Development of polymer-based delivery systems for the delivery of fusogenic factors

Machado, S.

http://hdl.handle.net/10400.1/3741

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Authors

Machado, S.

Advisor(s)

Silva, Gabriela

Santos, Marina I.

Abstract(s)

Ischemic stroke ranks among the leading cause of death and adult disability in developed countries. An ischemic event leads to the formation of an area- called penumbra – that despite the higher risk of permanent damage can be recovered with adequate therapy. Therefore it is critical to develop therapeutic approaches aimed at regenerating the ischemic brain. Due to the short time window for therapy and the complications associated with the administration of large and frequent doses of therapeutic molecules, it is vital to develop delivery systems with controlled release. Our aim is to develop such a system for delivery of therapeutic molecules to the stroke area, in order to enhance the recovery of the damaged brain. For this purpose, Poly-lactic Acid (PLA) nanoparticles and Alginate/Chitosan nanoparticles, with a mean diameter of 290 nm, were prepared by a multiple emulsion technique and by ionotropic pre-gelation of alginate/chitosan polyelectrolyte complexation, respectively. When BSA was used as a model protein, its release from Alginate/Chitosan nanoparticles showed a burst release in the first hours, with 80% of entrapped BSA released by day three. This result shows that these systems are adequate for treatment of an ischemic episode, where it is critical to deliver an initial burst of therapeutic agent followed by a steady, slow release over time. Both types of nanoparticles presented no in vitro toxicity on the tested cell lines and in vivo analysis of nanoparticles loaded with Rhodamine 6G injected into the subretinal space of C57Bl6 mice showed no macroscopic signs of inflammation. Finally, the biodistribution of nanoparticles administered intravenously in CD1 and nude mice suggest that the nanoparticles can travel along the bloodstream of the experimental animals and accumulate in particular tissues. These results show that the developed systems can be part of a successful approach to treat ischemic events, by delivering therapeutic molecules and releasing them with an adequate profile.