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Tenofovir alafenamide and elvitegravir loaded nanoparticles for long-acting prevention of HIV-1 vaginal transmission

Mandal, Subhra; Prathipati, Pavan K.; Kang, Guobin; Zhou, You; Yuan, Zhe; Fan, Wenjin; Li, Qingsheng; Destache, Christopher J.

doi: 10.1097/QAD.0000000000001349
Basic Science

Objective: This report presents tenofovir (TFV) alafenamide (TAF) and elvitegravir (EVG) fabricated into nanoparticles for subcutaneous delivery as prevention strategy.

Design: Prospective prevention study in humanized bone marrow–liver–thymus (hu-BLT) mice.

Methods: Using an oil-in-water emulsion solvent evaporation technique, TAF + EVG drugs were entrapped together into nanoparticles containing poly(lactic-co-glycolic acid). In-vitro prophylaxis studies (90% inhibition concentration) compared nanoparticles with drugs in solution. Hu-BLT (n = 5/group) mice were given 200 mg/kg subcutaneous, and vaginally challenged with HIV-1 [5 × 105 tissue culture infectious dose for 50% of cells cultures (TCID50)] 4 and 14 days post-nanoparticle administration (post-nanoparticle injection). Control mice (n = 5) were challenged at 4 days. Weekly plasma viral load was performed using RT-PCR. Hu-BLT mice were sacrificed and lymph nodes were harvested for HIV-1 viral RNA detection by in-situ hybridization. In parallel, CD34+ humanized mice (3/time point) compared TFV and EVG drug levels in vaginal tissues from nanoparticles and solution. TFV and EVG were analyzed from tissue using liquid chromatograph-tandem mass spectrometry (LC-MS/MS).

Results: TAF + EVG nanoparticles were less than 200 nm in size. In-vitro prophylaxis indicates TAF + EVG nanoparticles 90% inhibition concentration was 0.002 μg/ml and TAF + EVG solution was 0.78 μg/ml. TAF + EVG nanoparticles demonstrated detectable drugs for 14 days and 72 h for solution, respectively. All hu-BLT control mice became infected within 14 days after HIV-1 challenge. In contrast, hu-BLT mice that received nanoparticles and challenged at 4 days post-nanoparticle injection, 100% were uninfected, and 60% challenged at 14 days post-nanoparticle injection were uninfected (P = 0.007; Mantel–Cox test). In-situ hybridization confirmed these results.

Conclusion: This proof-of-concept study demonstrated sustained protection for TAF + EVG nanoparticles in a hu-BLT mouse model of HIV vaginal transmission.

aSchool of Pharmacy & Health Professions, Creighton University, Omaha

bNebraska Center for Virology and School of Biological Sciences

cNebraska Center for Virology and Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.

Correspondence to Christopher J. Destache, Pharm. D., Professor of Pharmacy Practice and Infectious Diseases, School of Pharmacy & Health Professions, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA. Tel: +1 402 280 4744; e-mail: destache@creighton.edu

Received 25 August, 2016

Revised 7 November, 2016

Accepted 14 November, 2016

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Copyright © 2017 Wolters Kluwer Health, Inc.