Drug Synergy of Tenofovir and Nanoparticle-Based Antiretrovirals for HIV Prophylaxis

Abstract

BackgroundThe use of drug combinations has revolutionized the treatment of HIV but there is no equivalent combination product that exists for prevention, particularly for topical HIV prevention. Strategies to combine chemically incompatible agents may facilitate the discovery of unique drug-drug activities, particularly unexplored combination drug synergy. We fabricated two types of nanoparticles, each loaded with a single antiretroviral (ARV) that acts on a specific step of the viral replication cycle. Here we show unique combination drug activities mediated by our polymeric delivery systems when combined with free tenofovir (TFV).Methodology/Principal FindingsBiodegradable poly(lactide-co-glycolide) nanoparticles loaded with efavirenz (NP-EFV) or saquinavir (NP-SQV) were individually prepared by emulsion or nanoprecipitation techniques. Nanoparticles had reproducible size (d ∼200 nm) and zeta potential (-25 mV). The drug loading of the nanoparticles was approximately 7% (w/w). NP-EFV and NP-SQV were nontoxic to TZM-bl cells and ectocervical explants. Both NP-EFV and NP-SQV exhibited potent protection against HIV-1 BaL infection in vitro. The HIV inhibitory effect of nanoparticle formulated ARVs showed up to a 50-fold reduction in the 50% inhibitory concentration (IC50) compared to free drug. To quantify the activity arising from delivery of drug combinations, we calculated combination indices (CI) according to the median-effect principle. NP-EFV combined with free TFV demonstrated strong synergistic effects (CI50 = 0.07) at a 1∶50 ratio of IC50 values and additive effects (CI50 = 1.05) at a 1∶1 ratio of IC50 values. TFV combined with NP-SQV at a 1∶1 ratio of IC50 values also showed strong synergy (CI50 = 0.07).ConclusionsARVs with different physicochemical properties can be encapsulated individually into nanoparticles to potently inhibit HIV. Our findings demonstrate for the first time that combining TFV with either NP-EFV or NP-SQV results in pronounced combination drug effects, and emphasize the potential of nanoparticles for the realization of unique drug-drug activities.

Electrospun Solid Dispersions of Maraviroc for Rapid Intravaginal Preexposure Prophylaxis of HIV

“…The in vitro cytotoxicity of the surfactants Tween 20 (Fisher), Tween 80 (Fisher), glycerol monolaurate (Sigma-Aldrich), and nonoxynol-9 (Options Conceptrol) were evaluated using a cell titer blue assay (Promega) according to the manufacturer's instructions. The in vitro activity of maraviroc in fiber eluates (from sink release assays) was evaluated using a cell-based reporter assay described previously (8,25). Briefly, TZM-bl cells and an HIV-1 BaL isolate were obtained from the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH (http://www.aidsreagent.org/).…”

Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment

“…Recently, there has been an increased interest in LA/ER ARV drug combinations for microbicides to enhance efficacy and user adherence. Nanotechnology-based drug delivery systems are a promising option to advance the field of microbicides by their ability to (1) facilitate drug/virus interactions, (2) increase synergy for drug cocktails (3) penetrate mucosa tissue, (4) provide sustained and triggered drug release, (5) target HIV susceptible cells, (6) improve drug solubility and permeability, and (7) serve as a drug barrier along the epithelial cell lining [74–76]. Recent review articles published earlier this year discuss the benefits and potential drawbacks of exploring nanotechnology-based solutions to improve the efficacy of vaginal microbicides [73, 77].…”

Precise engineering of dapivirine-loaded nanoparticles for the development of anti-HIV vaginal microbicides

“…This in turn may potential- 78 ly increase protection against infection while allowing obtaining 79 coitally-independent microbicides. [8], respond to physiological changes occurring upon sexual inter-85 course (e.g., pH changes) [9], enhance drug targeting [10], promote 86 drug penetration and accumulation at genital tissues [11], increase 87 intracellular drug delivery [12], and improve drug activity [13]. 88 Further, drug-loaded polymeric nanoparticles (NPs) may benefi-89 cially affect local genital pharmacokinetics (PK) and, therefore, 90 potentially enhance the ability of antiretroviral compounds to pro-91 tect against infection in a coitally-independent fashion [14].…”