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|Issue Date: ||25-Feb-2016|
|Authors: ||Giglio, Valentina|
|Title: ||Biofunctionalized systems for drug discovery and delivery|
|Abstract: ||During this doctoral research work new potential drug delivery vehicles for targeted treatment of cancers were developed. For this purpose, both soft and hard materials were subject of study.
Firstly, the synthesis, the characterization and the biological evaluation of monomeric â-cyclodextrins functionalized with folic acid (FA) were the focus of this research. In particular, four new conjugates (CyD-FAs), both 3- and 6-functionalized â-CyDs (â-CyD3 and â-CyD6) linked to the á- or ã-carboxylic group of the FA were synthesized, isolated and fully characterized. Furthermore, the ability of these compounds to include the anticancer drug LA-12 and to deliver it selectively to FR (+) tumor cell lines was investigated.
Since the promising results obtained with these CyD-FA conjugates as carriers for LA-12, polymeric nanoparticles based on cross-linked cyclodextrins were designed for drug delivery purposes. These systems, offer the advantages of CyD-type complexation in a synergistic way, resulting more effective than the parent CyDs. In particular, CyD-based polymers and oligomers were synthesized, functionalized with FA and tested as delivery systems towards different hydrophobic anticancer or anti-inflammatory agents. Furthermore, for selected systems, the binding constants of the formed inclusion complexes were determined as well.
Concerning hard materials, mesoporous silica nanoparticles were investigated. A new disc-shaped mesoporous material, the nanodiscs (NDs), was synthesized, isolated and fully characterized. This material was firstly used for the preparation of self-assembled monolayers (SAM), to be employed in targeted cancer cell adhesion and in-situ drug delivery. For this purpose, the NDs-monolayers were functionalized with FA as targeting moiety. Thanks to their large surface area and the possibility of high density of superficial functionalization with bioactive molecules, these systems resulted effective in binding cancer cells even upon short contact times. Moreover, exploiting the porosity of the synthesized particles, the intracellular release of small hydrophobic molecules pre-loaded in the channels of the NDs were achieved.
Secondly, preliminary biological experiments carried out to test the cellular uptake of NDs, and the drug-carrier ability were performed. Finally, in the attempt to increase the biodegradability of these interesting structures, disulfide-doped mesoporous silica nanodiscs (ss-NDs) were also prepared. Full characterization and preliminary biological assays of these hybrid materials was also performed, and their degradation in redox conditions investigated. This novel material, taking advantage of bio-redox reactions, undergoes a controlled disintegration process in presence of reducing agents (i.e. glutathione), displaying an improved drug delivery action.|
|Appears in Collections:||Area 06 - Scienze mediche|
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|GGLVNT84D57H163B-PhD_thesis_Giglio_Valentina.pdf||PhD thesis Valentina Giglio||11,05 MB||Adobe PDF||View/Open
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