TY - JOUR
T1 - Nanoencapsulation introduces long-acting phenomenon to tenofovir alafenamide and emtricitabine drug combination
T2 - A comparative pre-exposure prophylaxis efficacy study against HIV-1 vaginal transmission
AU - Mandal, Subhra
AU - Kang, Guobin
AU - Prathipati, Pavan Kumar
AU - Zhou, You
AU - Fan, Wenjin
AU - Li, Qingsheng
AU - Destache, Christopher J.
N1 - Publisher Copyright:
© 2018
PY - 2019/1/28
Y1 - 2019/1/28
N2 - Daily oral antiretroviral (ARV) drugs for pre-exposure prophylaxis (PrEP) has proven efficacy for diverse groups of high-risk individuals. However, daily dosing regimen has augmented non-adherence. These experiments comparatively investigated the long-acting (LA) PrEP potency of subcutaneous (SubQ) administrated tenofovir alafenamide (TAF) and emtricitabine (FTC) loaded nanoparticles (NPs) to solution in humanized (hu) mice. TAF + FTC NPs and TAF + FTC solution (each drug at 200 mg/kg) were administered to hu-CD34-NSG mice (n = 3/time point) for plasma and tissue pharmacokinetic parameter estimation using LC-MS/MS. NP enhanced tissue ARV assimilation compared to plasma. The same dose was administered for PrEP efficacy in HIV-1 challenged hu-BLT mice (n = 5/group). The hu-BLT mice were vaginally challenged with a transmission-founder (T/F) virus at 5 × 105 TCID50 inoculation, on day 4, 7 and 14 post-SubQ treatments (PT) and were compared to infected-untreated-control hu-BLT mice. By 21 days PT, 100% TAF + FTC solution-treated and control-untreated mice were infected. However, TAF + FTC NPs resulted in significant (p =.0002) protection from HIV-1 (day 4: 80%, day 7 and 14: 60%, respectively) compared to control mice. This proof-of-concept study demonstrated detectable TAF/FTC vaginal levels among TAF + FTC NP-treated hu-BLT mice correlating with prolonged PrEP efficacy, thus establishing long-acting TAF + FTC NPs as a potential PrEP modality.
AB - Daily oral antiretroviral (ARV) drugs for pre-exposure prophylaxis (PrEP) has proven efficacy for diverse groups of high-risk individuals. However, daily dosing regimen has augmented non-adherence. These experiments comparatively investigated the long-acting (LA) PrEP potency of subcutaneous (SubQ) administrated tenofovir alafenamide (TAF) and emtricitabine (FTC) loaded nanoparticles (NPs) to solution in humanized (hu) mice. TAF + FTC NPs and TAF + FTC solution (each drug at 200 mg/kg) were administered to hu-CD34-NSG mice (n = 3/time point) for plasma and tissue pharmacokinetic parameter estimation using LC-MS/MS. NP enhanced tissue ARV assimilation compared to plasma. The same dose was administered for PrEP efficacy in HIV-1 challenged hu-BLT mice (n = 5/group). The hu-BLT mice were vaginally challenged with a transmission-founder (T/F) virus at 5 × 105 TCID50 inoculation, on day 4, 7 and 14 post-SubQ treatments (PT) and were compared to infected-untreated-control hu-BLT mice. By 21 days PT, 100% TAF + FTC solution-treated and control-untreated mice were infected. However, TAF + FTC NPs resulted in significant (p =.0002) protection from HIV-1 (day 4: 80%, day 7 and 14: 60%, respectively) compared to control mice. This proof-of-concept study demonstrated detectable TAF/FTC vaginal levels among TAF + FTC NP-treated hu-BLT mice correlating with prolonged PrEP efficacy, thus establishing long-acting TAF + FTC NPs as a potential PrEP modality.
KW - Emtricitabine
KW - HIV-1 prevention
KW - Long-acting
KW - Nanoparticles
KW - Tenofovir alafenamide
UR - http://www.scopus.com/inward/record.url?scp=85058950216&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058950216&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2018.12.027
DO - 10.1016/j.jconrel.2018.12.027
M3 - Article
C2 - 30576746
AN - SCOPUS:85058950216
SN - 0168-3659
VL - 294
SP - 216
EP - 225
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -