A year-long extended release nanoformulated cabotegravir prodrug

Nat Mater. 2020 Aug;19(8):910-920. doi: 10.1038/s41563-020-0674-z. Epub 2020 Apr 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Retroviral Agents / metabolism*
  • Anti-Retroviral Agents / pharmacology
  • Anti-Retroviral Agents / toxicity
  • Biological Transport
  • Delayed-Action Preparations
  • Drug Compounding
  • Drug Interactions
  • Drug Stability
  • Mice
  • Nanostructures / chemistry*
  • Prodrugs / chemistry*
  • Prodrugs / metabolism*
  • Pyridones / metabolism*
  • Pyridones / pharmacology
  • Pyridones / toxicity


  • Anti-Retroviral Agents
  • Delayed-Action Preparations
  • Prodrugs
  • Pyridones
  • cabotegravir