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

Abstract

Objective This report presents tenofovir alafenamide (TAF) and elvitegravir (EVG) fabricated into nanoparticles (NPs) for subcutaneous (SubQ) delivery as prevention strategy. Design Prospective prevention study in hu-BLT mice. Methods Using an oil-in-water emulsion solvent evaporation technique, TAF+EVG drugs were entrapped together into NPs containing poly(lactic-co-glycolic acid) (PLGA). In vitro prophylaxis studies (IC90) compared NPs to drugs in solution. Humanized-BLT (n=5/group) mice were given 200 mg/kg SubQ, and vaginally challenged with HIV-1 (5×105 TCID50) 4 and 14 days (d) post-NP administration (PI). Control mice (n=5) were challenged at 4 d. Weekly plasma viral load (pVL) 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 (ISH). In parallel, CD34+ humanized mice (3/time point) compared tenofovir (TFV) and EVG drug levels in vaginal tissues from NPs and solution. TFV and EVG were analyzed from tissue using LC-MS/MS. Results TAF+EVG NPs were < 200 nm in size. In-vitro prophylaxis indicates TAF+EVG NPs IC90 was 0.002 μg/mL and TAF+EVG solution was 0.78 μg/mL. TAF+EVG NPs demonstrated detectable drugs for 14 days and 72 h for solution, respectively. All Hu-BLT control mice became infected within 14 d after HIV-1 challenge. In contrast, hu-BLT mice that received NPs and challenged at 4 d PI, 100% were uninfected, and 60% challenged at 14 d PI were uninfected (p = 0.007; Mantel-Cox test). ISH confirmed these results. Conclusions This proof-of-concept study demonstrated sustained protection for TAF+EVG NPs in a hu-BLT mouse model of HIV vaginal transmission.

Pharmacokinetic and Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and Elvitegravir Loaded Nanoparticles in Humanized Mice Model

“…The NPs physicochemical characterization has been reported in our earlier article (14). Briefly, the o-w emulsion methodology resulted in uniform well-defined TAF+EVG NPs having 221.6 ± 6.1 nm size, with PDI; a measure of the NP size variability of 0.107 ± 0.01 (less than < 0.2, i.e.…”

“…We have previously published the addition of EVG in vitro is synergistic to TFV for HIV-1 protection (14). However, further trials are appropriate in larger animal models for the ARV NPs to prove a link between tissue drug concentration and efficacy.…”

“…NP preparation and characterization was carried according to our previously reported publication (14). Briefly, to formulate TAF+EVG NPs, we followed oil-in-water (o-w) emulsion methodology.…”

“…We have previously reported the formulation and characterization of polymeric nanoparticles (NPs) with TAF and EVG entrapped within the polymer (14). In the present study, we report the pharmacokinetic profile and tissue distribution of TAF and EVG drugs after subcutaneous (SubQ) administration in humanized mice as TAF+EVG NPs and compared with TAF+EVG free drugs (in solution).…”

Targeted immuno-antiretroviral HIV therapeutic approach to provide dual protection and boosts cellular immunity: A proof-of-concept study

“…Even though the sustained ART-free remission is a well-accepted and effective strategy to control HIV infection, the main focus of HIV research is to develop strategies that prolong protection and target latent HIV+ cells. Recent studies have demonstrated designing a long-acting (LA) ARV delivery system would boost the HIV prevention and treatment strategy (6–9). The LA ARV delivery system has shown to enhance drug-solubility, stability, biodistribution, pharmacokinetics, efficiency, and concurrent drug safety, due to reduced ARV associated side-effects, such as mitochondrial toxicity, renal abnormality, and reduced bone mineral density (10–12).…”