Topical formulations, commonly applied for treatment of anterior eye diseases, require frequent administration due to rapid clearance from the ocular surface, typically through the lacrimal drainage system or through over-spillage onto the lids. We report on a mucoadhesive nanoparticle drug delivery system that may be used to prolong the precorneal residence time of encapsulated drugs. The nanoparticles were formed from self-assembly of block copolymers composed of poly(D, L-lactide) and Dextran. The enhanced mucoadhesion properties were achieved by surface functionalizing the nanoparticles with phenylboronic acid. The nanoparticles encapsulated up to 12 wt.% of Cyclosporine A (CycA) and sustained the release for up to five days at a clinically relevant dose, which led us to explore the therapeutic efficacy of the formulation with reduced administration frequency. By administering CycA-loaded nanoparticles to dry eye-induced mice once a week, inflammatory infiltrates were eliminated and the ocular surface completely recovered. The same once a week dosage of the nanoparticles also showed no signs of physical irritation or inflammatory responses in acute (1 week) and chronic (12 weeks) studies in healthy rabbit eyes. These findings indicate that the nanoparticles may significantly reduce the frequency of administration for effective treatment of anterior eye diseases without causing ocular irritation.

Nanoparticles (NPs) formulated using self-assembly of block copolymers have attracted significant attention as nano-scaled drug delivery vehicles. Here we report the development of a biodegradable NP using self-assembly of a linear amphiphilic block copolymer, Dex-b-PLA, composed of poly(D, L-lactide), and dextran. The size of the NPs can be precisely tuned between 15 and 70 nm by altering the molecular weight (M_W) of the two polymer chains. Using doxorubicin as a model drug, we demonstrated that the NPs can carry up to 21% (w/w) of the drug payload. The release profile of doxorubicin from NPs showed sustained release for over 6 days. Using a rat model, we explored the pharmacokinetics profiles of Dex-b-PLA NPs, and showed proof-of-concept that long circulation lifetime of the NPs can be achieved by tuning the M_W of Dex-b-PLA block copolymer. While the terminal half-life of Dex-b-PLA NPs (29.8 h) was similar to that observed in poly(ethylene glycol)-coated (PEG-coated) NPs (27.0 h), 90% of the injected Dex-b-PLA NPs were retained in the blood circulation for 38.3 h after injection, almost eight times longer than the PEG-coated NPs. The area under curve (AUC) of Dex-b-PLA NPs was almost four times higher than PEG-based NPs. The biodistribution study showed lower accumulation of Dex-b-PLA NPs in the spleen with 19.5% initial dose per gram tissue (IDGT) after 24 h compared to PEG-coated poly(lactide-co-glycolide) (PLGA) NPs (29.8% IDGT). These studies show that Dex-b-PLA block copolymer is a promising new biomaterial for making controlled nanoparticles as drug delivery vehicles.