A year-long extended release nanoformulated cabotegravir prodrug

Tanmay A. Kulkarni, Aditya N. Bade, Brady Sillman, Bhagya Laxmi Dyavar Shetty, Melinda S. Wojtkiewicz, Nagsen Gautam, James R. Hilaire, Sruthi Sravanam, Adam Szlachetka, Benjamin G. Lamberty, Brenda M. Morsey, Howard S. Fox, Yazen Alnouti, Jo Ellyn M. McMillan, R. Lee Mosley, Jane Meza, Paul L. Domanico, Tai Yuen Yue, Gary Moore, Benson J. EdagwaHoward E. Gendelman

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution. Pharmacokinetics studies, performed in mice and rhesus macaques, with the lead 18-carbon ester chain NM2CAB, showed plasma CAB levels above the protein-adjusted 90% inhibitory concentration for up to a year. NM2CAB, compared with NMCAB and NM3CAB, demonstrated a prolonged drug release, plasma circulation time and tissue drug concentrations after a single 45 mg per kg body weight intramuscular injection. These prodrug modifications could substantially improve CAB’s effectiveness.

Original languageEnglish (US)
JournalNature Materials
DOIs
StateAccepted/In press - 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics
  • Mechanics of Materials
  • Mechanical Engineering

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    Kulkarni, T. A., Bade, A. N., Sillman, B., Shetty, B. L. D., Wojtkiewicz, M. S., Gautam, N., Hilaire, J. R., Sravanam, S., Szlachetka, A., Lamberty, B. G., Morsey, B. M., Fox, H. S., Alnouti, Y., McMillan, J. E. M., Mosley, R. L., Meza, J., Domanico, P. L., Yue, T. Y., Moore, G., ... Gendelman, H. E. (Accepted/In press). A year-long extended release nanoformulated cabotegravir prodrug. Nature Materials. https://doi.org/10.1038/s41563-020-0674-z