Polyester micro- and nanoparticles for the delivery of therapeutic peptides or proteins

Abstract

The research presented in this thesis focuses on the preparation, characterization and testing of polymeric microparticles (µPs) and nanoparticles (NPs) for the administration of therapeutic biomolecules like proteins and peptides. Particles can improve the efficacy of biomolecules by protecting them from inactivation and increasing their blood circulation time and accumulation at the site of the disease. Furthermore, the composition and properties of the particles can be tailored to achieve either intra- or extracellular delivery of their content, as shown in this thesis. For instance, µPs were evaluated for the encapsulation and sustained extracellular release of a neuroprotective peptide. Preliminary in vivo studies showed that one subcutaneous administration of the peptide encapsulated in the µPs had similar therapeutic effects as four intravenous administrations of non-encapsulated peptide. Additionally, NPs decorated with a targeting ligand were studied for the intracellular delivery of a cell-killing protein. This formulation was selectively internalized into endosomal compartments of target breast cancer cells and, after escaping the endosome, showed cell-killing effect. Furthermore, NPs decorated with different targeting ligand densities were evaluated for their interaction with endothelial cells of blood vessels under static and flow conditions. Cell-particle interactions were time and ligand-density dependent. The addition of red blood cells in the experiments under flow resulted in higher association of the NPs to the cells, most likely due to the blood cells pushing the NPs towards the endothelial cells, thus favoring their contact. Results presented in this thesis thus show the suitability of Ps and NPs for drug delivery purposes.