Improving the Efficacy of Neovascular AMD Therapy with Long-Term Drug Delivery Systems

Neovascular age-related macular degeneration (nAMD) is a progressive condition that is common in individuals over 50 years of age and cannot be cured in 90% of patients, and is one of the most common causes of blindness affecting more than 200 million people worldwide. Current therapeutic approaches include periodic intravitreal injections of monoclonal antibody-based anti-VEGF (anti-Vascular Endothelial Growth Factor) drugs. In spite of successful progress in neovascular AMD therapy in recent years, anti-VEGF therapies have some limitations such as the high cost and limited half-lives of protein drugs, need for frequent intravitreal injections, intravitreal injection-related complications and inadequate response to some anti-VEGF drugs. Because of these drawbacks, new approaches need to be developed for long-lasting anti-VEGF drug delivery. Peptide drugs offer ease of production and storage, extended drug shelf life and reduced costs. Currently, a drug using anti-VEGF peptides in the treatment of nAMD is not available and several anti-VEGF peptides in the literature are waiting to be evaluated for their efficacy in nAMD therapy. This project aimed to develop a composite drug delivery system consisting of poly(glycerol sebacate) (PGS) nanoparticles and cross-linked hyaluronic acid hydrogel that reduces the frequency of intravitreal administration by providing sustained release (up to 6 months) of anti-VEGF peptide drugs as a new generation treatment method.<br/>In this study, PGS nanoparticles obtained by solvent evaporation method have high encapsulation efficiency (93,7%) and their size was around 200 nm. HA-DVS crosslinked hydrogel was synthesized by Oxa-Michael addition reaction and successful crosslinking was confirmed by FTIR spectroscopy. Drug delivery system was formed by incubating anti-VEGF peptide loaded PGS nanoparticle solutions with crosslinked HA-DVS hydrogel to have 25% (v/v). The <i>in-vitro</i> drug release from drug delivery system was less than 20% in the first month, consistent with the targeted long-term release profile. It was demonstrated by calculating cell viability that the anti-VEGF peptide loaded drug delivery system does not cause cytotoxic effects on human retinal pigmented epithelial (ARPE-19) cells for up to 72 hours. The inhibition effect of anti-VEGF peptide on angiogenesis was determined by calculating cell viability and examining tube formation by incubating human umbilical vein endothelial cells (HUVEC) with anti-VEGF peptide-loaded drug delivery system.<br/>Developing new generation biomaterials for the storage and preservation of therapeutic peptides and improving their bioavailability with prolonged release will significantly improve the efficiency of long-term treatment strategies for neovascular AMD.