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的铁螯合剂颗粒系统，用于从阿尔茨海默病（AD）患者的大脑中去除多余的金属（铁，铝等），并为这些系统在铁螯合治疗中的进一步发展奠定基础。尽管有强有力的证据（McLachlan等人，Lancet 337：1304.8，1991）已经表明，铁螯合可以通过从体内消耗过量的金属而有益于AD患者，毒性、给药途径和铁螯合剂穿过BBB的能力受限的问题阻碍了该方法的进一步发展。我们假设这些障碍可以通过将铁螯合剂缀合至纳米颗粒来克服，纳米颗粒可以用作将螯合剂携带到脑中并使用低密度脂蛋白（LDL）转运机制将铁-螯合剂复合物带出的媒介物。此外，该系统的脑靶向能力可以增加过量金属消耗的功效，从而降低潜在的毒性和给药难度。本初步研究将集中于合成铁螯合剂并通过共价键合将其与纳米颗粒缀合。此外，螯合剂纳米颗粒系统靶向脑和穿过脑血屏障（BBB）的潜力将通过使用2-D凝胶技术的蛋白质吸收模式来确定。更重要的是，将使用用这些系统治疗的阿尔茨海默氏症转基因小鼠进行体内研究，从而提供系统是否可以穿过BBB，将铁带出大脑并保护大脑免受氧化损伤的见解。这些可以通过使用组织化学、ICP-MS和免疫化学分析来检测。这些小鼠非常适合作为本研究的模型，因为它们大脑中的铁和氧化损伤水平增加。同样的增加已经在阿尔茨海默病患者的大脑中发现。我们认为，使用纳米粒子作为脑靶向载体可能提供铁螯合治疗AD的可能性，本研究可能奠定基础，进一步开发铁螯合剂纳米粒子系统在铁螯合治疗。此外，本研究也可能为铁螯合治疗其他神经退行性疾病，如帕金森病和弗里德赖希共济失调以及其他：铁过载介导的疾病提供一些见解。总体而言，这：探索性：这项研究可能为使用铁螯合剂纳米颗粒系统靶向患病器官进行铁螯合治疗打开大门。

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.