical applications Journal Article
In: Materials Science and Engineering: C, vol. 37, pp. 327–331, 2014, ISSN: 09284931.
Abstract | Links | BibTeX | Tags: Alginate, Hydrogel Modeling, Modeling, Pluronic, Reticulation
@article{Barba2014b,
title = {Modeling of the reticulation kinetics of alginate/pluronic blends for biomedical applications},
author = { Anna Angela Barba and Gaetano Lamberti and Luca Rabbia and Mario Grassi and Domenico Larobina and Gabriele Grassi},
url = {http://www.sciencedirect.com/science/article/pii/S0928493114000423},
doi = {10.1016/j.msec.2014.01.034},
issn = {09284931},
year = {2014},
date = {2014-01-01},
journal = {Materials Science and Engineering: C},
volume = {37},
pages = {327--331},
abstract = {In this work, blends of alginate/pluronic (F127) for biomedical applications were investigated. In particular, the kinetics of alginate chain reticulation by bivalent cations was studied by experimental and modeling approaches. Two kinds of sodium alginate were tested to obtain hard gel films. The thicknesses of the reticulated alginate films were measured as function of the exposure time and of the reticulating copper (Cu2+) solution concentration. The kinetics was described by a proper model able to reproduce the experimental data. The model parameters, evaluated based on the measurements of thicknesses as function of Cu2+ concentration and exposure time, were further validated by comparing the prediction of the model with another set of independent measurement; here, the depletion of Cu2+ ions in the conditioning solution above the reacting gel is measured as function of time. The tuned model could be used in the description of the future applications of the blends.},
keywords = {Alginate, Hydrogel Modeling, Modeling, Pluronic, Reticulation},
pubstate = {published},
tppubtype = {article}
}
Conference Proceedings
Read More2014
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}
}
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}
}
Dissemination
I meeting 5-6 February 2013 – Trieste
Program:
Download the flier: I meeting PRIN
II meeting 27-29 September 2013 – Palermo
Program:
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III meeting 20-21 June 2014 – Ustica
Program:
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IV meeting 2-3 February 2015 – Milano
Program:
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V meeting 14-15 September 2015 – Salerno
Go to the dedicated page: Workshop – New trends in gene therapy
Program:
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VI meeting 24-25 May 2016 – Trieste
Flyer and program:
Download the flier: VI meeting PRIN