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. 2016 Nov;12(8):2405-2413.
doi: 10.1016/j.nano.2016.07.004. Epub 2016 Jul 25.

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

Anita Leporati  1 , Mikhail S Novikov  2 , Vladimir T Valuev-Elliston  3 , Sergey P Korolev  4 , Anastasia L Khandazhinskaya  3 , Sergey N Kochetkov  3 , Suresh Gupta  1 , Julian Goding  1 , Elijah Bolotin  5 , Marina B Gottikh  4 , Alexei A Bogdanov Jr  6
Affiliations

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

Anita Leporati et al. Nanomedicine. 2016 Nov.

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.

Keywords: Benzophenone-uracyl; Copolymer; HIV-1; Microbicide; Nanoparticle; Non-nucleoside reverse transcriptase inhibitors.

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Figures

Figure 1
Figure 1
Chemical structures of BPU scaffold-derived NNRTI used in this work. Z007 and Z011 have been previously shown to be efficient NNRTI , while Z107 is new to this study.
Figure 2
Figure 2
The dependence of NP sizes (shown as number average diameters, mean±SD) on the content of Z107 NNRTI in the formulation with HC-PGC (M5P21OL, 10 mg/ml) as determined by dynamic light scattering (Zetasizer Nano ZS, Malvern Inst). The content of the main fraction in formulations is shown above the bars in grey. The remaining fraction of free (non-incorporated) MPEG-gPLL NP is shown as black bars.
Figure 3
Figure 3
Transmission electron microscopy of M5P21OL (1 mg/ml, A) and Z107-M5P21OL (2.5% NNRTI by weight, B), at 1 mg M5P21OL/ml after staining/fixation with uranyl acetate. Arrowheads point to stabilized crystalline NP of Z107. The inset in A shows M5P21OL NP at 128,000x. The bar= 200 nm.
Figure 4
Figure 4
Dependence of TZM-bl HIV-1 infection on the concentration of HC-PGC carriers alone (A) or NNRTI and NNRTI/HC-PGC (B). A- M5P21OL (black circles), M5P21S (red circles). M5P52S (blue circles). B- Titration of NNRTI was performed either from a stock solution of NNRTI in DMSO - solid symbols, or after formulating NNRTI using HC-PGC (M5P21OL) - open symbols. Z107 –red; Z011 – blue; Z007 – black. Inhibition of HIV-1 infection of TZM-bl cells determined by using fLuc expression luminescence assay. Data is shown as mean±SD. The obtained EC50 values are summarized in Table 3.
Figure 5
Figure 5
Confocal microscopy of control (A,C) or HIV-1 infected (B,D) TZM-bl cells. Cells were incubated for 24 h with AF488-labeled HC-PGC carrier only (1 M5P21OL mg/ml) (A,B) or with Z107 NNRTI/ M5P21OL NP (0.1 mg/ml Z107, 1 mg/ml M5P21OL) (C,D). Blue - DAPI, green - AF488. Large pinosomes are marked with arrows, NP within the peri-membrane compartment and NP adsorbed on plasma membrane are shown with arrowheads.
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References

    1. Kanmogne GD, Singh S, Roy U, Liu X, McMillan J, Gorantla S, et al. Mononuclear phagocyte intercellular crosstalk facilitates transmission of cell-targeted nanoformulated antiretroviral drugs to human brain endothelial cells. Int J Nanomedicine. 2012;7:2373–88. - PMC - PubMed
    1. Edagwa BJ, Zhou T, McMillan JM, Liu XM, Gendelman HE. Development of HIV reservoir targeted long acting nanoformulated antiretroviral therapies. Curr Med Chem. 2014;21:4186–98. - PMC - PubMed
    1. Ensign LM, Cone R, Hanes J. Nanoparticle-based drug delivery to the vagina: a review. J Control Release. 2014;190:500–14. - PMC - PubMed
    1. du Toit LC, Pillay V, Choonara YE. Nano-microbicides: Challenges in drug delivery, patient ethics and intellectual property in the war against HIV/AIDS. Adv Drug Deliv Rev. 2010;62:532–46. - PubMed
    1. Sanchez-Rodriguez J, Vacas-Cordoba E, Gomez R, De La Mata FJ, Munoz-Fernandez MA. Nanotech-derived topical microbicides for HIV prevention: The road to clinical development. Antiviral Res. 2015;113:33–48. - PubMed