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

Autor: Kim A. Woodrow, Emily Krogstad, Cameron Ball, Thanyanan Chaowanachan
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Cyclopropanes
Chemistry
Pharmaceutical
Human immunodeficiency virus (HIV)
lcsh:Medicine
HIV Infections
02 engineering and technology
Cervix Uteri
Pharmacology
medicine.disease_cause
Tissue Culture Techniques
Engineering
Polylactic Acid-Polyglycolic Acid Copolymer
Combination Product
Spectroscopy
Fourier Transform Infrared
Drug Interactions
lcsh:Science
Saquinavir
media_common
0303 health sciences
Drug Carriers
Multidisciplinary
virus diseases
Drug Synergism
021001 nanoscience & nanotechnology
3. Good health
Synergy
Alkynes
Drug delivery
Medicine
Infectious diseases
Drug Therapy
Combination
Female
0210 nano-technology
Drug carrier
medicine.drug
Combination drug
Research Article
Drug
Drugs and Devices
Drug Research and Development
Anti-HIV Agents
media_common.quotation_subject
Materials Science
HIV prevention
Biomedical Engineering
Organophosphonates
Bioengineering
Viral diseases
Models
Biological
Material by Attribute
Cell Line
Biomaterials
03 medical and health sciences
Inhibitory Concentration 50
medicine
Animals
Humans
Lactic Acid
Particle Size
Tenofovir
030304 developmental biology
Nanomaterials
business.industry
Adenine
lcsh:R
HIV
Virology
Benzoxazines
Delayed-Action Preparations
HIV-1
Macaca
Nanoparticles
lcsh:Q
business
Polyglycolic Acid
Zdroj: PLoS ONE
PLoS ONE, Vol 8, Iss 4, p e61416 (2013)
ISSN: 1932-6203
Popis: 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). Methodology/Principal Findings 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.
Databáze: OpenAIRE
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