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Fluorescent-based dendrimers as potential drug delivery carriers of cisplatin : from design and synthesis to platinum-membrane interactions
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Resumo(s)
Dendrimers are a class of polymers with high potential as drug delivery systems due to their unique scaffold and properties. Despite their early potential, dendrimer-based therapies have been limited in part due to the considerable lack of understanding of their in vivo behavior and in particular, how they interact and cross cellular membranes. Therefore, designing dendrimers with an attached fluorophore would allow their tracking while studying their behavior with lipid bilayers. This work explores the potential of fluorescent dendrimers as carriers for the anti-cancer drug cisplatin, which is known to interact with lipids and induce phase changes in cellular membranes. To this end, fluorescent poly(glutamic acid) (PG) dendrimers were designed in silico and suitable candidates were attempted to be synthesized. Furthermore, effects of cisplatin in phase change and integrity of lipid model bilayers was studied to further drive the design of these dendrimers. The choice of PG dendrimers backbone was driven by their ability to fully cover a small fluorophore from the external environment. To quickly generate dendrimers scaffolds a set of computational tools were created to automate this process and facilitate the modeling of any class of dendrimers. Different generations and architecture of PG dendrimers with a fluorophore attached to the core and different terminal groups were created and submitted to all-atom simulations. Data from molecular dynamics showed that generation 4 was necessary to fully cover a low molecular weight fluorophore and partially cover a high molecular weight fluorophore as measured by the solvent accessible surface area. However, the synthesis of these candidates was shown to be difficult due to the amount of side reactions and possible steric hindrance that arises at high generations. Furthermore, the attachment of NBD was required to be carried out at lower generations since its reactivity with higher generations of PG dendrimers was lower. Therefore, analogues of glutamic acid with NBD (nitrobenzoxadiazole) were synthesized to be used as the initial core. Finally, platinum membrane interactions were characterized by measuring the fluorescence anisotropy of different probes embedded in liposomes composed of different lipid mixtures. Results suggested that both cisplatin and its cationic aquated analogue had low perturbation on the lipid phase and integrity of model membranes. However, cisplatin was able to further reduce the membrane fluidity when a gel phase was present in the membrane. Furthermore, at high concentrations, platinum complexes were shown to compromise the permeability of lipid bilayers without inducing collapse of the membrane. This effect was again dependent on membrane lipid composition. Altogether, these findings were used as a proof-of-concept for designing dendrimers as potential tools to carry and study cisplatin interactions at the lipid membrane.
Descrição
Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2018
Palavras-chave
Teses de doutoramento - 2018