Design of Poly(lactic-co-glycolic Acid) (PLGA) Nanoparticles for Vaginal Co-Delivery of Griffithsin and Dapivirine and Their Synergistic Effect for HIV Prophylaxis.

Jing Li,Haitao Yang,Kenneth E Palmer,Brid Devlin,Lisa C Rohan,Sravan Kumar Patel

doi:10.3390/pharmaceutics11040184

Jing Li, Haitao Yang + Show 4 more

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https://doi.org/10.3390/pharmaceutics11040184

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Abstract

Long-acting topical products for pre-exposure prophylaxis (PrEP) that combine antiretrovirals (ARVs) inhibiting initial stages of infection are highly promising for prevention of HIV sexual transmission. We fabricated core-shell poly(lactide-co-glycolide) (PLGA) nanoparticles, loaded with two potent ARVs, griffithsin (GRFT) and dapivirine (DPV), having different physicochemical properties and specifically targeting the fusion and reverse transcription steps of HIV replication, as a potential long-acting microbicide product. The nanoparticles were evaluated for particle size and zeta potential, drug release, cytotoxicity, cellular uptake and in vitro bioactivity. PLGA nanoparticles, with diameter around 180–200 nm, successfully encapsulated GRFT (45% of initially added) and DPV (70%). Both drugs showed a biphasic release with initial burst phase followed by a sustained release phase. GRFT and DPV nanoparticles were non-toxic and maintained bioactivity (IC50 values of 0.5 nM and 4.7 nM, respectively) in a cell-based assay. The combination of drugs in both unformulated and encapsulated in nanoparticles showed strong synergistic drug activity at 1:1 ratio of IC50 values. This is the first study to co-deliver a protein (GRFT) and a hydrophobic small molecule (DPV) in PLGA nanoparticles as microbicides. Our findings demonstrate that the combination of GRFT and DPV in nanoparticles is highly potent and possess properties critical to the design of a sustained release microbicide.

Highlights

Human immunodeficiency virus (HIV) infection is one of the world’s most serious health challenges, and the development of means to prevent its spread is urgently needed
We investigated the ability of poly(lactic-co-glycolic acid) (PLGA) nanoparticles to deliver both GRFT and DPV simultaneously and their anti-HIV efficacy in combined application as ARVs
Nanoparticles have been intensively investigated in numerous biomedical applications, not many studies have been conducted on nanoparticles as a drug delivery system for pre-exposure prophylaxis (PrEP) products, especially the combination delivery of a protein drug with a water-insoluble drug

Summary

Introduction

Human immunodeficiency virus (HIV) infection is one of the world’s most serious health challenges, and the development of means to prevent its spread is urgently needed. To protect women from this global epidemic, it is critical to develop effective biomedical interventions for HIV/AIDS prevention and treatment. The low instance of condom use by men and other social factors could significantly increase HIV-1 infection in women [4,5]. With these considerations in mind, oral or topical pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs could be the most promising avenue for preventing sexually transmitted HIV infection. Topical PrEP products could be applied by women in the vaginal or rectal tract before sexual intercourse to inactivate pathogens, including HIV, providing a female-controlled strategy against HIV-1 infection [6,7,8]. Rectal-specific topical PrEP products are applicable to men who have sex with men (MSM)

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