Cationic self-assembled peptide-based molecular hydrogels for extended ocular drug delivery.

The physiological barriers and clearance mechanism of the eye challenge the therapeutic delivery for treating various ocular disorders effectively. Here, we show the use of a cationic peptide (i.e., Nap-FFKK) as the molecular hydrogelator for generating supramolecular hydrogels spontaneously in a pH value of 5-7 which allows it to function as a promising ocular drug vehicle. The cationic peptide-based hydrogel hardly exhibited the cytotoxicity against human corneal epithelial cell (i.e., HCEC) from the in vitro cytotoxicity assay. Moreover, the single topical instillation of the hydrogel resulted in high ocular tolerance and biocompatibility. In vivo corneal distribution of the cationic peptide-based hydrogel showed that it dramatically increased the retention and the adhesion on the surface of cornea, compared to the anionic peptide-based analogue, owing to the ionic interactions with mucin on the ocular surface. In addition, we also synthesized environment-sensitive fluorophore-conjugated analogues (i.e., NBD-FFKK and NBD-FFD) to visualize the uptake of hydrogels in HCEC cells, revealing that the cationic peptide-based hydrogel displayed the better in vitro cellular uptake than the anionic peptide-based hydrogel. More importantly, the resulting cationic Nap-FFKK supramolecular hydrogel displayed a superior ocular bioavailability over that of anionic Nap-FFD supramolecular hydrogel, as indicated by in vivo pharmacokinetics study. This work, as a systematic investigation of ionic peptide-based molecular hydrogels in the ocular application, illustrates a new and powerful supramolecular approach for antagonizing clinically difficult ocular drug delivery. STATEMENT OF SIGNIFICANCE: Here we show the use of a cationic peptide as the molecular hydrogelator for generating supramolecular hydrogels, which allows it to function as a promising ocular drug vehicle for antagonizing the therapeutic delivery difficulties associated with the physiological barriers and clearance mechanism of the eye. The in vitro and in vivo studies of the hydrogel both show high ocular tolerance and biocompatibility. Moreover, the in vivo corneal distribution of the hydrogel exhibits the increased retention and adhesion on the surface of cornea. This work, as an investigation of cationic peptide-based molecular hydrogels in the ocular application, illustrates a powerful supramolecular approach for overcoming clinically difficult ocular drug delivery.