Injectable Biodegradable Implantable Matrices For Prolonged Anti-VEGF Delivery: Toward Minimally Invasive Retinal Treatments

Introduction

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are leading causes of vision loss, primarily driven by pathological angiogenesis mediated by vascular endothelial growth factor (VEGF). Sunitinib, a multi-targeted tyrosine kinase inhibitor, offers potent anti-angiogenic activity but is limited by systemic toxicity and rapid degradation. This research aimed to develop and evaluate biocompatible, biodegradable elastomeric implants for the sustained intraocular delivery of sunitinib, thereby reducing injection frequency, maintaining therapeutic drug levels, and improving ocular tolerability.

Methodology

Implants were formulated using poly(diol-co-tricarballylate) elastomers via thermal crosslinking, incorporating sunitinib either through solvent casting or direct mixing. In vitro characterization included FTIR, DSC, XRD, drug release kinetics, and cytocompatibility on ARPE-19 cells. In vivo studies were conducted in rabbits, assessing ocular pharmacokinetics, fundoscopic examination, and histopathological analysis over a 42-day period following intravitreal implantation. Quantification of drug levels in vitreous humor and tissues was performed using validated LC-MS/MS.

Results

The elastomeric implants demonstrated amorphous drug dispersion, slow degradation, and pH-stable, diffusion-driven release extending up to 222 days. No burst effect was observed. Drug release followed Higuchi kinetics, with higher loading (1000 µg) resulting in increased release rates. Cytotoxicity studies revealed that controlled-release systems significantly reduced sunitinib-induced cell apoptosis and preserved proliferation in ARPE-19 cells. In vivo, all sunitinib implants were well tolerated with no significant vitreous hemorrhage or inflammation. Pharmacokinetic analysis confirmed sustained intraocular drug presence, with the highest levels seen in the 1000 µg implants.

Conclusion

This study successfully demonstrates the feasibility of using biodegradable elastomeric implants for long-term, controlled intraocular delivery of sunitinib. The system offers enhanced therapeutic duration, minimized dosing frequency, and improved safety compared to conventional injection-based therapies. These findings hold strong translational potential for treating neovascular retinal diseases such as DR and AMD, addressing the unmet clinical need for prolonged, cost-effective, and minimally invasive ocular drug delivery solutions.