Dose-Sparing Topical Administration: FK506-Loaded Nano-Micelles Achieve Efficient Therapy in a Murine Model of Vernal Keratoconjunctivitis.

Background/

Objectives

Vernal keratoconjunctivitis (VKC) is a chronic, recurrent allergic disease with the risk of permanent injury or visual disabilities. Tacrolimus (FK506) is a potent immunosuppressant with insoluble ability and a high molecular weight.

Methods

To address this disease, we successfully prepared FK506-loaded polymeric micelles (0.01%, FK506-MS) by a simple, organic solvent-free method. The physicochemical properties of FK506-MS were characterized. Corneal permeability, biocompatibility, and bioavailability were evaluated in vitro and in vivo in comparison with a commercially available FK506 suspension (0.1%, FK506-Susp). Therapeutic efficacy was also assessed in a murine model of VKC.

Results

FK506-MS exhibited a small, homogeneous particle size with near-neutral surface charge. FK506-MS displayed a rapid and sustained release, along with excellent biocompatibility and stability. Ocular pharmacokinetic studies in rabbits revealed that FK506-MS, despite being only one-tenth the concentration of FK506-Susp, could achieve sufficient concentration in the conjunctiva with a prolonged half-life (T1/2) while systemic exposure in blood was markedly reduced. FK506-MS elicited comparable therapeutic responses across evaluated parameters: clinical symptoms, molecular biomarkers of inflammation, and histopathological findings.

Conclusions

The dose-sparing advantage of FK506-MS suggests that the conventional paradigm of concentration-dependent therapeutic efficacy may require further refinement. The nanomicellar delivery system not only overcomes the solubility limitation of FK506 but also exhibits a potential therapeutic paradigm: achieving comparable clinical efficacy with a lower dose and reduced systemic exposure. These results provide a promising preclinical basis for the potential development of a topical tacrolimus therapy that may offer improved safety, cost-effectiveness, and patient adherence.