New targeted BDNF nanoparticles for treatment of METH addiction and neurotoxicity

新型靶向 BDNF 纳米颗粒用于治疗冰毒成瘾和神经毒性

• 批准号: 10474621
• 负责人: GORDANA D. VITALIANO
• 金额: $ 118.43万
• 依托单位: EXQOR TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474621
• 关键词: Abstinence; Affect; Affinity; Agonist; Animal Model; Antibodies; Area; Biochemical; Biological; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain region; Brain-Derived Neurotrophic Factor; Bypass; Cell Survival; Cell physiology; Chronic; Clathrin; Clinical Trials; Cocaine Dependence; Cognitive; Cognitive deficits; Complex; Corpus striatum structure; Cues; Data; Development; Diagnosis; Disease; Disease Progression; Dopamine; Dopamine Uptake Inhibitors; Dose; Down-Regulation; Drug Carriers; Drug Delivery Systems; Effectiveness; Exercise; Exposure to; Extinction (Psychology); FDA approved; Fiber; Free Radicals; Glutamates; Goals; HIV; Health; Immunohistochemistry; Impaired cognition; Inflammatory; Inpatients; Intranasal Administration; Ligands; Magic; Magnetic Resonance Imaging; Memory; Memory impairment; Methamphetamine; Methamphetamine dependence; Methamphetamine use disorder; Methods; Microglia; Molecular; Monitor; Motor; Mus; Nanotechnology; National Institute of Drug Abuse; Natural regeneration; Nerve Degeneration; Nerve Regeneration; Neurons; Nose; Oral; Organ; Outcome; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Positron-Emission Tomography; Psychotropic Drugs; Rattus; Recovery; Relapse; Reporting; Research; Research Project Grants; Ritalin; Role; Safety; Saline; Self Administration; Series; Signal Pathway; Signal Transduction; Site; Small Business Innovation Research Grant; Structure; System; Technology; Testing; Therapeutic; Time; Toxic effect; Toxicology; Training; Treatment Efficacy; Tyrosine 3-Monooxygenase; behavior test; blood-brain barrier crossing; cognitive function; cytokine; density; dopamine transporter; dopaminergic neuron; economic cost; extracellular; imaging agent; imaging study; improved; innovation; intravenous administration; medication safety; methamphetamine effect; methamphetamine exposure; methamphetamine use; motor deficit; mouse model; nanocarrier; nanoparticle; nanoparticle delivery; nanotechnology platform; neuroAIDS; neurogenesis; neuroinflammation; neuropsychiatry; neurotoxic; neurotoxicity; neurotrophic factor; next generation; novel; novel therapeutics; prevent; radiotracer; safety and feasibility; side effect; socioeconomics; success; synaptogenesis; tool

Methamphetamine use disorder (MUD) represents a major chronic health problem in the US and abroad. Magnetic Resonance Imaging (MRI) studies have consistently shown striatal structural and functional abnormalities and cognitive deficits in patients with MUD. Long-term methamphetamine (METH) use is associated with neurodegeneration of dopaminergic system and new pharmaceuticals are required for treatment of both METH addiction and toxicity. In SBIR Phase 1, ExQor developed a nanotechnology platform that provides an innovative approach for dual treatment of METH addiction and neurotoxicity and consists of 3 components: a clathrin carrier nanoparticle (CNP) with attached Dopamine Transporter (DAT) targeting ligand (Methylphenidate or GBR12909 or anti-DAT antibody), and brain-derived neurotrophic factor (BDNF). CNPs successfully bypassed the blood-brain barrier (BBB) and delivered adequate concentrations of BDNF to neurons expressing DAT in mouse brain. The striatal BDNF concentrations were over 100 fold higher than reported in previous BDNF systemic and nasal delivery studies. CNPs also rescued striatal tyrosine hydroxylase-positive fibers from HIV/Tat, METH and combined Tat/METH neurotoxicity in iTat mouse model of HIV/neuroAIDS. The goal of this Phase-2 effort is to demonstrate safety and feasibility of our novel bispecific CNP with attached Methylphenidate and BDNF to suppress METH seeking, reverse METH-induced neurotoxicity and successfully treat motor and memory deficits in rats exposed to METH. First, we plan to more thoroughly test our hypothesis that CNPs deliver BDNF to the affected brain regions, reverse neurotoxic effects of METH in these regions, and improve motor and memory functions in rats exposed to toxic doses of METH. Second, we also plan to test if CNPs suppress context-, cue- and METH-induced reinstatement of drug seeking in rats during 3 weeks of abstinence from METH self-administration. To accomplish our Phase-2 goals, we will execute a series of studies that will ascertain NP stability, brain and body distribution, safety and functionality. Rats will be tested with standard behavioral tests. Further, immunohistochemistry and molecular assays will be used to evaluate density of dopaminergic fibers, number of dopaminergic neurons and levels of dopamine and its metabolites, and toxicity of new CNPs. This research project will provide new noninvasive nanotechnology tools for treatment of METH addiction and neurotoxicity. The new nanotechnology may be able to target and regenerate dopaminergic neurons; block METH-induced DA release; and suppress context, cue and METH-induced reinstatement of drug seeking. It may prevent relapse, protect 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, nontoxic nanoparticle may also provide a major new tool for research of biomarkers in MUD. This nanotechnology may serve as the basis for a next generation neurotheranostic that can specifically target relevant brain systems, and also may have utility as an imaging agent to enhance diagnosis and monitor progression of the disease.

