Intraocular fate of surface charge-dependent nanomicelles via topical administration: Posterior delivery and transport pathway.

Short residence time and unexpected accumulation in anterior tissues restrict drug posterior delivery via non-invasive topical administration. How to increase the drug level in posterior tissues while avoiding accumulation in off-target sites is addressed. Inspired by the higher posterior delivery efficiency through conjunctival-scleral pathway and the varied preference of ocular tissues for surface charge, the objective of this study is to explore the feasibility of using surface charge to discriminate drug distribution in corneal/conjunctival-scleral pathway, thereby improving posterior delivery efficiency and reducing accumulation in anterior tissues. Herein, using triamcinolone acetonide as a model drug, Soluplus® nanomicelles (NMs) with positive, negative, and neutral surface charges were prepared by the modified thin-film hydration method. Precorneal retention, tissue penetration, intraocular distribution, and therapeutic efficacy were investigated systemically. It was demonstrated that compared to positive NMs, negative and neutral NMs exhibited prolonged retention in the conjunctival sac and higher permeability in conjunctiva than cornea, resulting in enhanced drug distribution in the conjunctival-scleral pathway. Negative and neutral NMs demonstrated 1.7- and 1.4-fold higher drug distribution in the choroid-retina than positive NMs. Following twice-daily administration for 14 days in a vascular endothelial growth factor-induced retinal neovascularization rabbit model, negative and neutral NMs presented therapeutic efficacy comparable to that of intravitreal injection in down-regulating neovascularization-related protein, which was remarkably superior to that of positive NMs. In conclusion, negative and neutral NMs present promising non-invasive drug delivery systems for ocular posterior disease therapy with enhanced posterior delivery efficiency. Our study provides scientific guidance for the rational design of nanocarriers' surface charge based on the ocular diseases to be treated.