title: Nano-NRTIs demonstrate low neurotoxicity and high antiviral activity against HIV infection in the brain.
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.
  
  
  BACKGROUND
  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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Gerson
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Makarov
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Thulani H
authors.initials: TH
authors.lastname: Senanayake
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Larisa Y
authors.initials: LY
authors.lastname: Poluektova
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: vinograd@unmc.edu.
authors.forename: Serguei V
authors.initials: SV
authors.lastname: Vinogradov
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D000080385:Nanogels; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D000080385:Nanogels; D017382:Reactive Oxygen Species; D018894:Reverse Transcriptase Inhibitors; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D054303:HIV Reverse Transcriptase
keywords: CNS drug delivery; HIV-1 infection; Nanogel; Neurotoxicity; Nucleoside reverse transcriptase inhibitors