Biomimetic Nanomicelles: Utilizing Peptide Transporters to Overcome Corneal Barrier for Treating Fungal Infection

The corneal barrier restricts the entry of xenobiotics (including drugs) in the anterior segment of the eye, resulting in less than 5% of the drug reaching the target site (deep corneal tissues) - necessitating frequent topical eye drop administration. Interestingly, despite these barriers, endogenous peptides are shuttled across the cornea by peptide transporters expressed on the corneal epithelium. The current study investigates the potential of targeting peptide transporters to increase the permeability of poorly permeable drugs across the cornea. D-α-tocopherol polyethylene glycol succinate (TPGS), an amphiphilic polymer, was conjugated with Glycyl-Sarcosine (Gly-Sar), a well-known peptide transporter ligand to develop nanomicelles. Natamycin, a poorly water-soluble and poorly permeable drug, was entrapped (0.6%) in Gly-Sar-TPGS-formulated nanomicelles. Both <i>ex vivo</i> and <i>in vivo</i> studies demonstrated that the natamycin-loaded Gly-Sar-TPGS nanomicelles (PeNatcel) enhanced permeation across the cornea. The PeNatcel demonstrated therapeutic efficiency against <i>Candida albicans</i> and <i>Aspergillus flavus</i> using <i>in vitro</i> and <i>ex vivo</i> antifungal studies. PeNatcel showed comparable activity against <i>Candida albicans</i> at 4 times a day dosing frequency compared to 12 times a day marketed 5% natamycin suspension. Consequently, the developed peptide transporter-specific ligand-conjugated nanomicelles delivery system can also be explored further for other water-insoluble and poorly permeable drugs.