Nanoparticle Brain Delivery of Iron Chelators for AD

铁螯合剂的纳米颗粒大脑输送治疗 AD

基本信息

批准号：
7588011
负责人：
GANG LIU
金额：
$ 32.92万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7588011
关键词：
AA Spectrophotometry Affect Aging Aluminum Alzheimer disease prevention Alzheimer&apos s Disease Animals Apolipoprotein E Apolipoproteins Binding Blood - brain barrier anatomy Blood Circulation Brain Brain Injuries Cell Culture Techniques Chelating Agents Chelation Therapy Chromatography Coculture Techniques Complex Copper Degenerative Disorder Development Disease Drug Delivery Systems Drug Transport Etiology Excision Excretory function Feces Free Radical Formation Free Radicals Friedreich Ataxia Gel Goals Heart Histocytochemistry Human Image In Vitro Insecta Ions Iron Iron Chelation Kidney Kinetics Lead Left Lipoprotein Receptor Lipoproteins Literature Liver Low-Density Lipoproteins Lung Measures Mediating Metals Methods Modeling Molecular Weight Mus Natural graphite Neurodegenerative Disorders Organ Parkinson Disease Pathogenesis Patients Pattern Penetration Pharmaceutical Preparations Plasma Proteins Play Polymers Procedures Process Proteins Rattus Recommendation Reporting Research Personnel Research Project Grants Risk Factors Role Route Side Site Spleen Surface Surface Properties System Technology Testing Therapeutic Therapeutic Agents Toxic effect Transgenic Mice Transition Elements Urine Zinc absorption base bone brain tissue catalyst chelation design harman hydrophilicity in vivo insight iron chelation therapy lipophilicity metal chelator metal complex mouse model nanoparticle novel novel therapeutics oxidative damage particle polyacrylamide prevent programs receptor theories tool two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Strong evidence has shown that iron chelation therapy can benefit Alzheimer's disease (AD) patients by depleting excess metals from the body. Unfortunately, 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. Our long-term goal is to develop novel iron chelation therapeutic agents using nanoparticle drug delivery technology for AD prevention and treatment. The specific hypothesis is that nanoparticles conjugated with iron chelators can serve as vehicles not only to send chelators into the brain but also bring the iron (and some other metals)-chelator complexes out of the brain, hence preventing excess metal associated brain damage. This hypothesis is based on 1) nanoparticles can mimic selected lipoprotein particles and enter the brain via lipoprotein receptor-mediated mechanisms. 2) Some lipoprotein particles can also leave the brain via the same receptor-mediated mechanisms. 3) Our preliminary studies show that iron chelators can conjugate with nanoparticles and the formed particles have the potential to enter the brain by mimicking lipoprotein. More important, the chelators conjugated to nanoparticles retain metal binding ability and the metal-chelator-nanoparticle complexes are capable of mimicking some lipoprotein particles that can leave the brain. To demonstrate our hypothesis, the specific aims are proposed. 1. Synthesize iron chelators and conjugate them to nanoparticles, then test the metal-binding ability of the formed systems. Copper chelators will also be used for conjugation and testing to obtain insights into the roles of different metals in AD. The methods for synthesis and conjugation have already been developed by us or according to literature. 2. Characterize the plasma protein absorption patterns (PPAP) on the formed systems and the systems complexed with metals. The PPAP will be determined by the 2-dimensional gel analysis, and indicate the capabilities of the systems to mimic lipoproteins. Kinetic studies of the particle delivery systems bi-directionally across Brain Blood Barrier (BBB) will be conducted using an in vitro coculture BBB model. 3. Examine the ability of the systems to enter and leave the brain using in vivo kinetic studies with a modified procedure. The contents of nanoparticles and metal irons in mouse brain will be assessed using chromatography, Graphite Furnace Atomic Absorption Spectrometry (GFAAS), respectively. These contents in other organs, bloodstream and excretions will also be examined. 4. Demonstrate whether the systems remove iron or other metals from the brain of Alzheimer transgenic mice and Parkinson's disease rats, and prevent the brain from oxidative damage. In addition to brain, other compartments like in aim 3 will be examined for the nanoparticle, metal and oxidative damage levels. These endpoints will be determined by bio-, histo- and immunochemical methods and instrumental analyses such as GFAAS. This study will not only provide the insights into the mechanisms of AD development associated with excess metal ions, but also provide potential therapeutics. Moreover, this approach may be applied to other neurodegenerative diseases mediated by excess metals, and to neuro-imaging.

描述（由申请人提供）：有力的证据表明，铁螯合疗法可以通过从人体中耗尽过多的金属来使阿尔茨海默氏病（AD）患者受益。不幸的是，铁螯合剂越过BBB的毒性，给药途径和限制能力的问题阻碍了这种方法的进一步发展。我们的长期目标是使用纳米颗粒药物递送技术开发新的铁螯合治疗剂，以预防和治疗。具体的假设是，与铁螯合剂结合的纳米颗粒不仅可以用作将螯合剂送入大脑的车辆，而且还可以将铁（和其他一些金属） - 螯合剂络合物从大脑中带出来，从而防止过量金属相关的脑损伤。该假设基于1）纳米颗粒可以模仿选定的脂蛋白颗粒并通过脂蛋白受体介导的机制进入大脑。 2）一些脂蛋白颗粒也可以通过相同的受体介导的机制离开大脑。 3）我们的初步研究表明，铁螯合剂可以与纳米颗粒结合，并且形成的颗粒具有通过模仿脂蛋白来进入大脑的潜力。更重要的是，与纳米颗粒结合的螯合剂保持金属结合能力，金属芯纳米颗粒络合物能够模仿一些可以离开大脑的脂蛋白颗粒。为了证明我们的假设，提出了具体目标。 1。合成铁螯合剂，并将它们缀合至纳米颗粒，然后测试形成系统的金属结合能力。铜螯合剂还将用于结合和测试，以了解对AD中不同金属的作用的见解。我们或根据文献已经开发了合成和共轭的方法。 2。表征形成的系统和与金属复合的系统上的血浆蛋白吸收模式（PPAP）。 PPAP将由二维凝胶分析确定，并指示系统对模拟脂蛋白的能力。将使用体外共培养BBB模型对粒子输送系统进行双向粒子递送系统（BBB）的动力学研究。 3。检查系统使用体内动力学研究进行修改的过程进入和离开大脑的能力。将分别使用色谱，石墨炉原子吸收光谱法（GFAAS）评估小鼠脑中纳米颗粒和金属铁的含量。还将检查其他器官，血液和排泄物中的这些含量。 4。证明系统是否从阿尔茨海默氏症转基因小鼠和帕金森氏病大鼠的大脑中除去铁或其他金属，并防止大脑氧化损伤。除了大脑外，还将检查纳米颗粒，金属和氧化损伤水平的其他隔室。这些终点将由生物，组织和免疫化学方法和工具分析（例如GFAAS）确定。这项研究不仅将提供有关与过量金属离子相关的AD发育机制的见解，而且还提供了潜在的治疗剂。此外，这种方法可以应用于由过量金属介导的其他神经退行性疾病和神经成像。