Nanoparticle Brain Delivery of Iron Chelators for AD

描述(由申请人提供)： 这项初步研究的目标是开发和测试新型铁络合剂颗粒系统，用于从阿尔茨海默病(AD)患者的大脑中去除多余的金属(铁、铝和其他)，并为这些系统在铁络合治疗中的进一步开发奠定基础。尽管强有力的证据(McLachlan等人，《柳叶刀》第337：1304.8,1991年)已经表明铁络合可以通过消耗体内多余的金属而使AD患者受益，但毒性、给药途径以及铁络合剂跨越血脑屏障的能力受限等问题阻碍了这一方法的进一步发展，我们假设这些障碍可以通过将铁络合剂连接到纳米颗粒来克服，这可能是一种将螯合剂带入大脑并使用低密度脂蛋白(LDL)运输机制将铁络合剂复合体带出体外的载体。此外，该系统的脑靶向能力可以增加过量金属耗竭的效果，从而降低潜在的毒性和给药难度，本初步研究将集中在合成铁络合剂并通过共价键合将其与纳米粒子偶联。此外，螯合剂纳米颗粒系统靶向大脑并通过脑-血屏障(BBB)的潜力将取决于使用二维凝胶技术的蛋白质吸收模式。更重要的是，使用这些系统治疗的阿尔茨海默病转基因小鼠将进行体内研究，从而深入了解这些系统是否可以跨越血脑屏障，将铁从大脑中带出，并保护大脑免受氧化损伤。这些可以通过组织化学、电感耦合等离子体质谱和免疫化学分析来检测。这些小鼠非常适合作为这项研究的模型，因为它们大脑中的铁和氧化损伤水平增加。在阿尔茨海默病患者的大脑中已经发现了同样的增加。我们认为，纳米粒子作为脑靶向载体的使用可能为铁离子螯合治疗AD提供可能性，本研究可能为进一步开发铁络合剂纳米粒子系统用于铁离子螯合治疗奠定基础。此外，本研究还可能为其他神经退行性疾病，如帕金森氏病和Friedreich‘s共济失调，以及其他：铁超载介导的疾病的铁螯合治疗提供一些启示。总体而言，这是探索性的：研究可能会为使用铁络合剂纳米颗粒系统靶向疾病器官进行铁络合治疗打开大门。

DESCRIPTION (provided by applicant): The goals of this initial research are to develop and test novel iron-chelatorman particle systems for removing excess metals (iron, aluminium, and others) from the brains of Alzheimer's disease (AD) patients and to lay the groundwork for further development of these systems in iron chelation: therapy. Although strong evidence (McLachlan et al., Lancet 337:1304.8, 1991) has shown that iron chelation can benefit AD patients by depleting excess metals from body, problems with toxicity, route of administration and restricted ability of the iron chelators to cross the BBB, have impeded the further development of this approach, We hypothesize that these impediments may be overcome by conjugating iron chelators to nanoparticles, which may serve as a vehicle to carry the chelators into the brain and bring iron-chelator complexes out using low density lipoprotein (LDL) transport mechanisms. Moreover, the brain targeting ability of the systems may increase the efficacy of excess metal depletion and hence lower potential toxicity and difficulty of administration, This pilot study will focus on synthesizing iron chelators and conjugating them with nanoparticles by covalently bonding. Also, the potential of the chelator nanoparticle systems to target the brain and cross the brain-blood barrier (BBB) will be determined by protein absorption pattern using 2-D gel technology. More important, an in vivo study using Alzheimer transgenic mice treated with these systems will be performed and thereby provide the insight in whether the systems can cross the BBB, bring iron out of the brain and protect against oxidative damage in the brain. These can be detected by using histochemical, ICP-MS, and immunochemical analyses. These mice are suited well to serve as a model in this study because of increased iron and oxidative damage levels in their brain. The same increases have already been found in the brain of the patients with Alzheimer's disease. We believe that the use of nanoparticles as a brain targeting vehicle may provide the possibility of iron chelation therapy for AD and this study may lay the groundwork for further development of iron chelator nanoparticle systems in iron chelation therapy. Moreover, this investigation may also provide some insights into iron chelation treatment for some other neurodegenerative diseases, such as Parkinson's disease and Friedreich's ataxia as well as:other: iron overload mediated diseases. Overall, this: exploratory: study may open the door for the use of iron chelator nanoparticle systems to target diseased organs for iron chelation therapy.