Smart self-assembled nanoparticles for the treatment of age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a common cause of blindness among the elderly, and is characterized by choroidal neovascularization (CNV). Traditional therapies for wet AMD with anti-vascular endothelial growth factor (anti-VEGF) agents have several limitations, mainly due to the invasiveness of intravitreal injection and its arising risks of ocular complications. However, the efficacy of drugs administered via non-invasive routes (e.g., topical and systemic administration) is severely hindered by inefficient drug delivery and adverse off-target effect. To overcome these challenges, the development of stimuli-responsive drug delivery systems has emerged as an attractive approach, enabling effective drug accumulation in CNV lesions while minimizing both localized and systemic toxicity.

This thesis is dedicated to developing stimuli-activatable nanoparticles for minimally invasive management of wet AMD. Two stimuli-responsive drug delivery strategies were explored in this work, which utilized excessive oxidative stress as an endogenous trigger and light irradiation as an exogenous trigger for precisely controlled drug release. This work also investigated the potential of combination treatment of anti-angiogenic and angio-occlusive therapies for wet AMD.

In the first project, reactive oxygen species (ROS)-responsive prodrug eyedrops (Di-DAS/P-PCD) were fabricated for precise delivery of anti-angiogenic agent dasatinib (DAS) to the oxidative microenvironment of CNV. The prodrug nanoparticles were formed by cell-penetrating peptide-modified polyethylene glycol-cyclodextrin (P-PCD) and ROS-sensitive DAS prodrug Di-DAS. The prodrug eyedrops exhibited reduced cytotoxicity to normal ocular cell lines due to the inactivity of the prodrug. Topical administration of Di-DAS/P-PCD facilitated efficient choroidal penetration and was specifically activated by elevated ROS levels in a laser-induced CNV mouse model.

In the second project, a therapeutic strategy combining anti-angiogenic and photodynamic therapies was developed for wet AMD, which was achieved by intravenous administration of photoactivatable prodrug nanoparticles (Di-DAS-VER NPs). The nanoparticles were self-assembled by ROS-sensitive anti-angiogenic prodrug Di-DAS, FDA-approved photosensitizer verteporfin (VER), and biocompatible polymer-lipid. After red-light irradiation to the diseased eyes, intraocular release of DAS was observed, together with selective occlusion of neovessels by photodynamic therapy (PDT) in CNV mice.

In the third project, a near-infrared light (NIR)-cleavable cyanine prodrug system was developed to deliver both anti-angiogenic and vascular-disrupting agents to CNV lesions. A novel cyanine prodrug of the microtubule-destabilizing agent combretastatin A-4 (CA4), IR820-CA4, was co-assembled with VEGF receptor inhibitor sorafenib (SOR) into nanoparticles (SOR/IR820-CA4 NPs) without the need for additional excipients. After intravenous administration of the nanoparticles into CNV mice, 690 nm light irradiation triggered nanoparticle decomposition, releasing SOR to inhibit angiogenesis and CA4 to devastate established CNV vasculature. The treatment did not cause any noticeable systemic side effects or localized photodamage effects in vivo.

In conclusion, this thesis presents three novel stimuli-responsive nanoparticle systems for wet AMD treatment, demonstrating improved efficacy in CNV suppression alongside favorable biosafety. This study may provide novel insights into the development of stimuli-responsive prodrug systems as minimally invasive therapeutics for wet AMD and other neovascular eye diseases.