An enhanced Emtricitabine loaded long-acting nano-formulation for prevention or treatment of HIV infection. [PublishAheadOfPrint]

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 L/kg) and short plasma half-life (8-10 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 (sized <200 nm and surface-charge of -23 mV), and no to low cytotoxicity with improved biocompatibility compared to FTC solution. An ex-vivo endosomal release assay illustrated 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 ~0.74 ìg/10⁵ cells mean retention FTC drug concentration after 4 days of study period. In vitro HIV-1 inhibition study demonstrated FTC-NPs treatment results in IC₅₀ value ~43 times lower in TZM-bl cells (0.00043 μg/mL) and ~3.7 times lower (0.009 μg/mL) IC₅₀ in PBMCs, compared to FTC solution (TZM-bl cells 0.01861 and PBMCs 0.033 μg/mL). Further on primary PBMCs, FTC-NPs also illustrates a comparable HIV-1 infection blocking efficacy to FTC solution. All the above studies substantiate that FTC nano-formulation 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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