New targeted BDNF nanoparticles for treatment of METH addiction and neurotoxicity

甲基苯丙胺使用障碍(MUD)是美国和国外的一个主要的慢性健康问题。 磁共振成像(MRI)研究一直显示纹状体结构和功能 肌萎缩侧索硬化症患者的异常和认知缺陷。长期使用甲基苯丙胺(冰毒) 与多巴胺能系统的神经退行性变相关，需要新的药物 冰毒成瘾和中毒的治疗。在SBIR第一阶段，ExQor开发了一个纳米技术平台 这为冰毒成瘾和神经毒性的双重治疗提供了一种创新的方法，由3个 成分：连接了多巴胺转运体(DAT)靶向的笼状蛋白载体纳米粒(CNP) 配体(哌酸甲酯或GBR12909或抗DAT抗体)和脑源性神经营养因子(BDNF)。 CNPs成功地绕过了血脑屏障(BBB)，并将足够浓度的BDNF输送到 小鼠脑内表达DAT的神经元。纹状体内脑源性神经营养因子浓度比 在以前的脑源性神经营养因子全身和鼻腔给药研究中已有报道。CNPS还挽救了纹状体酪氨酸 HIV/TAT、METH和TAT/METH联合神经毒性在ITAT小鼠模型中的羟基酶阳性纤维 艾滋病毒/神经艾滋病。 这项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 哌醋甲酯和脑源性神经营养因子抑制冰毒寻找，逆转冰毒神经毒性并成功 治疗冰毒暴露大鼠的运动和记忆障碍。首先，我们计划更彻底地测试我们的 假设CNPs将BDNF运送到受影响的脑区，逆转冰毒在这些区域的神经毒性作用 并改善染毒剂量冰毒大鼠的运动和记忆功能。第二，我们也 计划测试CNPs是否在3个月期间抑制上下文、线索和冰毒诱导的大鼠寻求药物的恢复 连续几周禁食冰毒自我管理。为了实现我们的第二阶段目标，我们将执行一系列 将确定NP稳定性、脑和身体分布、安全性和功能性的研究。老鼠将会是 通过标准的行为测试进行测试。此外，免疫组织化学和分子检测将用于 评估多巴胺能纤维密度、多巴胺能神经元数量和多巴胺及其受体的水平 代谢物，以及新的CNPs的毒性。 该研究项目将为冰毒成瘾的治疗和治疗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；阻断 冰毒诱导的DA释放；抑制上下文、线索和冰毒诱导的药物寻找的恢复。它 可能比现有的治疗方法更快、更彻底地防止复发、保护和恢复大脑功能 方法，同时使用较低的治疗药物剂量，且副作用较少。开发一种新的 稳定、无毒的纳米颗粒也可能为泥浆中生物标志物的研究提供一个重要的新工具。这 纳米技术可能成为下一代神经热疗麻醉剂的基础，它可以特异性地靶向 相关的大脑系统，也可能作为一种显像剂来加强诊断和监测 疾病的发展。

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.