Abstract
BackgroundCombination antiretroviral (AR) therapy continues to be the mainstay for HIV treatment. However, antiretroviral drug nonadherence can lead to the development of resistance and treatment failure. We have designed nanoparticles (NP) that contain three AR drugs and characterized the size, shape, and surface charge. Additionally, we investigated the in vitro release of the AR drugs from the NP using peripheral blood mononuclear cells (PBMCs).MethodsPoly-(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing ritonavir (RTV), lopinavir (LPV), and efavirenz (EFV) were fabricated using multiple emulsion-solvent evaporation procedure. The nanoparticles were characterized by electron microscopy and zeta potential for size, shape, and charge. The intracellular concentration of AR drugs was determined over 28 days from NPs incubated with PBMCs. Macrophages were imaged by fluorescent microscopy and flow cytometry after incubation with fluorescent NPs. Finally, macrophage cytotoxicity was determined by MTT assay.ResultsNanoparticle size averaged 262 ± 83.9 nm and zeta potential -11.4 ± 2.4. AR loading averaged 4% (w/v). Antiretroviral drug levels were determined in PBMCs after 100 μg of NP in 75 μL PBS was added to media. Intracellular peak AR levels from NPs (day 4) were RTV 2.5 ± 1.1; LPV 4.1 ± 2.0; and EFV 10.6 ± 2.7 μg and continued until day 28 (all AR ≥ 0.9 μg). Free drugs (25 μg of each drug in 25 μL ethanol) added to PBMCs served as control were eliminated by 2 days. Fluorescence microscopy and flow cytometry demonstrated phagocytosis of NP into monocytes-derived macrophages (MDMs). Cellular MTT assay performed on MDMs demonstrated that NPs are not significantly cytotoxic.ConclusionThese results demonstrated AR NPs could be fabricated containing three antiretroviral drugs (RTV, LPV, EFV). Sustained release of AR from PLGA NP show high drug levels in PBMCs until day 28 without cytotoxicity.
Highlights
Combination antiretroviral (AR) therapy continues to be the mainstay for HIV treatment
Dosing regimens that require multiple daily dosing with diet considerations and AR side effects have compromised the achievement of long-term human immunodeficiency type-1 (HIV-1) suppression in infected patients [4]
Osmium tetroxide ladened AR NPs were incubated with macrophages for 0, 0.5, and 1 hour
Summary
Combination antiretroviral (AR) therapy continues to be the mainstay for HIV treatment. Antiretroviral drug nonadherence can lead to the development of resistance and treatment failure. The majority of infected people live in the developing world with limited treatment resources. Antiretroviral (AR) therapy has significantly reduced HIV-1 disease morbidity and improved life expectancy. The economics of drug treatment, treatment failures due to the development of resistance, and limited global access has prevented world-wide utility of AR therapy [2,3]. Dosing regimens that require multiple daily dosing with diet considerations and AR side effects have compromised the achievement of long-term HIV-1 suppression in infected patients [4]. The use of AR requires a concerted level of commitment from the patient to prevent treatment failure due to resistance
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