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Pharmaceutics. 2019 Apr 16;11(4). pii: E184. doi: 10.3390/pharmaceutics11040184.

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

Yang H1,2, Li J3,4, Patel SK5,6, Palmer KE7, Devlin B8, Rohan LC9,10,11.

Author information

1
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. hyang96@its.jnj.com.
2
Magee-Womens Research Institute, Pittsburgh, PA 15213, USA. hyang96@its.jnj.com.
3
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. jil132@pitt.edu.
4
Magee-Womens Research Institute, Pittsburgh, PA 15213, USA. jil132@pitt.edu.
5
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. patels10@mwri.magee.edu.
6
Magee-Womens Research Institute, Pittsburgh, PA 15213, USA. patels10@mwri.magee.edu.
7
Center for Predictive Medicine and Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA. kenneth.palmer@louisville.edu.
8
International Partnership for Microbicides, Silver Spring, MD 20910, USA. bdevlin@ipmglobal.org.
9
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. rohanlc@upmc.com.
10
Magee-Womens Research Institute, Pittsburgh, PA 15213, USA. rohanlc@upmc.com.
11
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA. rohanlc@upmc.com.

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.

KEYWORDS:

HIV; PLGA nanoparticles; co-delivery; combination ARVs; microbicides; sustained release; synergism

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