Exploring the Effect of Surface Hydrophilicity of Nanoparticles on Ocular Posterior Transport Pathway via Non‐Invasive Topical Administration

Short residence time and off-target accumulation restrict ocular posterior delivery via topical administration. How to improve posterior drug delivery through non-invasive method is the issue to be addressed. Inspired by the higher posterior delivery efficiency of conjunctival-scleral pathway and hydrophilicity-related tissue preference, the objective is to verify the feasibility of altering posterior tissue distribution via conjunctival-scleral pathway by tuning nanoparticles (NPs) hydrophilicity. Herein, triamcinolone acetonide-loaded NPs with different surface hydrophilicity were prepared by mixing poly(lactide-co-glycolide) and poly(lactide-co-glycolide)-polyethylene glycol (PLGA-PEG) at different ratios. 3.5% and 16.7% PEG NPs displayed 1.5- and 1.8-fold higher sclera P_app than 0% PEG NPs. Furthermore, the higher the surface hydrophilicity, the more NPs in conjunctiva but less in cornea, 3.5% and 16.7% PEG NPs showed 1.4- and 1.8-fold higher choroid-retina distribution than 0% PEG NPs via conjunctival-scleral pathway. The higher posterior delivery was confirmed by enhanced therapeutic efficacy in vascular endothelial growth factor-induced retinal neovascularization rabbit model. After dropped twice daily for 14 days, 3.5% and 16.7% PEG NPs reached comparable therapeutic effect with intravitreal injection. This study demonstrated the significance of NPs surface hydrophilicity in posterior delivery, providing theoretical basis for rational design of NPs for ocular posterior diseases therapy by topical dropping.