Nanodelivery of active NRTI to the central nervous system: humanized HIV murine m

活性 NRTI 纳米递送至中枢神经系统：人源化 HIV 小鼠 m

• 批准号: 7622398
• 负责人: SERGUEI V VINOGRADOV
• 金额: $ 20.09万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7622398
• 关键词: AIDS chemotherapy; AIDS neuropathy; Acquired Immunodeficiency Syndrome; Adverse effects; Amaze; Anti-Retroviral Agents; Antiviral Agents; Antiviral Therapy; Apolipoprotein E; Apoptotic; Biodistribution; Blood - brain barrier anatomy; Brain; Caliber; Cell model; Cells; Cessation of life; Chronic; Complication; Development; Didanosine; Dose; Drug Delivery Systems; Drug Formulations; Drug resistance; Encapsulated; Encephalitis; Environment; Goals; HIV; HIV-1; HIV-1 drug resistance; Highly Active Antiretroviral Therapy; In Vitro; Induction of Apoptosis; Infection; Inflammation; Injectable; Injection of therapeutic agent; Life; Measures; Mitochondria; Modality; Modeling; Mus; NanoGel; Neuraxis; Neurologic; Neurons; Neuropathy; Oral; Particle Size; Patients; Peptides; Peripheral; Permeability; Pharmaceutical Preparations; Public Health; Range; Reverse Transcriptase Inhibitors; System; Testing; Therapeutic; Toxic effect; Urticaria; Viral; Viral Load result; Virus; Zidovudine; chemotherapy; concept; drug efficacy; gastrointestinal epithelium; in vitro Model; in vivo; in vivo Model; innovation; macrophage; mortality; mouse model; mutant; nano; nanoformulation; neuron apoptosis; neuron loss; neuropathology; neurotoxic; neurotoxicity; novel; nucleoside analog; prospective; release factor; research study; response; tripolyphosphate; zidovudine triphosphate

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：高度活跃的抗逆转录病毒疗法（HAART）能够显着降低艾滋病患者的死亡率和延长寿命。核苷类似物（Na），又称逆转录酶抑制剂（NRTIS）是HAART的基石。高剂量NRTI的长期治疗可能会导致各种毒性副作用，而神经毒性是最严重的并发症之一。大脑中的HIV-1感染伴有脑炎（Hive），由于许多药物对血脑屏障（BBB）的不可测能而受到治疗不佳。 HIV-1和NRTI的神经性效应在中枢神经系统中重叠。现在，新药或治疗方式迫切需要克服BBB并消除中枢神经系统的病毒，同时导致神经元毒性降低。我们引入了新型药物制剂，具有将NRTI的全身性传递到大脑的潜力，可注射的纳米NRTI，由NRTIS（NATP）（NATP）组成，这些NRTIS（NATP）包装在聚合物纳米凝胶中。这些纳米-NRTI在耐药性HIV-1突变体，神经元细胞凋亡和线粒体毒性较低的情况下也表现出抗病毒作用，而不是NRTIS。注射的裸或肽装饰的纳米凝胶可以在大脑中被巨噬细胞捕获后有效地跨BBB递送NATP并释放该药物。该提案的核心目的是评估在几个细胞系统的体外和体内两种纳米-NRTI的抗病毒功效和神经毒性相关参数。关于纳米-NRTI的治疗优势的假设将在人源化的HIV-1鼠模型中进行测试，并使我们能够定量和定性地确定中枢神经系统积累的功效，抑制病毒复制和神经元损伤，对长期NRTI药物治疗进行了对一个实验的长期NRTI药物进行建模。我们的具体目的1是使用抗病毒NAS或纳米凝胶-NATP制剂比较培养巨噬细胞中病毒载荷的减少，并使用神经毒性NRTI，Didanosine（DDI）和Zidovudine（AZT）及其衍生物，DDI-TP和AZT-TP。 5'-三磷酸盐将从DDI和AZT合成，并在由BBB特异性APOE肽修饰的保护性纳米凝胶壳中配制。具体目的2是评估抗病毒NAS或纳米NATP制剂的神经毒性潜力，测量了两个细胞模型，测量线粒体毒性和神经元死亡，NATP与天然NTP的NATP进行了替代神经元保护组合。发现一些纳米凝胶-NTP制剂会增加神经元的生存率，以响应促凋亡剂。具体目的3：抗逆转录病毒疗法后，在应用神经病理学（神经胶质激活和神经元丧失）中验证HIV-1感染的人性化小鼠模型并测试病毒乘法，线粒体毒性和炎症因子释放，从而导致神经毒性并发性。积极的“概念证明”将对进一步开发纳米-NRTI化学疗法的进一步开发。公共卫生相关性：使用核苷类似物（NRTIS）高度活跃的抗逆转录病毒疗法，可能导致严重的神经毒性并发症。大脑中的HIV-1感染还伴有脑炎，由于许多药物对血脑屏障的不可渗透性而受到治疗不佳。我们介绍了新型的纳米凝胶制剂，具有向大脑的全身药物输送，可注射的纳米-NRTIS。裸或脑特异性肽装饰的纳米凝胶可以将活化的药物输送到大脑中感染的巨噬细胞。该提案的核心目标是评估和比较在几个细胞系统中，在几个细胞系统中和独特的人源化HIV-1鼠模型中，两种纳米-NRTI的抗病毒功效和与神经毒性相关的参数。我们假设纳米NRTI将比NRTI具有治疗优势，并且神经毒性降低。积极的“概念证明”将开放实用场所，以进一步开发纳米-NRTI方法进行神经辅助化疗。