Topical tenofovir disoproxil fumarate nanoparticles prevent HIV-1 vaginal transmission in a humanized mouse model

Christopher J. Destache, Subhra Mandal, Zhe Yuan, Guobin Kang, Abhijit A. Date, Wuxun Lu, Annemarie Shibata, Rachel Pham, Patrick Bruck, Michael Rezich, You Zhou, Renuga Vivekanandan, Courtney V. Fletcher, Qingsheng Li

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Abstract

Preexposure prophylaxis (PrEP) with 1% tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification. The efficacy of TDF-NP-TMS gel was tested in humanized bone marrow-liver-thymus (hu-BLT) mice. Hu-BLT mice in the treatment group (Rx; n = 15) were administered TDF-NP-TMS gel intravaginally, having TDF at 0.1%, 0.5%, and 1% (wt/vol) concentrations, whereas the control (Ctr; n = 8) group received a blank TMS gel. All Rx mice (0.1% [n = 4], 0.5% [n = 6], and 1% [n = 5]) were vaginally challenged with two transmitted/founder (T/F) HIV-1 strains (2.5 × 105 50% tissue culture infectious doses). Rx mice were challenged at 4 h (0.1%), 24 h (0.5%), and 7 days (1%) posttreatment (p.t.) and Ctr mice were challenged at 4 h p.t. Blood was drawn weekly for 4 weeks postinoculation (p.i.) for plasma viral load (pVL) using reverse transcription-quantitative PCR. Ctr mice had positive pVL within 2 weeks p.i. Rx mice challenged at 4 h and 24 h showed 100% protection and no detectable pVL throughout the 4 weeks of follow-up (P = 0.009; Mantel-Cox test). Mice challenged at 7 days were HIV-1 positive at 14 days p.i. Further, HIV-1 viral RNA (vRNA) in vaginal and spleen tissues of Rx group mice with negative pVL were examined using an in situ hybridization (ISH) technique. The detection of vRNA was negative in all Rx mice studied. The present studies elucidate TDF-NP-TMS gel as a long-acting, coitus-independent HIV-1 vaginal protection modality.

Original languageEnglish
Pages (from-to)3633-3639
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number6
DOIs
StatePublished - Jun 1 2016

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Tenofovir
Nanoparticles
HIV-1
Gels
Viral Load
Foams and Jellies Vaginal Creams
Viral RNA

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Topical tenofovir disoproxil fumarate nanoparticles prevent HIV-1 vaginal transmission in a humanized mouse model. / Destache, Christopher J.; Mandal, Subhra; Yuan, Zhe; Kang, Guobin; Date, Abhijit A.; Lu, Wuxun; Shibata, Annemarie; Pham, Rachel; Bruck, Patrick; Rezich, Michael; Zhou, You; Vivekanandan, Renuga; Fletcher, Courtney V.; Li, Qingsheng.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 6, 01.06.2016, p. 3633-3639.

Research output: Contribution to journalArticle

Destache, CJ, Mandal, S, Yuan, Z, Kang, G, Date, AA, Lu, W, Shibata, A, Pham, R, Bruck, P, Rezich, M, Zhou, Y, Vivekanandan, R, Fletcher, CV & Li, Q 2016, 'Topical tenofovir disoproxil fumarate nanoparticles prevent HIV-1 vaginal transmission in a humanized mouse model', Antimicrobial Agents and Chemotherapy, vol. 60, no. 6, pp. 3633-3639. https://doi.org/10.1128/AAC.00450-16
Destache, Christopher J. ; Mandal, Subhra ; Yuan, Zhe ; Kang, Guobin ; Date, Abhijit A. ; Lu, Wuxun ; Shibata, Annemarie ; Pham, Rachel ; Bruck, Patrick ; Rezich, Michael ; Zhou, You ; Vivekanandan, Renuga ; Fletcher, Courtney V. ; Li, Qingsheng. / Topical tenofovir disoproxil fumarate nanoparticles prevent HIV-1 vaginal transmission in a humanized mouse model. In: Antimicrobial Agents and Chemotherapy. 2016 ; Vol. 60, No. 6. pp. 3633-3639.
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abstract = "Preexposure prophylaxis (PrEP) with 1{\%} tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification. The efficacy of TDF-NP-TMS gel was tested in humanized bone marrow-liver-thymus (hu-BLT) mice. Hu-BLT mice in the treatment group (Rx; n = 15) were administered TDF-NP-TMS gel intravaginally, having TDF at 0.1{\%}, 0.5{\%}, and 1{\%} (wt/vol) concentrations, whereas the control (Ctr; n = 8) group received a blank TMS gel. All Rx mice (0.1{\%} [n = 4], 0.5{\%} [n = 6], and 1{\%} [n = 5]) were vaginally challenged with two transmitted/founder (T/F) HIV-1 strains (2.5 × 105 50{\%} tissue culture infectious doses). Rx mice were challenged at 4 h (0.1{\%}), 24 h (0.5{\%}), and 7 days (1{\%}) posttreatment (p.t.) and Ctr mice were challenged at 4 h p.t. Blood was drawn weekly for 4 weeks postinoculation (p.i.) for plasma viral load (pVL) using reverse transcription-quantitative PCR. Ctr mice had positive pVL within 2 weeks p.i. Rx mice challenged at 4 h and 24 h showed 100{\%} protection and no detectable pVL throughout the 4 weeks of follow-up (P = 0.009; Mantel-Cox test). Mice challenged at 7 days were HIV-1 positive at 14 days p.i. Further, HIV-1 viral RNA (vRNA) in vaginal and spleen tissues of Rx group mice with negative pVL were examined using an in situ hybridization (ISH) technique. The detection of vRNA was negative in all Rx mice studied. The present studies elucidate TDF-NP-TMS gel as a long-acting, coitus-independent HIV-1 vaginal protection modality.",
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N2 - Preexposure prophylaxis (PrEP) with 1% tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification. The efficacy of TDF-NP-TMS gel was tested in humanized bone marrow-liver-thymus (hu-BLT) mice. Hu-BLT mice in the treatment group (Rx; n = 15) were administered TDF-NP-TMS gel intravaginally, having TDF at 0.1%, 0.5%, and 1% (wt/vol) concentrations, whereas the control (Ctr; n = 8) group received a blank TMS gel. All Rx mice (0.1% [n = 4], 0.5% [n = 6], and 1% [n = 5]) were vaginally challenged with two transmitted/founder (T/F) HIV-1 strains (2.5 × 105 50% tissue culture infectious doses). Rx mice were challenged at 4 h (0.1%), 24 h (0.5%), and 7 days (1%) posttreatment (p.t.) and Ctr mice were challenged at 4 h p.t. Blood was drawn weekly for 4 weeks postinoculation (p.i.) for plasma viral load (pVL) using reverse transcription-quantitative PCR. Ctr mice had positive pVL within 2 weeks p.i. Rx mice challenged at 4 h and 24 h showed 100% protection and no detectable pVL throughout the 4 weeks of follow-up (P = 0.009; Mantel-Cox test). Mice challenged at 7 days were HIV-1 positive at 14 days p.i. Further, HIV-1 viral RNA (vRNA) in vaginal and spleen tissues of Rx group mice with negative pVL were examined using an in situ hybridization (ISH) technique. The detection of vRNA was negative in all Rx mice studied. The present studies elucidate TDF-NP-TMS gel as a long-acting, coitus-independent HIV-1 vaginal protection modality.

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