Topical Formulation of Self-Assembled Antiviral Prodrug Nanomicelles for Targeted Retinal Delivery

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Abstract
Topical drug administration for back of the eye delivery is extremely challenging due to the presence of protection mechanisms and physiological barriers. Self-assembled polymeric nanomicelles have emerged as promising vehicles for drug delivery. Apart from serving as an inert nanocarrier for therapeutic agents, polymeric nanomicelles are known to bypass mononuclear phagocytic system (MPS) and efflux transporters thereby improving drug bioavailability. In this investigation, a highly efficacious biotinylated lipid prodrug of cyclic cidofovir (B–C12-cCDF) was formulated within polymeric nanomicelles as a carrier for targeted retinal delivery. Polymeric nanomicelles were prepared from polyoxyethylene hydrogenated castor oil 40 (HCO-40) and octoxynol 40 (OC-40). In vitro release studies revealed that B–C12-cCDF-loaded nanomicelles released B–C12-cCDF at a faster rate in stimulated tear fluid (STF) in comparison to PBST. MTT and LDH assays demonstrated negligible cytotoxicity of B–C12-cCDF-loaded nanomicelles relative to CDF and B–C12-cCDF in HRPE (human retinal pigment epithelial, D407), HCE-T (human corneal epithelial), and CCL 20.2 (human conjunctival epithelial) cells. Confocal laser scanning microscopy and flow cytometry analyses indicated that B–C12-cCDF-loaded nanomicelles were efficiently internalized into D407 and HCE-T cells in contrast to CDF and B–C12-cCDF. Moreover, little B–C12-cCDF was also observed in the nuclei after 24 h of incubation. Polymeric nanomicelles carrying the transporter targeted prodrug did not produce any cytotoxic effects and were internalized into the cells effectively. Permeability experiments across HCE-T cells further confirmed significant transport of prodrug loaded nanomicelles and their subsequent uptake into D407 cells. These findings indicate that HCO-40/OC-40 based polymeric nanomicelles could become a promising topical delivery system for ocular administration of antiviral agents.
Funding Information
  • U.S. Department of Health and Human Services (R01 EY010659-14, R01 EY09171-16)

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