title: Drug synergy of tenofovir and nanoparticle-based antiretrovirals for HIV prophylaxis.
abstract: BACKGROUND
  The 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).
  
  
  RESULTS
  Biodegradable 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).
  
  
  CONCLUSIONS
  ARVs 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.
authors: Department of Bioengineering, University of Washington, Seattle, Washington, United States of America.
authors: Thanyanan
authors: T
authors: Chaowanachan
authors: Emily
authors: E
authors: Krogstad
authors: Cameron
authors: C
authors: Ball
authors: Kim A
authors: KA
authors: Woodrow
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000480:Alkynes; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000633:toxicity; D048588:Benzoxazines / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002584:Cervix Uteri / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003521:Cyclopropanes; D003692:Delayed-Action Preparations / Q000494:pharmacology / Q000633:toxicity; D004337:Drug Carriers / Q000494:pharmacology / Q000633:toxicity; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D019344:Lactic Acid / Q000737:chemistry; D008251:Macaca; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D063065:Organophosphonates / Q000494:pharmacology* / Q000633:toxicity; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D019258:Saquinavir / Q000494:pharmacology* / Q000633:toxicity; D017550:Spectroscopy, Fourier Transform Infrared; D000068698:Tenofovir; D046509:Tissue Culture Techniques
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D063065:Organophosphonates; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000068698:Tenofovir; D000225:Adenine; C098320:efavirenz; D019258:Saquinavir
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