Hydrophobic-core PEGylated graft copolymer-stabilized nanoparticles composed of insoluble non-nucleoside reverse transcriptase inhibitors exhibit strong anti-HIV activity

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• 作者：Anita Leporati^a ; Mikhail S. Novikov^b ; Vladimir T. Valuev-Elliston^c ; Sergey P. Korolev^d ; Anastasia L. Khandazhinskaya^c ; Sergey N. Kochetkov^c ; Suresh Gupta^a ; Julian Goding^a ; Elijah Bolotin^e ; Marina B. Gottikh^d ; Alexei A. Bogdanov Jr.^a ; ^{Alexei.Bogdanov@umassmed.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Non-nucleoside reverse transcriptase inhibitors ; Microbicide ; HIV-1 ; Nanoparticle ; Copolymer ; Benzophenone-uracyl
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：12
• 期：8
• 页码：2405-2413
• 全文大小：1264 K

文摘

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.