Topical formulation of self-assembled antiviral prodrug nanomicelles for targeted retinal delivery
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.
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B-C12-CCDF-loaded nanomicelles self-assembled from HCO-40 and OC-40 have a small particle size of about 17.73 nm adapted to scleral pores; the encapsulated prodrug targets SMVT and C12 lipid chain in the retina to enhance lipid solubility and interaction with the cell membrane, facilitating cross-cell layer of HCE-T and D407 through endocytosis.
“The encapsulated prodrug, by means of biotin, targets the highly expressed sodium-dependent vitamin transporter (SMVT) and C12 lipid chain in the retina to enhance lipid solubility and interaction with the cell membrane, facilitating the efficient cross-cell layer of corneal epithelium (HCE-T) and retinal pigment epithelium (D407) through the endocytosis pathway [48].”
From From design to Deployment: The innovative role of nanomicelles in targeted ophthalmic therapeutics (2025) · cites this paper as [48]
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- Authors
- Mandal, A., Cholkar, K., Khurana, V., Shah, A., Agrahari, V., Bisht, R., Pal, D., & Mitra, A. K.
- Affiliations
- University of Missouri–Kansas City (US)
- Ricon Pharmaceuticals LLC, 100 Ford Road, Denville, New Jersey 07834, United States
- Nevakar LLC, R&D, Bridgewater, New Jersey 08807, United States
- University of Auckland (NZ)
- Corresponding author
- Mitra, Ashim K.
- ORCID
- Venue
- Molecular Pharmaceutics
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-05-17
- Volume
- 14
- Issue
- 6
- Pages
- 2056-2069
- ISSN
- 1543-8384 (ISSN-L)
- 1543-8392
- OpenAlex
- W2611535148
- Cited by
- 60
- References
- 38
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 3 · 2023: 4 · 2022: 9 · 2021: 9 · 2020: 9 · 2019: 8 · 2018: 4 · 2017: 1
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmaceutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services (R01 EY010659-14, R01 EY09171-16)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Ophthalmology › Ocular Infections and Treatments
- Keywords
- polymeric micelles, topical drug delivery, retinal drug delivery, antiviral prodrugs, ocular drug delivery, retinal pigment epithelium, corneal epithelium, conjunctival epithelium, cellular uptake, cytotoxicity, ocular permeability
- MeSH terms
- RAW 264.7 Cells, Animals, Antiviral Agents, Cell Line, Humans, Micelles, Prodrugs, Retina, Drug Delivery Systems, Cytomegalovirus Retinitis, Mice, Nanoparticles, Administration, Ophthalmic
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