CNS Delivery of Activated Antiviral Drugs with Reduced Neurotoxicity (Nano-NRTIs)

中枢神经系统递送神经毒性较低的活化抗病毒药物（纳米 NRTI）

基本信息

批准号：
8867298
负责人：
Santhi Gorantla
金额：
$ 37.13万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8867298
关键词：
AIDS Dementia Complex ATP-Binding Cassette Transporters Acquired Immunodeficiency Syndrome Address Adverse effects Antiviral Agents Applications Grants Astrocytes Binding Biopolymers Biotechnology Blood - brain barrier anatomy Brain Bypass Capillary Endothelial Cell Cell model Cells Charge Chronic Dementia Development Drug Administration Schedule Drug Carriers Drug Delivery Systems Drug Design Drug Efflux Drug Formulations Drug Targeting Drug Transport Encapsulated Encephalitis Endothelial Cells Endothelium Future Generations Goals HIV HIV encephalitis HIV-1 Highly Active Antiretroviral Therapy In Vitro Infection Inflammatory LDL-Receptor Related Protein 1 Lead Licensing Mediation Methods Mitochondria Modification NanoGel Nanotechnology Neuraxis Neuroglia Neurologic Neurons Nucleic Acids Nucleosides Oral Patients Penetration Peptides Peripheral Phagocytes Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Polyamines Preparation Process Public Health Research Reverse Transcriptase Inhibitors Scheme Solutions Spermine Surface Testing Therapeutic Time Tissues Toxic effect Vascular Endothelial Cell Vascular Endothelium Viral Virus Replication base cytotoxicity design dosage drug resistant virus hazard improved in vivo innovation macrophage mitochondrial membrane mouse model nano nanoassembly nanocarrier nanoengineering nanoformulation nanoparticle neuropathology neurotoxic neurotoxicity novel nucleoside kinase nucleoside triphosphate phase 1 study pre-clinical research prevent receptor targeted delivery therapy design transcytosis uptake

项目摘要

DESCRIPTION (provided by applicant): The problem. Serious HIV-associated neuropathology and the neurological side effects of Highly Active Antiretroviral Therapy (HAART) have been recently identified as the major hazards of chronic AIDS treatment. The important components of HAART, nucleoside reverse transcriptase inhibitors (NRTI), induce neurotoxicity due to the degradation of mitochondrial functions in peripheral and CNS neurons during long-term therapy. Since the treatment of HIV-1 located in phagocytic cells in CNS is far from satisfactory due to the blood-brain barrier (BBB) preventing drugs from reaching therapeutic levels in the brain, HIV-associated inflammatory processes make a negative impact on the viability of neurons and result in the development of HIV-induced encephalitis (HIVE) and dementia. The development of novel NRTI drug forms with reduced neurotoxicity and special approaches to their efficient delivery to the CNS is the major goal of this grant application. Hypothesis. Phosphorylated NTRI (pNRTI), as an active drug form, would be less toxic and more efficient drugs for the treatment of HIV-1 infection than the currently available NRTI. The major advantages of pNRTI, which will illustrate our choice, are as follows: (1) potential higher efficacy against HIV-1 in the infected host cells (macrophages, astrocytes, glial cells) deficient by kinase activities or against drug-resistant virus forms, (2) limited pNRTI access in mitochondria (lower mitochondrial toxicity), and (3) restricted cellular accumulation of negatively-charged pNRTI (reduced nonspecific toxicity). Since the majority of pNRTI are unstable in vivo, we hypothesize that the encapsulation of pNRTI in nanocarriers optimized for drug delivery across the BBB would provide efficient drug access to HIV-1-bearing peripheral or brain-harboring phagocytes. We have developed novel stable drug nanoformulations (Nano-NRTI), which can suppress virus multiplication more effectively than NRTI in macrophages and have a lower chance of accumulating in other tissues and exerting nonspecific toxicities. Modification with brain receptor-specific peptides or polyamines is proposed in order to enhance the cooperativity of Nano-NRTI binding with the BBB following drug administration. Nano-NRTI would then cross the BBB endothelium and release activated pNRTI in the brain parenchyma and brain-harboring macrophages. To address this hypothesis, we propose the following Specific aims: (1) to apply rational drug design and nanoengineering to the construction of nanocarriers loaded with pNRTI; (2) to optimize the antiviral effect and low cytotoxicity of Nano-NRTI in cultured macrophages, brain vascular endothelial cells, and neurons in vitro; (3) to enhance the efficiency of Nano-NRTI to cross the blood-brain barrier and accumulate in the brain; (4) to evaluate the effects of Nano-NRTI treatment on neuropathology in a mouse model of HIVE. Significance and impact. The less-neurotoxic version of HAART is likely to come from studies on rational drug design and targeted delivery. We develop a pNRTI-based HAART design (Nano-HAART), which enables the delivery of brain-targeted and oral activated drug formulations with reduced neurotoxicity into the CNS.

