TY - JOUR
T1 - Creation of a long-acting rilpivirine prodrug nanoformulation
AU - Hilaire, James R.
AU - Bade, Aditya N.
AU - Sillman, Brady
AU - Gautam, Nagsen
AU - Herskovitz, Jonathan
AU - Dyavar Shetty, Bhagya Laxmi
AU - Wojtkiewicz, Melinda S.
AU - Szlachetka, Adam
AU - Lamberty, Benjamin G.
AU - Sravanam, Sruthi
AU - Fox, Howard S.
AU - Alnouti, Yazen
AU - Dash, Prasanta K.
AU - McMillan, Jo Ellyn M.
AU - Edagwa, Benson J.
AU - Gendelman, Howard E.
N1 - Funding Information:
We wish to thank the University of Nebraska Medicine cores for NMR Spectroscopy (Ed Ezell), Elutriation and Cell Separation (Myhanh Che and Na Ly), Electron Microscopy (Tom Bargar and Nicholas Conoan), as well as Comparative Medicine for technical assistance. Furthermore, we would like to acknowledge Dr. Won-Bin Young and Kamel Khalili at Temple University for HIV-1NL4-3-eGFP molecular clone plasmid. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: CEM CD4+ Cells from Dr. J.P. Jacobs. Thank you to Dr. Samuel Cohen for the tissue histopathology assessments. 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, and the Frances and Louie Blumkin, and Harriet Singer Endowments, the Vice Chancellor's Office of the University of Nebraska Medical Center for Core Facilities and the National Institutes of Health grants P01 DA028555, R01 NS36126, P01 NS31492, 2R01 NS034239, P01 MH64570, P01 NS43985, P30 MH062261 and R01 AG043540, 1 R56 Al138613-01A1.
Funding Information:
We wish to thank the University of Nebraska Medicine cores for NMR Spectroscopy (Ed Ezell), Elutriation and Cell Separation (Myhanh Che and Na Ly), Electron Microscopy (Tom Bargar and Nicholas Conoan), as well as Comparative Medicine for technical assistance. Furthermore, we would like to acknowledge Dr. Won-Bin Young and Kamel Khalili at Temple University for HIV-1 NL4-3-eGFP molecular clone plasmid. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: CEM CD4+ Cells from Dr. J.P. Jacobs. Thank you to Dr. Samuel Cohen for the tissue histopathology assessments. 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, and the Frances and Louie Blumkin, and Harriet Singer Endowments, the Vice Chancellor's Office of the University of Nebraska Medical Center for Core Facilities and the National Institutes of Health grants P01 DA028555 , R01 NS36126 , P01 NS31492 , 2R01 NS034239 , P01 MH64570 , P01 NS43985 , P30 MH062261 and R01 AG043540 , 1 R56 Al138613-01A1 .
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/10
Y1 - 2019/10
N2 - Antiretroviral therapy requires lifelong daily dosing to attain viral suppression, restore immune function, and improve quality of life. As a treatment alternative, long-acting (LA) antiretrovirals can sustain therapeutic drug concentrations in blood for prolonged time periods. The success of recent clinical trials for LA parenteral cabotegravir and rilpivirine highlight the emergence of these new therapeutic options. Further optimization can improve dosing frequency, lower injection volumes, and facilitate drug-tissue distributions. To this end, we report the synthesis of a library of RPV prodrugs designed to sustain drug plasma concentrations and improved tissue biodistribution. The lead prodrug M3RPV was nanoformulated into the stable LA injectable NM3RPV. NM3RPV treatment led to RPV plasma concentrations above the protein-adjusted 90% inhibitory concentration for 25 weeks with substantial tissue depots after a single intramuscular injection in BALB/cJ mice. NM3RPV elicited 13- and 26-fold increases in the RPV apparent half-life and mean residence time compared to native drug formulation. Taken together, proof-of-concept is provided that nanoformulated RPV prodrugs can extend the apparent drug half-life and improve tissue biodistribution. These results warrant further development for human use.
AB - Antiretroviral therapy requires lifelong daily dosing to attain viral suppression, restore immune function, and improve quality of life. As a treatment alternative, long-acting (LA) antiretrovirals can sustain therapeutic drug concentrations in blood for prolonged time periods. The success of recent clinical trials for LA parenteral cabotegravir and rilpivirine highlight the emergence of these new therapeutic options. Further optimization can improve dosing frequency, lower injection volumes, and facilitate drug-tissue distributions. To this end, we report the synthesis of a library of RPV prodrugs designed to sustain drug plasma concentrations and improved tissue biodistribution. The lead prodrug M3RPV was nanoformulated into the stable LA injectable NM3RPV. NM3RPV treatment led to RPV plasma concentrations above the protein-adjusted 90% inhibitory concentration for 25 weeks with substantial tissue depots after a single intramuscular injection in BALB/cJ mice. NM3RPV elicited 13- and 26-fold increases in the RPV apparent half-life and mean residence time compared to native drug formulation. Taken together, proof-of-concept is provided that nanoformulated RPV prodrugs can extend the apparent drug half-life and improve tissue biodistribution. These results warrant further development for human use.
KW - Antiretroviral therapy
KW - Long-acting slow effective release antiretroviral therapy
KW - Monocyte-derived macrophages
KW - Nanoformulation
KW - Prodrugs
KW - Rilpivirine
UR - http://www.scopus.com/inward/record.url?scp=85071847261&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071847261&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2019.09.001
DO - 10.1016/j.jconrel.2019.09.001
M3 - Article
C2 - 31491432
AN - SCOPUS:85071847261
SN - 0168-3659
VL - 311-312
SP - 201
EP - 211
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -