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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.

Although endophthalmitis is a serious sight-threatening disorder, combining anti-inflammatory agents and antibiotics has provided new methods for effectively controlling it. This paper reports that the co-assembly of a sparingly soluble antibiotic (levofloxacin; Lev) and dexamethasone-peptide amphiphile (Dex-SA-RGD) instantly generates a macroscopically supramolecular hydrogel (Lev/Dex-SA-RGD) without any external stimulus under physiological conditions, which could be used in synergistic therapy to cure endophthalmitis induced by Staphylococcus aureus (i.e., S. aureus). The resulting co-assembled supramolecular hydrogel was thoroughly characterized using rheology, circular dichroism, and transmission electron microscopy. An in vitro drug release study showed that Lev was rapidly released from the supramolecular hydrogel within 6 h, while Dex-SA-RGD escaped from the supramolecular hydrogel as a result of matrix erosion, and then acted as a prodrug to provide the sequentially slow release of active dexamethasone via the hydrolytic route. The Lev/Dex-SA-RGD supramolecular hydrogel showed high antibacterial activities against both gram-negative and gram-positive strains. Moreover, a rabbit endophthalmitis model induced by S. aureus showed that the intravitreal injection of the Lev/Dex-SA-RGD supramolecular hydrogel resulted in excellent therapeutic efficacy with no apparent damage or destruction of the retina, and dramatically suppressed inflammatory responses (e.g., leukocyte and lymphocyte infiltration, microglial activation, cytokine production, and retinal cell death). As a rational approach to investigate and apply the co-assembled hydrogel, this work presents the potential of synergistic intervention to prevent retinal tissue damage and vision impairment, and ultimately shows the clinical benefits of using supramolecular hydrogels for ocular drug delivery.