描述（由申请人提供）：问题。严重的HIV相关神经病理学和高度活性抗逆转录病毒疗法（HAART）的神经系统副作用最近被确定为慢性艾滋病治疗的主要危害。 HAART，核苷逆转录酶抑制剂（NRTI）的重要成分，由于长期治疗过程中外周和CNS神经元中线粒体功能降解而引起的神经毒性。由于CNS中吞噬细胞中的HIV-1的处理远非令人满意，这是由于血脑屏障（BBB）防止药物达到大脑中治疗水平的治疗，因此HIV相关的炎症过程对神经元的可行性产生了负面影响，并对HIV诱导的Encephaliatia（Hece诱导的HIV诱导的hiv诱导的）和DempiA（Hiveia）和Dempia（Hive）和Dempia（Hive）和Dempia（hive）和Dembia（Demp）和Dectia产生了影响。新型NRTI药物形式的开发降低了神经毒性，并有效地递送到中枢神经系统的方法是该赠款应用的主要目标。假设。与当前可用的NRTI相比，作为活性药物形式的磷酸化NTRI（PNRTI）作为一种活性药物形式，用于治疗HIV-1感染的毒性和高效药物。 PNRTI的主要优点（将说明我们的选择）如下：（1）在感染的宿主细胞（巨噬细胞，星形胶质细胞，星形胶质细胞，神经胶质细胞）中对HIV-1的潜在较高的疗效。负电荷PNRTI（非特异性毒性降低）。由于大多数PNRTI在体内不稳定，因此我们假设在优化用于跨BBB药物的纳米载体中PNRTI的封装将为您提供有效的药物访问HIV-1含HIV-1含HIV-1的外周或脑 - 脑 - 脑吞噬细胞。我们已经开发了新型的稳定药物纳米制剂（纳米-NRTI），可以在巨噬细胞中比NRTI更有效地抑制病毒繁殖，并且在其他组织中积累并施加非特异性毒性的机会较低。提出了用脑受体特异性肽或多胺修饰，以增强药物给药后与BBB结合的纳米-NRTI结合的合作。然后，纳米-NRTI将越过BBB内皮，并在脑实质和脑部刺激性巨噬细胞中释放激活的PNRTI。为了解决这一假设，我们提出了以下具体目的：（1）将合理的药物设计和纳米工程应用于装有PNRTI的纳米载体的构建；（2）优化纳米-NRTI在培养的巨噬细胞，脑血管内皮细胞和神经元体外的抗病毒作用和低细胞毒性；（3）提高纳米-NRTI越过血脑屏障并积聚在大脑中的效率；（4）评估纳米-NRTI治疗对蜂巢小鼠模型中神经病理学的影响。意义和影响。 HAART的神经毒性版本较低的版本很可能来自有关理性药物设计和目标递送的研究。我们开发了一种基于PNRTI的HAART设计（Nano-Haart），该设计使脑靶向和口服激活的药物配方的递送降低了CNS的神经毒性。