Highly active anti-retroviral therapy (HAART) was capable to significantly reduce mortality and prolong lives of patients with AIDS. Nucleoside analogs (NA), aka reverse transcriptase inhibitors (NRTIs), are cornerstones of the HAART. Long-term treatment with high doses of NRTIs may result in various toxic side effects, and neurotoxicity is among the most severe complications. HIV-1 infection in the brain is accompanied by encephalitis (HIVE) that is poorly treated because of the impenetrability of the blood-brain barrier (BBB) for many drugs. Both neuropathic effects of HIV-1 and NRTIs are overlapping in the CNS. There is now an urgent need in new drugs or treatment modalities with ability to overcome the BBB and eradicate virus in the CNS while causing reduced neuronal toxicity. We introduce novel drug formulations with potential for systemic delivery of NRTIs to the brain, injectable Nano-NRTIs, which consist of 5'-triphosphates of NRTIs (NATP) packaged in polymeric nanogels. These Nano-NRTIs demonstrated antiviral effect even in drug-resistant HIV-1 mutants, lower neuronal apoptosis and mitochondrial toxicity than NRTIs. Injected naked or peptide-decorated nanogels could efficiently deliver NATP across the BBB and release the drug following their capture by macrophages in the brain. The central goal of this proposal is to evaluate antiviral efficacy and neurotoxicity- related parameters of two Nano-NRTIs in several cellular systems in vitro and in vivo. The hypothesis about therapeutic advantage of Nano-NRTIs will be tested in a humanized HIV-1 murine model and will allow us to determine quantitatively and qualitatively the efficacy of the CNS accumulation, inhibition of viral replication and neuronal damage, modeling the long-term NRTI drug treatment in one experiment.
Our Specific Aim 1 is to compare reduction of viral load in cultured macrophages by antiviral NAs or nanogel-NATP formulations, using the neurotoxic NRTI, didanosine (ddI), and zidovudine (AZT), and their derivatives, ddI-TP and AZT-TP. 5'- Triphosphates will be synthesized from ddI and AZT, formulated in protective nanogel shells modified by the BBB-specific ApoE-peptide.
Specific Aim 2 is to evaluate neurotoxic potential of antiviral NAs or nanogel-NATP formulations measuring mitochondrial toxicity and neuronal death in two cellular models, testing also alternative neurons-protective combinations of NATP with natural NTPs. Some nanogel-NTP formulations were found to increase survival of neurons in response to pro-apoptotic agents.
Specific Aim 3 : To validate humanized mouse model of HIV-1 infection in application to development of neuropathology (glial activation and neuronal loss) after anti-retroviral therapy and test the viral multiplication, mitochondrial toxicity and inflammation factor release resulting in neurotoxic complications. Positive """"""""proof-of-the-concept"""""""" would become instrumental for further development of the Nano-NRTI approach to AIDS chemotherapy.
Highly active anti-retroviral therapy using nucleoside analogs (NRTIs), may result in severe neurotoxicity complications. HIV-1 infection in the brain is also accompanied by encephalitis that is poorly treated because of the impenetrability of the blood-brain barrier for many drugs. We introduce novel nanogel formulations with potential for systemic drug delivery to the brain, injectable Nano-NRTIs. Naked or brain-specific peptide- decorated nanogels can deliver activated drugs to infected macrophages in the brain. The central goal of this proposal is to evaluate and compare antiviral efficacy and neurotoxicity-related parameters of two Nano-NRTIs in several cellular systems in vitro and in a unique humanized HIV-1 murine model. We hypothesize that Nano- NRTIs will have therapeutic advantage over NRTIs and lower neurotoxicity. Positive """"""""proof-of-the-concept"""""""" would open practical venues for further development of the Nano-NRTI approach to NeuroAIDS chemotherapy. ? ? ? ?
| Vinogradov, Serguei V; Senanayake, Thulani (2013) Nanogel-drug conjugates: a step towards increasing the chemotherapeutic efficacy. Nanomedicine (Lond) 8:1229-32 |
| Zhang, Hongwei; Gerson, Trevor; Varney, Michelle L et al. (2010) Multifunctional peptide-PEG intercalating conjugates: programmatic of gene delivery to the blood-brain barrier. Pharm Res 27:2528-43 |
| Vinogradov, Serguei V (2010) Nanogels in the race for drug delivery. Nanomedicine (Lond) 5:165-8 |
| Vinogradov, Serguei V; Poluektova, Larisa Y; Makarov, Edward et al. (2010) Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity. Antivir Chem Chemother 21:1-14 |
