An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection.
Among various FDA-approved combination antiretroviral drugs (cARVs), emtricitabine (FTC) has been a very effective nucleoside reverse transcriptase inhibitor. Thus far, FTC is the only deoxycytidine nucleoside analog. However, a major drawback of FTC is its large volume distribution (averaging 1.4 liters/kg) and short plasma half-life (8 to 10 h), necessitating a high daily dosage. Thus, we propose an innovative fabrication method of loading FTC in poly(lactic-co-glycolic acid) polymeric nanoparticles (FTC-NPs), potentially overcoming these drawbacks. Our nanoformulation demonstrated enhanced FTC loading (size of <200 nm and surface charge of -23 mV) and no to low cytotoxicity with improved biocompatibility compared to those with FTC solution. An ex vivo endosomal release assay illustrated that NP entrapment prolongs FTC release over a month. Intracellular retention studies demonstrate sustained FTC retention over time, with approximately 8% (24 h) to 68% (96 h) release with a mean retention of ∼0.74 μg of FTC/105cells after 4 days. An in vitro HIV-1 inhibition study demonstrated that FTC-NP treatment results in a 50% inhibitory concentration (IC50) ∼43 times lower in TZM-bl cells (0.00043 μg/ml) and ∼3.7 times lower (0.009 μg/ml) in peripheral blood mononuclear cells (PBMCs) than with FTC solution (TZM-bl cells, 0.01861, and PBMCs, 0.033 μg/ml). Further, on primary PBMCs, FTC-NPs also illustrate an HIV-1 infection blocking efficacy comparable to that of FTC solution. All the above-described studies substantiate that FTC nanoformulation prolongs intracellular FTC concentration and inhibition of HIV infection. Therefore, FTC-NPs potentially could be a long-acting, stable formulation to ensure once-biweekly dosing to prevent or treat HIV infection.
Department of Pharmacy Practice, School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska, USA SubhraMandal@creighton.edu ChrisDestache@creighton.edu.
Subhra
S
Mandal
Department of Medical Microbiology & Immunology, Creighton University School of Medicine, Creighton University, Omaha, Nebraska, USA.
Michael
M
Belshan
Department of Pharmacy Practice, School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska, USA.|Department of Medical Microbiology & Immunology, Creighton University School of Medicine, Creighton University, Omaha, Nebraska, USA.
Ashley
A
Holec
Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
You
Y
Zhou
Department of Pharmacy Practice, School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska, USA SubhraMandal@creighton.edu ChrisDestache@creighton.edu.
Christopher J
0000-0001-7923-3939
CJ
Destache
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D000068679:Emtricitabine / Q000494:pharmacology*; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D053758:Nanoparticles
D019380:Anti-HIV Agents; D000068679:Emtricitabine
ARV drug; HIV infection; PLGA polymer; antiretroviral drug; emtricitabine; nanoparticles