甲基苯丙胺的使用障碍（MUD）代表了美国和国外的主要慢性健康问题。 磁共振成像（MRI）研究始终显示出纹状体结构和功能 泥浆患者的异常和认知缺陷。长期甲基苯丙胺（甲基苯丙胺）的使用是 与多巴胺能系统和新药的神经变性有关 治疗甲基成瘾和毒性。在SBIR第1阶段，Exqor开发了纳米技术平台 这提供了一种创新的方法，用于双重治疗甲基成瘾和神经毒性，包括3 组件：带有多巴胺转运蛋白（DAT）靶向的网状蛋白载体纳米颗粒（CNP） 配体（哌醋甲酯或GBR12909或抗DAT抗体）和脑衍生的神经营养因子（BDNF）。 CNP成功绕过了血脑屏障（BBB），并将足够浓度的BDNF传递到 在小鼠大脑中表达DAT的神经元。纹状体BDNF浓度高于100倍以上 在先前的BDNF全身和鼻输送研究中报道。 CNP还营救了纹状体酪氨酸 ITAT小鼠模型中的HIV/TAT，METH和TAT/METH神经毒性的羟化酶阳性纤维 艾滋病毒/神经辅助。 这一2阶段努力的目的是证明我们新颖的双特异性CNP的安全性和可行性 哌醋甲酯和BDNF抑制甲基苯甲酸甲酯，以抑制甲基甲酯，反向甲酯诱导的神经毒性并成功地 治疗暴露于甲基苯丙胺的大鼠的运动和记忆缺陷。首先，我们计划更彻底地测试我们的 CNP向受影响的大脑区域提供BDNF的假设，在这些区域中反向神经毒性作用 区域，并改善暴露于有毒剂量甲基的大鼠的运动和记忆功能。其次，我们也是 计划测试CNP是否抑制上下文，提示和甲基苯丙胺引起的恢复在3期间大鼠的药物寻求药物的恢复原状 甲基自助给药的禁欲数周。为了实现我们的第二阶段目标，我们将执行系列 可以确定NP稳定性，大脑和身体分布，安全性和功能的研究。老鼠会 通过标准行为测试测试。此外，免疫组织化学和分子测定将用于 评估多巴胺能纤维的密度，多巴胺能神经元的数量和多巴胺水平及其水平 代谢物和新CNP的毒性。 该研究项目将提供新的无创纳米技术工具，用于治疗甲基苯丙胺成瘾和 神经毒性。新的纳米技术可能能够靶向和再生多巴胺能神经元。堵塞 甲基诱导的DA释放；并抑制背景，提示和甲基苯丙胺引起的恢复毒品。它 与现有治疗相比，可以防止复发，保护和恢复大脑功能 方法，同时使用较低的治疗药物剂量，并造成更少的副作用。一个发展 稳定的无毒纳米颗粒也可能为研究泥浆中的生物标志物研究提供了一个主要的新工具。这 纳米技术可以作为下一代神经抑制剂的基础，可以专门针对 相关的大脑系统，并且可能具有实用性作为成像剂，以增强诊断和监测 疾病的进展。