New Targeted BDNF Nanoparticles for Treatment of Dopaminergic Neurodegeneration in METH Addiction and HAND

新型靶向 BDNF 纳米颗粒用于治疗冰毒成瘾和 HAND 中的多巴胺能神经变性

• 批准号: 9346250
• 负责人: GORDANA D. VITALIANO
• 金额: $ 22.5万
• 依托单位: EXQOR TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9346250
• 关键词: Adverse effects; Affect; Agonist; Animal Model; Anti-Retroviral Agents; Biodistribution; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain region; Brain-Derived Neurotrophic Factor; Bypass; Calcium; Cell Proliferation; Cell Survival; Cells; Chronic; Clathrin; Cognitive; Corpus striatum structure; Data; Development; Diagnosis; Diagnostic; Disease Progression; Dopamine; Dose; Down-Regulation; Doxycycline; Drug Addiction; Drug Carriers; Drug Delivery Systems; Drug usage; Effectiveness; Exercise; Foundations; Free Radicals; Genes; Genetic Transcription; Glucocorticoid Receptor; Glutamates; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV-associated neurocognitive disorder; Health; Hippocampus (Brain); Immunohistochemistry; In Vitro; Inflammatory; Injectable; Intravenous; Lead; Ligands; Magnetic Resonance Imaging; Memory; Methamphetamine; Methamphetamine dependence; Methods; Microglia; Modeling; Molecular; Molecular Abnormality; Molecular Target; Monitor; Motor; Mus; N-Methylaspartate; Nanotechnology; Nerve Degeneration; Nerve Regeneration; Neuronal Plasticity; Neurons; Oral; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Polyethylene Glycols; Positron-Emission Tomography; Prosthesis; Proteins; Radioactive; Recovery; Reporting; Research; Research Project Grants; Resolution; Saline; Series; Signal Transduction; Small Business Innovation Research Grant; Specificity; Structure; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Trans-Activators; brain tissue; cognitive function; crosslink; cytokine; density; design; dopamine transporter; dopaminergic neuron; drug candidate; imaging agent; imaging modality; imaging study; improved; in vivo; intraperitoneal; methamphetamine effect; mouse model; nanocarrier; nanometer; nanoparticle; nanoprobe; neurogenesis; neuron loss; neuronal survival; neuropsychiatry; neurotoxic; neurotoxicity; neurotrophic factor; next generation; novel; novel therapeutics; overexpression; prevent; small molecule; socioeconomics; targeted delivery; tool

ABSTRACT Methamphetamine (METH) addiction and Human immunodeficiency virus (HIV) associated neurocognitive disorder (HAND) represent major chronic health problems in the US and abroad. Magnetic Resonance Imaging (MRI) studies have consistently shown structural and functional abnormalities in the dopaminergic system, while Positron Emission Tomography (PET) studies reported dopamine transporter (DAT) density reductions in patients with HIV and METH. Advances in treatment of METH toxicity and HAND have been made by administering brain derived neurotrophic factor (BDNF) directly to the CNS, or by using drugs that can increase BDNF indirectly. BDNF promotes neuronal survival, plasticity and restores brain functions. However, BDNF cannot cross an intact blood brain barrier (BBB), and is unstable in the blood or when delivered orally. The goal of this effort is to produce nontoxic, BDNF-nanoparticles (NPs), and test the hypothesis that (a) these NPs bypass the BBB intranasally, (b) target dopaminergic brain regions, and (c) prevent or reverse neurotoxic effects of METH and HIV transactivator of transcription (tat) protein in a mouse model relevant to HAND (the GT-tg bi-genic mouse induced with doxycycline to overexpress tat protein). To accomplish these goals we will design a three-part nanoparticle (<50 nanometers). A nanocarrier will be constructed out of clathrin, a naturally occurring protein the body uses for transporting molecules into cells. The second component will be a BDNF protein drug. The third part will be a targeting DAT ligand (e.g., GBR12935). BDNF and DAT ligands will be attached to clathrin via polyethylene glycol (PEG) molecules. A series of studies will ascertain specificity and functionality of the NP in vivo. We plan to demonstrate the feasibility of this novel nanotechnology to treat METH and tat-induced neurotoxicity. If this research project is successful it will provide new noninvasive nanotechnology tools for treatment of neurotoxicity in METH addiction and HAND. The new nanotechnology may be able to enhance neuronal survival and plasticity and restore brain functions more quickly and completely than existing treatment methods, while using much lower therapeutic drug doses and causing fewer side effects. The development of a stable, targeted molecular NP may also provide a major new tool for research of molecular abnormalities in HAND and drug addiction. This novel nanotechnology may serve as the basis for a next generation drug- delivery system that can specifically target relevant brain systems and release drugs on demand, and may also have utility as an imaging agent to enhance diagnosis and monitor progression of the disease.

摘要 甲基苯丙胺（METH）成瘾与人类免疫缺陷病毒（HIV）相关的神经认知 手功能障碍（HAND）代表了美国和国外的主要慢性健康问题。磁共振 成像（MRI）研究一直显示多巴胺能神经元的结构和功能异常， 系统，而正电子发射断层扫描（PET）研究报告多巴胺转运蛋白（DAT）密度 减少艾滋病毒和甲基苯丙胺患者。METH中毒和HAND的治疗进展已经 通过将脑源性神经营养因子（BDNF）直接给予CNS，或通过使用 可以间接增加BDNF。BDNF促进神经元存活、可塑性和恢复脑功能。 然而，BDNF不能穿过完整的血脑屏障（BBB），并且在血液中或当血液中的BDNF被激活时是不稳定的。 口服。这项工作的目标是生产无毒的脑源性神经营养因子纳米颗粒（NPs），并测试其 假设（a）这些NP鼻内绕过BB B，（B）靶向多巴胺能脑区，和（c） 预防或逆转METH和HIV转录反式激活因子（达特）蛋白在小鼠中的神经毒性作用 与HAND相关的模型（用多西环素诱导以过表达达特蛋白的GT-tg双基因小鼠）。 为了实现这些目标，我们将设计一种由三部分组成的纳米颗粒（<50纳米）。纳米载体将 由网格蛋白构成，网格蛋白是一种天然存在的蛋白质，身体用来将分子转运到细胞中。 第二种成分将是BDNF蛋白药物。第三部分将是靶向DAT配体（例如， GBR 12935）。BDNF和DAT配体将通过聚乙二醇（PEG）分子连接到网格蛋白上。一 一系列的研究将确定NP在体内的特异性和功能性。我们计划展示 这种新型纳米技术治疗METH和Tat诱导的神经毒性的可行性。 如果这项研究项目成功，它将为治疗糖尿病提供新的非侵入性纳米技术工具。 神经毒性的甲基成瘾和手。新的纳米技术可能能够增强神经元 存活和可塑性，并比现有治疗更快和更完全地恢复大脑功能 方法，同时使用低得多的治疗药物剂量和引起更少的副作用。的发展 稳定的、靶向的分子NP也可能提供用于研究以下疾病中的分子异常的主要新工具： 手和毒瘾。这种新的纳米技术可能作为下一代药物的基础- 可以特异性靶向相关脑系统并按需释放药物的递送系统，并且还可以 具有作为成像剂以增强诊断和监测疾病进展的效用。