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

Serguei V. Vinogradov, Larisa Y. Poluektova, Edward Makarov, Trevor Gerson, Madapathage T. Senanayake

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 200x 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.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalAntiviral Chemistry and Chemotherapy
Volume21
Issue number1
DOIs
StatePublished - Dec 1 2010

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Reverse Transcriptase Inhibitors
Nucleosides
HIV-1
Macrophages
Antiviral Agents
Polyethyleneimine
Brain
Mitochondrial DNA
Low Density Lipoprotein Receptor-Related Protein-1
Pharmaceutical Preparations
Didanosine
Dendrimers
Poloxamer
Peptides
Freeze Drying
Ethylene Glycol
RNA-Directed DNA Polymerase
Hep G2 Cells
Central Nervous System

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Virology

Cite this

Nano-NRTIs : Efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity. / Vinogradov, Serguei V.; Poluektova, Larisa Y.; Makarov, Edward; Gerson, Trevor; Senanayake, Madapathage T.

In: Antiviral Chemistry and Chemotherapy, Vol. 21, No. 1, 01.12.2010, p. 1-14.

Research output: Contribution to journalArticle

Vinogradov, Serguei V. ; Poluektova, Larisa Y. ; Makarov, Edward ; Gerson, Trevor ; Senanayake, Madapathage T. / Nano-NRTIs : Efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity. In: Antiviral Chemistry and Chemotherapy. 2010 ; Vol. 21, No. 1. pp. 1-14.
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AU - Senanayake, Madapathage T.

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