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: 10258139
• 负责人: GORDANA D. VITALIANO
• 金额: $ 119.47万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10258139
• 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; 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; 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 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.

甲基苯丙胺使用障碍（MUD）是美国和国外的一个主要慢性健康问题。 磁共振成像（MRI）研究一致表明纹状体的结构和功能 MUD 患者的异常和认知缺陷。长期使用甲基苯丙胺 (METH) 是 与多巴胺能系统的神经变性有关，需要新的药物 治疗冰毒成瘾和毒性。在 SBIR 第一阶段，ExQor 开发了一个纳米技术平台 为冰毒成瘾和神经毒性的双重治疗提供了一种创新方法，由 3 部分组成 成分：带有多巴胺转运蛋白（DAT）靶向的网格蛋白载体纳米颗粒（CNP） 配体（哌甲酯或GBR12909或抗DAT抗体）和脑源性神经营养因子（BDNF）。 CNPs 成功绕过血脑屏障 (BBB) 并输送足够浓度的 BDNF 小鼠大脑中表达 DAT 的神经元。纹状体 BDNF 浓度比对照组高 100 倍以上 先前的 BDNF 全身和鼻腔递送研究中已有报道。 CNP 还拯救了纹状体酪氨酸 iTat 小鼠模型中 HIV/Tat、METH 和组合 Tat/METH 神经毒性的羟化酶阳性纤维 艾滋病毒/神经艾滋病。 第二阶段工作的目标是证明我们的新型双特异性 CNP 的安全性和可行性 哌醋甲酯和 BDNF 抑制 METH 寻求，逆转 METH 诱导的神经毒性，并成功 治疗暴露于冰毒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 假设 CNP 将 BDNF 传递到受影响的大脑区域，逆转冰毒对这些区域的神经毒性作用 区域，并改善暴露于有毒剂量冰毒的大鼠的运动和记忆功能。其次，我们还 计划测试 CNP 是否会在 3 天内抑制大鼠中情境、提示和 METH 诱导的药物寻找恢复 戒断冰毒自我管理数周。为了实现我们的第二阶段目标，我们将执行一系列 一系列研究将确定 NP 稳定性、大脑和身体分布、安全性和功能。老鼠将会 通过标准行为测试进行测试。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以及多巴胺及其水平 新 CNP 的代谢物和毒性。 该研究项目将为治疗冰毒成瘾提供新的非侵入性纳米技术工具 神经毒性。新的纳米技术可能能够靶向并再生多巴胺能神经元；堵塞 METH 诱导 DA 释放；并抑制环境、暗示和冰毒诱导的药物寻求恢复。它 与现有治疗相比，可以更快、更彻底地预防复发、保护和恢复大脑功能 方法，同时使用低得多的治疗药物剂量，并引起更少的副作用。的发展 稳定、无毒的纳米颗粒也可能为 MUD 生物标志物的研究提供重要的新工具。这 纳米技术可以作为下一代神经治疗学的基础，可以专门针对 相关的大脑系统，也可能具有作为成像剂的用途，以增强诊断和监测 疾病的进展。