Antiretroviral Hydrophobic Core Graft-Copolymer Nanoparticles: The Effectiveness against Mutant HIV-1 Strains and in Vivo Distribution after Topical Application

Autor: Suresh Gupta, Joshua F. Alfaro, Elijah M. Bolotin, Anita M. Leporati, Alexei A. Bogdanov, Marina Gottikh, Gerardo M. Castillo
Rok vydání: 2018
Předmět:
Cyclopropanes
Pharmaceutical Science
HIV Infections
02 engineering and technology
Pharmacology
Quinolones
030226 pharmacology & pharmacy
Polyethylene Glycols
chemistry.chemical_compound
0302 clinical medicine
Pharmacology (medical)
Polylysine
Tissue Distribution
Cytotoxicity
Drug Carriers
biology
Chemistry
Elvitegravir
virus diseases
021001 nanoscience & nanotechnology
Integrase
Drug Combinations
Alkynes
Molecular Medicine
Reverse Transcriptase Inhibitors
Female
0210 nano-technology
Hydrophobic and Hydrophilic Interactions
Biotechnology
medicine.drug
Biodistribution
Efavirenz
Anti-HIV Agents
Molecular Dynamics Simulation
Article
Cell Line
03 medical and health sciences
In vivo
Drug Resistance
Viral
medicine
Distribution (pharmacology)
Animals
HIV Integrase Inhibitors
Organic Chemistry
Bioavailability
Benzoxazines
Rats
Drug Liberation
Mutation
biology.protein
HIV-1
Nanoparticles
Zdroj: Pharmaceutical research. 36(5)
ISSN: 1573-904X
Popis: PURPOSE. Developing and testing of microbicides for pre-exposure prophylaxis and post-exposure protection from HIV are on the list of major HIV/AIDS research priorities. To improve solubility and bioavailability of highly potent anti-retroviral drugs, we explored the use of a nanoparticle (NP) for formulating a combination of two water-insoluble HIV inhibitors. METHODS. The combination of a non-nucleoside HIV reverse transcriptase inhibitor (NNRTI), Efavirenz (EFV), and an inhibitor of HIV integrase, Elvitegravir (ELV) was stabilized with a graft copolymer of methoxypolyethylene glycol-polylysine with a hydrophobic core (HC) composed of fatty acids (HC-PGC). Formulations were tested in TZM-bl cells infected either with wild-type HIV-1(IIIB), or drug-resistant HIV-1 strains. In vivo testing of double-labeled NP formulations was performed in female rats after a topical intravaginal administration using SPECT/CT imaging and fluorescence microscopy. RESULTS. We observed a formation of stable 23–30 nm NP with very low cytotoxicity when EFV and ELV were combined with HC-PGC at a 1:10 weight ratio. For NP containing ELV and EFV (at 1:1 by weight) we observed a remarkable improvement of EC50 of EFV by 20 times in the case of A17 strain. In vivo imaging and biodistribution showed in vivo presence of NP components at 24 and 48h after administration, respectively. CONCLUSIONS. Insoluble orthogonal inhibitors of HIV-1 life cycle may be formulated into the non-aggregating ultrasmall NP which are highly efficient against NNRTI-resistant HIV-1 variant.
Databáze: OpenAIRE
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