Amphiphilic Cationic Nanogels as Brain-Targeted Carriers for Activated Nucleoside Reverse Transcriptase Inhibitors

G. Warren, E. Makarov, Y. Lu, T. Senanayake, K. Rivera, S. Gorantla, L. Y. Poluektova, S. V. Vinogradov

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Progress in AIDS treatment shifted emphasis towards limiting adverse effects of antiviral drugs while improving the treatment of hard-to-reach viral reservoirs. Many therapeutic nucleoside reverse transcriptase inhibitors (NRTI) have a limited access to the central nervous system (CNS). Increased NRTI levels induced various complications during the therapy, including neurotoxicity, due to the NRTI toxicity to mitochondria. Here, we describe an innovative design of biodegradable cationic cholesterol-ε-polylysine nanogel carriers for delivery of triphosphorylated NRTIs that demonstrated high anti-HIV activity along with low neurotoxicity, warranting minimal side effects following systemic administration. Efficient CNS targeting was achieved by nanogel modification with brain-specific peptide vectors. Novel dual and triple-drug nanoformulations, analogous to therapeutic NRTI cocktails, displayed equal or higher antiviral activity in HIV-infected macrophages compared to free drugs. Our results suggest potential alternative approach to HIV-1 treatment focused on the effective nanodrug delivery to viral reservoirs in the CNS and reduced neurotoxicity.

Original languageEnglish (US)
Pages (from-to)88-101
Number of pages14
JournalJournal of Neuroimmune Pharmacology
Volume10
Issue number1
DOIs
StatePublished - Feb 20 2015

Keywords

  • Abacavir
  • Blood–brain barrier
  • Brain-specific peptides
  • Central nervous system
  • HIV-1
  • Lamivudine
  • NRTI 5′-triphosphates
  • Nanogels
  • Neurotoxicity
  • Nucleoside reverse transcriptase inhibitors
  • Zidovudine
  • ε-polylysine

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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