Hydrophobic-core PEGylated graft copolymer-stabilized nanoparticles composed of insoluble non-nucleoside reverse transcriptase inhibitors exhibit strong anti-HIV activity
Department of Radiology
Nanomedicine | Radiology
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.
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Citation: Nanomedicine. 2016 Jul 25;12(8):2405-2413. doi: 10.1016/j.nano.2016.07.004. Link to article on publisher's site
Benzophenone-uracyl, Copolymer, HIV-1, Microbicide, Nanoparticle, Non-nucleoside reverse transcriptase inhibitors
Leporati, Anita M.; Novikov, Mikhail S.; Valuev-Elliston, Vladimir T.; Korolev, Sergey P.; Khandazhinskaya, Anastasia L.; Kochetkov, Sergey N.; Gupta, Suresh; Goding, Julian; Bolotin, Elijah M.; Gottikh, Marina B.; and Bogdanov, Alexei A. Jr., "Hydrophobic-core PEGylated graft copolymer-stabilized nanoparticles composed of insoluble non-nucleoside reverse transcriptase inhibitors exhibit strong anti-HIV activity" (2016). Radiology Publications and Presentations. 185.