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慢性健康问题。 磁共振成像（MRI）研究一直显示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） 与多巴胺能系统的神经变性相关， METH成瘾和毒性的治疗。在SBIR第一阶段，ExQor开发了一个纳米技术平台， 它为METH成瘾和神经毒性的双重治疗提供了一种创新方法，由3个 组分：连接多巴胺转运蛋白（DAT）靶向的网格蛋白载体纳米颗粒（CNP） 配体（哌醋甲酯或GBR 12909或抗DAT抗体）和脑源性神经营养因子（BDNF）。 CNP成功地绕过血脑屏障（BBB），并提供足够浓度的BDNF， 表达DAT的神经元。纹状体的BDNF浓度比大脑皮层高100倍以上， 在以前的BDNF全身和鼻腔给药研究中报告。CNPs还拯救了纹状体酪氨酸 iTat小鼠模型中HIV/达特、METH和达特/METH联合神经毒性的羟化酶阳性纤维 HIV/neuroAIDS 该2期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，并成功地 治疗暴露于METH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CNPs将BDNF递送到受影响的脑区域，逆转了METH在这些脑细胞中的神经毒性作用， 区域，并改善运动和记忆功能的大鼠暴露于毒性剂量的甲基。第二，我们也 计划测试CNPs是否会抑制大鼠在3年内上下文、暗示和METH诱导的药物寻求恢复 从METH自我管理的禁欲周。为了实现我们的第二阶段目标，我们将执行一系列 这些研究将确定NP的稳定性、大脑和身体分布、安全性和功能性。大鼠将 用标准行为测试来测试此外，免疫组织化学和分子测定将用于 评价多巴胺能纤维的密度、多巴胺能神经元的数量和多巴胺及其受体的水平。 代谢物和新CNP的毒性。 该研究项目将为治疗METH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和再生多巴胺能神经元;阻断 METH诱导的DA释放;抑制背景、线索和METH诱导的药物寻求恢复。它 可以预防复发，保护和恢复大脑功能，比现有的治疗更快，更完全 方法，同时使用低得多的治疗药物剂量，并导致更少的副作用。的发展 稳定、无毒纳米颗粒也可能为MUD生物标志物研究提供主要的新工具。这 纳米技术可以作为下一代神经治疗诊断的基础， 相关的脑系统，并且还可以具有作为成像剂以增强诊断和监测的效用。 疾病的进展。

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.