The Optimized Lipid-Modified Prodrug for CNV Treatment

Abstract

Choroidal neovascularization (CNV) is a prevalent cause of vision impairment. The primary treatment for CNV involves intravitreal injections of anti-vascular endothelial growth factor antibodies. Nevertheless, this approach still faces numerous limitations like poor patient compliance, high therapy expenditure and lack of response in some individuals. Herein, a series of anti-neovascularization prodrugs, SU5402 (SU), modified with lipids of varying chain lengths (C12, C16, C20, C24, C28) is synthesized (SU-C12, SU-C16, SU-C20, SU-C24, SU-C28). 1% polyvinyl alcohol (PVA) is used as a stabilizer to create nanoformulations of five prodrugs named SU-C12 NPs, SU-C16 NPs, SU-C20 NPs, SU-C24 NPs, SU-C28 NPs. Among these, SU-C20 NPs significantly prolong the retention of bioactive drug in the eye for up to 70 d. Moreover, SU-C20 NPs demonstrate superior tissue permeability via enhanced cellular endocytosis and exocytosis. With its prolonged retention and improved penetration, SU-C20 NPs reduce the fluorescence intensity of fundus leakage by 42.5% and the fluorescence area by 51.5% in CNV mice after four weeks, effectively inhibiting the progression of CNV. Altogether, small molecule drug SU is innovatively modified to improve its effectiveness for treating fundus neovascular diseases, proposing an alternative therapy for wet age-related macular degeneration (wAMD).