TY - JOUR
T1 - Synthesis of a long acting nanoformulated emtricitabine ProTide
AU - Soni, Dhruvkumar
AU - Bade, Aditya N.
AU - Gautam, Nagsen
AU - Herskovitz, Jonathan
AU - Ibrahim, Ibrahim M.
AU - Smith, Nathan
AU - Wojtkiewicz, Melinda S.
AU - Dyavar Shetty, Bhagya Laxmi
AU - Alnouti, Yazen
AU - McMillan, Jo Ellyn
AU - Gendelman, Howard E.
AU - Edagwa, Benson J.
N1 - Funding Information:
We wish to thank the University of Nebraska Medical Center Cores for Electron Microscopy (Tom Bargar and Nicholas Conoan), NMR Spectroscopy (Ed Ezell), Elutriation and Cell Separation (Myhanh Che and Na Ly) and Comparative Medicine for technical assistance. We would like to acknowledge Temple University and Drs. Won-Bin Young and Kamel Khalili for construction of HIV-1 NL4-3-eGFP molecular clone plasmid and T cell assay support, respectively. We thank Dr. Bhavesh Kevadia of University of Nebraska Medical Center and Shah Valloppilly of the University of Nebraska for Materials and Nanoscience X-Ray Structural Characterization Facility for support in characterizing the modified antiretroviral drug(s) used in this study. We thank Dr. You Zhou of University of Nebraska Lincoln Center for Biotechnology for carrying out TEM imaging of nanoparticles. The research was supported by the University of North Florida , 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 Endowment, the Vice Chancellor's Office of the University of Nebraska Medical Center for Core Facility Developments and National Institutes of Health grants P01 DA028555 , R01 NS36126 , P01 NS31492 , 2R01 NS034239 , P01 MH64570 , P01 NS43985 , P30 MH062261 and R01 AG043540 , 1 R56 AI138613-01A1 .
Funding Information:
We wish to thank the University of Nebraska Medical Center Cores for Electron Microscopy (Tom Bargar and Nicholas Conoan), NMR Spectroscopy (Ed Ezell), Elutriation and Cell Separation (Myhanh Che and Na Ly) and Comparative Medicine for technical assistance. We would like to acknowledge Temple University and Drs. Won-Bin Young and Kamel Khalili for construction of HIV-1NL4-3-eGFP molecular clone plasmid and T cell assay support, respectively. We thank Dr. Bhavesh Kevadia of University of Nebraska Medical Center and Shah Valloppilly of the University of Nebraska for Materials and Nanoscience X-Ray Structural Characterization Facility for support in characterizing the modified antiretroviral drug(s) used in this study. We thank Dr. You Zhou of University of Nebraska Lincoln Center for Biotechnology for carrying out TEM imaging of nanoparticles. The research was supported by the University of North Florida, 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 Endowment, the Vice Chancellor's Office of the University of Nebraska Medical Center for Core Facility Developments and National Institutes of Health grants P01 DA028555, R01 NS36126, P01 NS31492, 2R01 NS034239, P01 MH64570, P01 NS43985, P30 MH062261 and R01 AG043540, 1 R56 AI138613-01A1.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/11
Y1 - 2019/11
N2 - While antiretroviral therapy (ART) has revolutionized treatment and prevention of human immunodeficiency virus type one (HIV-1) infection, regimen adherence, viral mutations, drug toxicities and access stigma and fatigue are treatment limitations. These have led to new opportunities for the development of long acting (LA) ART including implantable devices and chemical drug modifications. Herein, medicinal and formulation chemistry were used to develop LA prodrug nanoformulations of emtricitabine (FTC). A potent lipophilic FTC phosphoramidate prodrug (M2FTC) was synthesized then encapsulated into a poloxamer surfactant (NM2FTC). These modifications extended the biology, apparent drug half-life and antiretroviral activities of the formulations. NM2FTC demonstrated a >30-fold increase in macrophage and CD4+ T cell drug uptake with efficient conversion to triphosphates (FTC-TP). Intracellular FTC-TP protected macrophages against an HIV-1 challenge for 30 days. A single intramuscular injection of NM2FTC, at 45 mg/kg native drug equivalents, into Sprague Dawley rats resulted in sustained prodrug levels in blood, liver, spleen and lymph nodes and FTC-TP in lymph node and spleen cells at one month. In contrast, native FTC-TPs was present for one day. These results are an advance in the transformation of FTC into a LA agent.
AB - While antiretroviral therapy (ART) has revolutionized treatment and prevention of human immunodeficiency virus type one (HIV-1) infection, regimen adherence, viral mutations, drug toxicities and access stigma and fatigue are treatment limitations. These have led to new opportunities for the development of long acting (LA) ART including implantable devices and chemical drug modifications. Herein, medicinal and formulation chemistry were used to develop LA prodrug nanoformulations of emtricitabine (FTC). A potent lipophilic FTC phosphoramidate prodrug (M2FTC) was synthesized then encapsulated into a poloxamer surfactant (NM2FTC). These modifications extended the biology, apparent drug half-life and antiretroviral activities of the formulations. NM2FTC demonstrated a >30-fold increase in macrophage and CD4+ T cell drug uptake with efficient conversion to triphosphates (FTC-TP). Intracellular FTC-TP protected macrophages against an HIV-1 challenge for 30 days. A single intramuscular injection of NM2FTC, at 45 mg/kg native drug equivalents, into Sprague Dawley rats resulted in sustained prodrug levels in blood, liver, spleen and lymph nodes and FTC-TP in lymph node and spleen cells at one month. In contrast, native FTC-TPs was present for one day. These results are an advance in the transformation of FTC into a LA agent.
KW - Emtricitabine
KW - Formulation
KW - Long-acting slow effective release anti-retroviral therapy (LASER) ART
KW - Prodrug
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U2 - 10.1016/j.biomaterials.2019.119441
DO - 10.1016/j.biomaterials.2019.119441
M3 - Article
C2 - 31472458
AN - SCOPUS:85071385408
VL - 222
JO - Biomaterials
JF - Biomaterials
SN - 0142-9612
M1 - 119441
ER -