Rational design of mixed nanomicelle eye drops with structural integrity investigation

Chitosan oligosaccharide-stearic acid-Valyl-Valyl-Valine/1-2-Dioleoyl-sn-glycero-3-phosphoethanolamine (CSO-SA-VVV_5:2/DOPE) nanomicelles were rationally designed and developed for topical drug delivery to the posterior segment of the eye. The new ligand of VVV selected by computer-aided design exhibited better peptide transporter 1 active targeting in human conjunctival epithelial cells (HConEpiC) than other ligands mentioned in this project. The classic membrane fusion lipid of DOPE was indicated to facilitate the stability and lysosomal escape of the mixed nanomicelles. Förster Resonance Energy Transfer was used to investigate the integrity of mixed nanomicelles in HConEpiC after passing through cell monolayer as well as in ocular tissues after topical administration. The results indicated that mixed nanomicelles could keep more intact micellar structure than CSO-SA nanomicelles in transit. These findings suggested that CSO-SA-VVV_5:2/DOPE nanomicelles could overcome multiple ocular barriers and offer an efficient strategy for drug delivery from ocular surface to the posterior segment of the eye. STATEMENT OF SIGNIFICANCE: Ocular drug delivery systems face multiple physiological barriers in delivering drugs to the posterior segment of the eye by topical administration. In this study, new ligand of Valyl-Valyl-Valine was selected with computer-aided design for active targeting to peptide transporter 1 and anchored onto nanomicelles. Chitosan oligosaccharide-stearic acid- Valyl-Valyl-Valine/1-2-Dioleoyl-sn-glycero-3-phosphoethanolamine nanomicelles were rational designed. The mixed nanomicelles exhibited better active targeting ability and lysosomal escape. Nanomicellar integrity analysis with fluorescence resonance energy transfer technique demonstrated that mixed nanomicelles significantly enhanced cell permeability and exhibited more intact micellar structure in transit. These results suggested that the mixed nanomicelle eye drops have the potential to deliver drugs from ocular surface to the posterior segment of the eye.