Nano-NRTIs demonstrate low neurotoxicity and high antiviral activity against HIV infection in the brain

Trevor Gerson, Edward Makarov, Thulani H. Senanayake, Santhi Gorantla, Larisa Y. Poluektova, Serguei V. Vinogradov

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Antiviral therapy using nucleoside reverse transcriptase inhibitors (NRTIs) is neurotoxic and has low efficiency in eradication of HIV-1 harbored in central nervous system (CNS). Previously, we reported that active 5'-triphosphates of NRTIs encapsulated in cationic nanogels (nano-NRTIs) suppress HIV-1 activity more efficiently than NRTIs and exhibit reduced mitochondrial toxicity [Vinogradov SV, Poluektova LY, Makarov E, Gerson T, Senanayake MT. Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity. Antivir Chem Chemother. 2010; 21:1-14. Makarov E, Gerson T, Senanayake T, Poluektova LY, Vinogradov. Efficient suppression of Human Immunodeficiency Virus in Macrophages by Nano-NRTIs. Antiviral Res. 2010; 86(1):A38-9]. Here, we demonstrated low neurotoxicity and excellent antiviral activity of nano-NRTIs decorated with the peptide (AP) binding brain-specific apolipoprotein E receptor. Nano-NRTIs induced lower levels of apoptosis and formation of reactive oxygen species, a major cause of neuron death, than free NRTIs. Optimization of size, surface decoration with AP significantly increased brain accumulation of nano-NRTIs. The efficient CNS delivery of nano-NRTIs resulted in up to 10-fold suppression of retroviral activity and reduced virus-associated inflammation in humanized mouse model of HIV-1 infection in the brain. Our data provide proof of the advanced efficacy of nano-NRTIs as safer alternative of current antiviral drugs. From the Clinical Editor: This team of investigators demonstrated low neurotoxicity and excellent anti-HIV activity of nano-nucleoside reverse transcriptase inhibitors decorated with the peptide (AP) binding brain-specific apolipoprotein E receptor, providing proof of enhanced efficacy and a safer alternative compared with current antiviral drugs.

Original languageEnglish (US)
Pages (from-to)177-185
Number of pages9
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2014

Fingerprint

Reverse Transcriptase Inhibitors
Nucleosides
HIV Infections
Antiviral Agents
Brain
HIV-1
Low Density Lipoprotein Receptor-Related Protein-1
Macrophages
Neurology
Viruses
Peptides
Toxicity
Central Nervous System
HIV
Cell death
Neurons
Cause of Death
Reactive Oxygen Species

Keywords

  • CNS drug delivery
  • HIV-1 infection
  • Nanogel
  • Neurotoxicity
  • Nucleoside reverse transcriptase inhibitors

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biomedical Engineering
  • Materials Science(all)
  • Pharmaceutical Science

Cite this

Nano-NRTIs demonstrate low neurotoxicity and high antiviral activity against HIV infection in the brain. / Gerson, Trevor; Makarov, Edward; Senanayake, Thulani H.; Gorantla, Santhi; Poluektova, Larisa Y.; Vinogradov, Serguei V.

In: Nanomedicine: Nanotechnology, Biology, and Medicine, Vol. 10, No. 1, 01.01.2014, p. 177-185.

Research output: Contribution to journalArticle

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