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

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 (postnanoparticle 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 200nm in size. In-vitro prophylaxis indicates TAF+EVG nanoparticles 90% inhibition concentration was 0.002mg/ml and TAF+EVG solution was 0.78mg/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.

Original languageEnglish (US)
Pages (from-to)469-476
Number of pages8
JournalAIDS
Volume31
Issue number4
DOIs
StatePublished - Feb 20 2017

Fingerprint

Nanoparticles
HIV-1
Tenofovir
Pharmaceutical Preparations
Injections
In Situ Hybridization
GS-7340
JTK 303
Viral RNA
Tandem Mass Spectrometry
Emulsions
Viral Load
Thymus Gland
Oils
Cell Culture Techniques
Lymph Nodes
Bone Marrow
HIV
Prospective Studies
Polymerase Chain Reaction

Keywords

  • Elvitegravir
  • HIV-1 prevention
  • Humanized mouse model
  • Poly(lactic-co-glycolic acid) nanoparticles
  • Tenofovir alafenamide

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

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.

In: AIDS, Vol. 31, No. 4, 20.02.2017, p. 469-476.

Research output: Contribution to journalArticle

Mandal, Subhra ; Prathipati, Pavan K. ; Kang, Guobin ; Zhou, You ; Yuan, Zhe ; Fan, Wenjin ; Li, Qingsheng ; Destache, Christopher J. / Tenofovir alafenamide and elvitegravir loaded nanoparticles for long-acting prevention of HIV-1 vaginal transmission. In: AIDS. 2017 ; Vol. 31, No. 4. pp. 469-476.
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abstract = "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 (postnanoparticle 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 200nm in size. In-vitro prophylaxis indicates TAF+EVG nanoparticles 90{\%} inhibition concentration was 0.002mg/ml and TAF+EVG solution was 0.78mg/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.",
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AU - Kang, Guobin

AU - Zhou, You

AU - Yuan, Zhe

AU - Fan, Wenjin

AU - Li, Qingsheng

AU - Destache, Christopher J.

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N2 - 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 (postnanoparticle 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 200nm in size. In-vitro prophylaxis indicates TAF+EVG nanoparticles 90% inhibition concentration was 0.002mg/ml and TAF+EVG solution was 0.78mg/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.

AB - 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 (postnanoparticle 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 200nm in size. In-vitro prophylaxis indicates TAF+EVG nanoparticles 90% inhibition concentration was 0.002mg/ml and TAF+EVG solution was 0.78mg/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.

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