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.
Highlights
Sexual transmission is the primary cause of new HIV-1 infections worldwide, which today exceed 6,000 infections daily [1,2]
Our findings demonstrate for the first time that combining TFV with either nanoparticles loaded with efavirenz (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
We demonstrate that ARV compounds with low aqueous solubility can be formulated into PLGA nanoparticles with reproducible size, shape, and high drug loading content
Summary
Sexual transmission is the primary cause of new HIV-1 infections worldwide, which today exceed 6,000 infections daily [1,2]. In the absence of an effective vaccine, and as long as new infections continue to outpace advances made in treatment with antiretroviral (ARV) drugs [5], biomedical prevention strategies are critical for stemming the spread of HIV. Oral pre-exposure prophylaxis (PrEP) and topical microbicides are the lead strategies for preventing HIV infection, but there is still a critical need for methods with greater efficacy to protect women [6]. Long-acting ARV drug combinations have the potential to enhance the efficacy of current ARV-based prevention strategies by overcoming low user adherence, and harnessing drug combinations with synergistic activity and breadth of coverage against the global diversity of HIV variants. Strategies that enable ARV drugs to be combined and provide sustained antiretroviral activity have the greatest potential to impact the efficacy of future biomedical prevention methods. We show unique combination drug activities mediated by our polymeric delivery systems when combined with free tenofovir (TFV)
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