Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reducedmitochondrial toxicity.

摘要

BACKGROUND: Macrophages serve as a depot for HIV type-1 (HIV-1) in the centralnervous system. To efficiently target macrophages, we developed nanocarriers forpotential brain delivery of activated nucleoside reverse transcriptase inhibitors(NRTIs) called nano-NRTIs.METHODS: Nanogel carriers consisting of poly(ethylene glycol) (PEG)- orPluronic-polyethylenimine (PEI) biodegradable networks, star PEG-PEI orpoly(amidoamine) dendrimer-PEI-PEG dendritic networks, as well as nanogelsdecorated with brain-targeting peptide molecules, specifically binding to theapolipoprotein E receptor, were synthesized and evaluated. Nano-NRTIs wereobtained by mixing aqueous solutions of zidovudine 5'-triphosphate or didanosine5'-triphosphate and nanocarriers, followed by freeze-drying. Intracellularaccumulation, cytotoxicity and antiviral activity of nano-NRTIs were monitored inmonocyte-derived macrophages (MDMs). HIV-1 viral activity in infected MDMs wasmeasured by a reverse transcriptase activity assay following treatment withnano-NRTIs. Mitochondrial DNA depletion in MDMs and human HepG2 cells wasassessed by quantitative PCR.RESULTS: Nanogels were efficiently captured by MDMs and demonstrated lowcytotoxicity, and no antiviral activity without drugs. All nano-NRTIsdemonstrated high efficacy of HIV-1 inhibition at drug levels as low as 1 μmol/l,representing a 4.9- to 14-fold decrease in 90% effective drug concentrations ascompared with NRTIs, whereas 50% cytotoxicity effects started at 200× higherconcentrations. Nano-NRTIs with a core-shell structure and decorated withbrain-targeting peptides displayed the highest antiviral efficacy. MitochondrialDNA depletion, a major cause of NRTI neurotoxicity, was reduced threefoldcompared with NRTIs at application of selected nano-NRTIs.CONCLUSIONS: Nano-NRTIs demonstrated a promising antiviral efficacy against HIV-1in MDMs and showed strong potential as nanocarriers for delivery of antiviraldrugs to macrophages harbouring in the brain.