title: Amphiphilic cationic nanogels as brain-targeted carriers for activated nucleoside reverse transcriptase inhibitors.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: G
authors.initials: G
authors.lastname: Warren
authors.forename: E
authors.initials: E
authors.lastname: Makarov
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: T
authors.initials: T
authors.lastname: Senanayake
authors.forename: K
authors.initials: K
authors.lastname: Rivera
authors.forename: S
authors.initials: S
authors.lastname: Gorantla
authors.forename: L Y
authors.initials: LY
authors.lastname: Poluektova
authors.forename: S V
authors.initials: SV
authors.lastname: Vinogradov
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D002412:Cations; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005782:Gels; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D049329:Nanostructures; D009474:Neurons / Q000187:drug effects; D011107:Polylysine; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D002412:Cations; D004337:Drug Carriers; D005782:Gels; D018894:Reverse Transcriptase Inhibitors; D011107:Polylysine; D002784:Cholesterol; D054303:HIV Reverse Transcriptase