Antiretroviral Hydrophobic Core Graft-Copolymer Nanoparticles: The Effectiveness against Mutant HIV-1 Strains and in Vivo Distribution after Topical Application
Authors
Leporati, Anita M.Gupta, Suresh
Bolotin, Elijah
Castillo, Gerardo
Alfaro, Joshua
Gottikh, Marina B.
Bogdanov, Alexei A. Jr.
UMass Chan Affiliations
Laboratory of Molecular Imaging Probes, Department of RadiologyDocument Type
Journal ArticlePublication Date
2019-03-27Keywords
HIV integraseHIV reverse transcriptase
imaging
inhibitor
nanoparticle
Enzymes and Coenzymes
Immune System Diseases
Immunology and Infectious Disease
Nanomedicine
Pharmaceutical Preparations
Radiology
Therapeutics
Virus Diseases
Viruses
Metadata
Show full item recordAbstract
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-1IIIB, 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 48 h 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.Source
Pharm Res. 2019 Mar 27;36(5):73. doi: 10.1007/s11095-019-2604-9. Link to article on publisher's site
DOI
10.1007/s11095-019-2604-9Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48368PubMed ID
30919089Related Resources
ae974a485f413a2113503eed53cd6c53
10.1007/s11095-019-2604-9