期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 61, 期 1, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01475-16
关键词
antiretroviral drug; emtricitabine; nanoparticles; HIV infection; ARV drug; PLGA polymer
资金
- NIAID [R01AI117740-01]
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 nano-formulation 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 similar to 0.74 mu g of FTC/10(5) cells after 4 days. An in vitro HIV-1 inhibition study demonstrated that FTC-NP treatment results in a 50% inhibitory concentration (IC50) similar to 43 times lower in TZM-bl cells (0.00043 mu g/ml) and similar to 3.7 times lower (0.009 mu g/ml) in peripheral blood mononuclear cells (PBMCs) than with FTC solution (TZM-bl cells, 0.01861, and PBMCs, 0.033 mu g/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.
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