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

13 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

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

All Science Journal Classification (ASJC) codes

  • 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 - Mandal, Subhra

AU - Prathipati, Pavan K.

AU - Kang, Guobin

AU - Zhou, You

AU - Yuan, Zhe

AU - Fan, Wenjin

AU - Li, Qingsheng

AU - Destache, Christopher J.

PY - 2017/2/20

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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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