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

1
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
2
Magee-Womens Research Institute, Pittsburgh, PA 15213, USA
3
Center for Predictive Medicine and Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA
4
International Partnership for Microbicides, Silver Spring, MD 20910, USA
5
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
*
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(4), 184; https://doi.org/10.3390/pharmaceutics11040184
Received: 21 February 2019 / Revised: 3 April 2019 / Accepted: 11 April 2019 / Published: 16 April 2019
(This article belongs to the Special Issue Novel Approaches for Delivery of Anti-HIV Drugs)
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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. View Full-Text
Keywords: microbicides; HIV; combination ARVs; sustained release; synergism; PLGA nanoparticles; co-delivery microbicides; HIV; combination ARVs; sustained release; synergism; PLGA nanoparticles; co-delivery
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Yang, H.; Li, J.; Patel, S.K.; Palmer, K.E.; Devlin, B.; Rohan, L.C. Design of Poly(lactic-co-glycolic Acid) (PLGA) Nanoparticles for Vaginal Co-Delivery of Griffithsin and Dapivirine and Their Synergistic Effect for HIV Prophylaxis. Pharmaceutics 2019, 11, 184.

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