TY - JOUR
T1 - A year-long extended release nanoformulated cabotegravir prodrug
AU - Kulkarni, Tanmay A.
AU - Bade, Aditya N.
AU - Sillman, Brady
AU - Shetty, Bhagya Laxmi Dyavar
AU - Wojtkiewicz, Melinda S.
AU - Gautam, Nagsen
AU - Hilaire, James R.
AU - Sravanam, Sruthi
AU - Szlachetka, Adam
AU - Lamberty, Benjamin G.
AU - Morsey, Brenda M.
AU - Fox, Howard S.
AU - Alnouti, Yazen
AU - McMillan, Jo Ellyn M.
AU - Mosley, R. Lee
AU - Meza, Jane
AU - Domanico, Paul L.
AU - Yue, Tai Yuen
AU - Moore, Gary
AU - Edagwa, Benson J.
AU - Gendelman, Howard E.
N1 - Funding Information:
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.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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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U2 - 10.1038/s41563-020-0674-z
DO - 10.1038/s41563-020-0674-z
M3 - Article
C2 - 32341511
AN - SCOPUS:85084132874
SN - 1476-1122
VL - 19
SP - 910
EP - 920
JO - Nature Materials
JF - Nature Materials
IS - 8
ER -