Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity

Antivir Chem Chemother. 2010 Oct 28;21(1):1-14. doi: 10.3851/IMP1680.

Abstract

Background: Macrophages serve as a depot for HIV type-1 (HIV-1) in the central nervous system. To efficiently target macrophages, we developed nanocarriers for potential brain delivery of activated nucleoside reverse transcriptase inhibitors (NRTIs) called nano-NRTIs.

Methods: Nanogel carriers consisting of poly(ethylene glycol) (PEG)- or Pluronic-polyethylenimine (PEI) biodegradable networks, star PEG-PEI or poly(amidoamine) dendrimer-PEI-PEG dendritic networks, as well as nanogels decorated with brain-targeting peptide molecules, specifically binding to the apolipoprotein E receptor, were synthesized and evaluated. Nano-NRTIs were obtained by mixing aqueous solutions of zidovudine 5'-triphosphate or didanosine 5'-triphosphate and nanocarriers, followed by freeze-drying. Intracellular accumulation, cytotoxicity and antiviral activity of nano-NRTIs were monitored in monocyte-derived macrophages (MDMs). HIV-1 viral activity in infected MDMs was measured by a reverse transcriptase activity assay following treatment with nano-NRTIs. Mitochondrial DNA depletion in MDMs and human HepG2 cells was assessed by quantitative PCR.

Results: Nanogels were efficiently captured by MDMs and demonstrated low cytotoxicity, and no antiviral activity without drugs. All nano-NRTIs demonstrated 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 as compared with NRTIs, whereas 50% cytotoxicity effects started at 200× higher concentrations. Nano-NRTIs with a core-shell structure and decorated with brain-targeting peptides displayed the highest antiviral efficacy. Mitochondrial DNA depletion, a major cause of NRTI neurotoxicity, was reduced threefold compared with NRTIs at application of selected nano-NRTIs.

Conclusions: Nano-NRTIs demonstrated a promising antiviral efficacy against HIV-1 in MDMs and showed strong potential as nanocarriers for delivery of antiviral drugs to macrophages harbouring in the brain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / toxicity
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Drug Carriers / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Hep G2 Cells
  • Humans
  • Macrophages / drug effects*
  • Macrophages / pathology
  • Macrophages / virology*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Nanogels
  • Nucleosides / adverse effects
  • Nucleosides / chemistry
  • Nucleosides / pharmacology*
  • Nucleosides / toxicity
  • Organ Specificity
  • Peptides / metabolism
  • Polyethylene Glycols / metabolism*
  • Polyethyleneimine / metabolism*
  • Reverse Transcriptase Inhibitors / adverse effects
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Reverse Transcriptase Inhibitors / toxicity

Substances

  • Anti-HIV Agents
  • Drug Carriers
  • Nanogels
  • Nucleosides
  • Peptides
  • Reverse Transcriptase Inhibitors
  • polyethylene glycol polyethyleneimine nanogel
  • Polyethylene Glycols
  • Polyethyleneimine