Biplab Sarkar1 Sruti Rachapudi1 Peter Nguyen1 Vivek Kumar1

1, New Jersey Institute of Technology, Newark, New Jersey, United States

Diabetic Retinopathy (DR) and Macular Degeneration (MD) are diseases of the posterior segment of the eye that disproportionately affect the geriatric population. These diseases lead to significant deterioration in the quality of life in affected demographic and are among the leading causes of blindness (4.8% and 8.7% of occurrence, respectively), globally. Both diseases share a common cause — aberrant neovascularization in the posterior segment that lead to occlusion, hemorrhage, and edema. Intraocular delivery of the inhibitors of vascular endothelial growth factor (VEGF) have shown promise to block the progression of the diseases, as they prevent the neovascularization in the retina and the choroid. A drawback of the current treatment is the requirement of monthly intraocular injection schedule that leads to patient discomfort and higher chances of endophthalmitis. The issue can be addressed by a less-frequent dosing schedule that would need a more sustained release profile. The development of a bifunctional hydrogel-based delivery method is described that encapsulates an anti-VEGF antibody inside an anti-angiogenic peptide scaffold. The hydrogel platform is biodegradable and thixotropic. The bimodal and sustained release of bevacizumab and the anti-angiogenic peptide from the hydrogel can inhibit abnormal neovascularization in the tissue microenvironment of the choriocapillaris, Bruch’s membrane, and the retina. The technology is based on a b-sheet-based self-assembling peptide hydrogel (SAPH) platform to which biofunctional moieties can be attached, without negatively affecting the secondary structure or viscoelastic properties. The different combinations of the peptide hydrogels with different loading of bevacizumab were tested for their biocompatibility (fibroblast cell culture), immunogenicity (mouse model), and their potential to inhibit angiogenesis in vitro (tube formation assays) and in vivo (rabbit model). The release profile of the antibody and the anti-angiogenic peptide were monitored in vitro and in vivo to test the suitability for a less-frequent dosing schedule. The proposed therapy may be an important advance toward clinically useful abrogation of aberrant neovascularization in the posterior segment that would address the root cause of DR and MD and would improve the quality of life for the patients. Modular nature of the therapy also makes it an ideal choice to be modified depending on the specific disease phenotype — for example, the sequestered drug could be changed without altering the peptide backbone to better target sub-classes of the diseases. Finally, our bimodal delivery system may prove to be useful for localized prevention of vascularization in neoplastic microenvironment, leading to translation to anti-cancer therapies in the future.