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.
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We thank the University of Nebraska Medical Center (UNMC) cores for NMR (E. Ezell), elutriation and cell separation (M. Che, N. Ly and L. Wu), electron microscopy (N. Conoan and T. Bargar) and comparative medicine for technical assistance and animal care. We also thank S. Valloppilly of the University of Nebraska-Lincoln Nebraska Center for Materials and Nanoscience for X-ray structural characterization. We thank Z. You of the University of Nebraska-Lincoln Center for Biotechnology for SEM analysis of the nanoparticles. We thank A. Dash and D. Munt of Creighton University for the assistance in FTIR characterization and analysis. A special thank you to S. Cohen, UNMC, for the tissue histopathology assessments, and to P. K. Dash and J. Herskovitz, UNMC, for assistance in the execution and interpretation of experiments used in these and related works. R. Taylor, UNMC, is thanked for outstanding editorial support. This research is supported by the University of Nebraska Foundation, which includes donations from the Carol Swarts, M.D. Emerging Neuroscience Research Laboratory, the Margaret R. Larson Professorship, the Frances and Louie Blumkin Endowment and the Harriet Singer Endowment, the Vice Chancellor’s Office of the University of Nebraska Medical Center for Core Facilities and the National Institutes of Health grants 1R01AI145542–01A1, P01 DA028555, R01 NS36126, P01 NS31492, 2R01 NS034239, P01 MH64570, P01 NS43985, P30 MH062261, R01 AG043540 and 1 R56 AI138613–01A1. A special thank you is extended to J. Gold for his continuous support of translational research activities for our medical centre.
B.J.E. and H.E.G. are named inventors on patents that cover the medicinal and polymer chemistry technologies employed in this article that encompass the synthesis of long-acting cabotegravir prodrugs and formulation manufacturing. H.E.G. is the Interim Director of the Nebraska Nanomedicine Production Plant, a good manufacturing programme facility. The authors declare that this work was produced solely by the authors and that no other individuals or entities influenced any aspects of the work including, but not limited to, the study conception and design, data acquisition, analyses and interpretation, and writing of the manuscript. No other entities provided funds for the work. The authors further declare that they have received no financial compensation from any other third parties for any aspects of the published work. The remaining authors declare no competing interests.
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Kulkarni, T.A., Bade, A.N., Sillman, B. et al. A year-long extended release nanoformulated cabotegravir prodrug. Nat. Mater. (2020). https://doi.org/10.1038/s41563-020-0674-z