title: Hydrophobic-core PEGylated graft copolymer-stabilized nanoparticles composed of insoluble non-nucleoside reverse transcriptase inhibitors exhibit strong anti-HIV activity.
abstract: Benzophenone-uracil (BPU) scaffold-derived candidate compounds are efficient non-nucleoside reverse transcriptase inhibitors (NNRTI) with extremely low solubility in water. We proposed to use hydrophobic core (methoxypolyethylene glycol-polylysine) graft copolymer (HC-PGC) technology for stabilizing nanoparticle-based formulations of BPU NNRTI in water. Co-lyophilization of NNRTI/HC-PGC mixtures resulted in dry powders that could be easily reconstituted with the formation of 150-250 nm stable nanoparticles (NP). The NP and HC-PGC were non-toxic in experiments with TZM-bl reporter cells. Nanoparticles containing selected efficient candidate Z107 NNRTI preserved the ability to inhibit HIV-1 reverse transcriptase polymerase activities with no appreciable change of EC50. The formulation with HC-PGC bearing residues of oleic acid resulted in nanoparticles that were nearly identical in anti-HIV-1 potency when compared to Z107 solutions in DMSO (EC50=7.5±3.8 vs. 8.2±5.1 nM). Therefore, hydrophobic core macromolecular stabilizers form nanoparticles with insoluble NNRTI while preserving the antiviral activity of the drug cargo.
authors.affiliation: Laboratory of Molecular Imaging Probes, Department of Radiology, University of Massachusetts Medical School,Worcester,MA.
authors.forename: Anita
authors.initials: A
authors.lastname: Leporati
authors.affiliation: Volgograd State Medical University, Volgograd, Russia.
authors.forename: Mikhail S
authors.initials: MS
authors.lastname: Novikov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences,Moscow, Russia.
authors.forename: Vladimir T
authors.initials: VT
authors.lastname: Valuev-Elliston
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology and Chemistry Department, Moscow, Russia.
authors.forename: Sergey P
authors.initials: SP
authors.lastname: Korolev
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences,Moscow, Russia.
authors.forename: Anastasia L
authors.initials: AL
authors.lastname: Khandazhinskaya
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences,Moscow, Russia.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Kochetkov
authors.affiliation: Laboratory of Molecular Imaging Probes, Department of Radiology, University of Massachusetts Medical School,Worcester,MA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Laboratory of Molecular Imaging Probes, Department of Radiology, University of Massachusetts Medical School,Worcester,MA.
authors.forename: Julian
authors.initials: J
authors.lastname: Goding
authors.affiliation: PharmaIN Corp., Bothell, WA.
authors.forename: Elijah
authors.initials: E
authors.lastname: Bolotin
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology and Chemistry Department, Moscow, Russia.
authors.forename: Marina B
authors.initials: MB
authors.lastname: Gottikh
authors.affiliation: Laboratory of Molecular Imaging Probes, Department of Radiology, University of Massachusetts Medical School,Worcester,MA. Electronic address: Alexei.Bogdanov@umassmed.edu.
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Bogdanov
mesh_terms: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D016503:Drug Delivery Systems; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase; D015497:HIV-1; D053758:Nanoparticles; D018894:Reverse Transcriptase Inhibitors
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase
keywords: Benzophenone-uracyl; Copolymer; HIV-1; Microbicide; Nanoparticle; Non-nucleoside reverse transcriptase inhibitors