title: Tenofovir alafenamide and elvitegravir loaded nanoparticles for long-acting prevention of HIV-1 vaginal transmission.
abstract: This report presents tenofovir (TFV) alafenamide (TAF) and elvitegravir (EVG) fabricated into nanoparticles for subcutaneous delivery as prevention strategy.
  
  
  
  Prospective prevention study in humanized bone marrow-liver-thymus (hu-BLT) mice.
  
  
  
  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 × 10 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).
  
  
  
  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.
  
  
  
  This proof-of-concept study demonstrated sustained protection for TAF + EVG nanoparticles in a hu-BLT mouse model of HIV vaginal transmission.
authors.affiliation: aSchool of Pharmacy & Health Professions, Creighton University, OmahabNebraska Center for Virology and School of Biological SciencescNebraska Center for Virology and Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: Subhra
authors.initials: S
authors.lastname: Mandal
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Prathipati
authors.forename: Guobin
authors.initials: G
authors.lastname: Kang
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yuan
authors.forename: Wenjin
authors.initials: W
authors.lastname: Fan
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Li
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Destache
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000409:Alanine; D000818:Animals; D003692:Delayed-Action Preparations / Q000008:administration & dosage*; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission*; D007279:Injections, Subcutaneous; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles / Q000008:administration & dosage*; D010949:Plasma / Q000821:virology; D015363:Quinolones / Q000008:administration & dosage*; D000068698:Tenofovir / Q000031:analogs & derivatives; D016896:Treatment Outcome; D014621:Vagina / Q000821:virology; D019562:Viral Load
chemical_list: D003692:Delayed-Action Preparations; D015363:Quinolones; C509700:elvitegravir; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine