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

摘要 甲基苯丙胺成瘾与人类免疫缺陷病毒相关神经认知 手部疾病是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)研究报告了多巴胺转运体(DAT)密度 减少艾滋病毒和冰毒患者的数量。冰毒和手的治疗进展 通过将脑源性神经营养因子(BDNF)直接注射到中枢神经系统或通过使用 可间接增加脑源性神经营养因子。脑源性神经营养因子可促进神经元存活、可塑性和恢复大脑功能。 然而，BDNF不能穿过完整的血脑屏障(BBB)，并且在血液中不稳定或在 口服药。这项工作的目标是生产无毒的BDNF纳米颗粒(NPs)，并测试 假设(A)这些NPs在鼻腔内绕过血脑屏障，(B)靶向多巴胺能脑区，以及(C) 预防或逆转冰毒和HIV转录反式激活因子蛋白对小鼠的神经毒性作用 与手相关的模型(强力霉素诱导的GT-TG双基因小鼠过表达Tat蛋白)。 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)。一种纳米载体将是 由笼状蛋白构成，这是一种天然存在的蛋白质，身体用来将分子输送到细胞中。 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， GBR12935)。BDNF和DAT配体将通过聚乙二醇(PEG)分子连接到分子筛上。一个 一系列研究将确定NP在体内的特异性和功能。我们计划演示 这一新的纳米技术治疗冰毒和TAT引起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 冰毒成瘾和手的神经毒性。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、更完全地恢复大脑功能 方法使用低得多的治疗药物剂量，且副作用少。开发一种新的 稳定、靶向的分子NP也可能为分子异常的研究提供一个重要的新工具。 手和毒瘾。这种新颖的纳米技术可能会成为下一代药物的基础-- 可以专门针对相关大脑系统并按需释放药物的递送系统，还可以 具有作为显像剂的效用，以加强诊断和监测疾病的进展。

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.