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Physicochemical characterization of nanosystems - polyplexes - for the specific delivery of siRNA targeting HDAC7
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Orientador(es)
Resumo(s)
Cancer is one of the most deadly pathologies in the world; therefore it is important to have as many and different approaches as possible when it comes to its treatment. As it is a complex and highly heterogeneous pathology, classic treatments are often lacking efficiency and are insufficient, which makes even more important the development of new strategies, such as gene targeting therapy.
Concerning different delivery system-based approaches, there are both viral and non-viral vectors. The non-viral vectors, which are here under discussion, are resultant from the complexation of siRNA molecules with cationic polymers.
Preliminary formulation studies have been performed using several polymers – C93, C122, C145, C172 and C173 - in which several tests were performed. These tests included determination of polyplexes capacity to release siRNA into the cytoplasm in the presence of heparin, polyplexes stability and diameter variation depending on pH modulation, and polyplexes capacity to protect siRNA from serum nuclease RNase A.
Regarding the heparin destabilization, the developed polyplexes proved to effectively release siRNA in the presence of heparin, being the amount released dependent on the quantity of heparin used (1 UI being the minimum quantity to effectively promote the release of siRNA).
About the pH, the polyplexes proved to be stable at pH values varying from 7.5 to 5 (pH 6.0–6.5 in early endosomes to pH 4.5–5.5 in late endosomes and lysosomal compartment) and to have no significant variation in particle size diameter at lower pH values.
Concerning the complexes resistance to RNase A, all proved to be resistant to this enzyme.
The polymers used for siRNA complexation lead to complexes that have shown to have promising parameters being thus promising candidates for further in vitro studies, as cellular uptake and viability studies, assessment of topographical profiles and complexes’ biological effect by inferring their ability to reduce the level of the HDAC7 protein and thus inhibit its biological function.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2014
Palavras-chave
Cancer therapies Angiogenesis Polyplexes Heparin HDAC7 siRNA Mestrado Integrado - 2014