Nanoparticle Brain Delivery of Iron Chelators for AD

铁螯合剂的纳米颗粒大脑输送治疗 AD

• 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
• 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' 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

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）：强有力的证据表明，铁螯合疗法可以通过消耗体内多余的金属而使阿尔茨海默病（AD）患者受益。不幸的是，毒性、给药途径和铁螯合剂穿过BBB的能力有限等问题阻碍了这种方法的进一步发展。我们的长期目标是开发新型铁螯合治疗剂，使用纳米药物递送技术预防和治疗AD。具体的假设是，与铁螯合剂缀合的纳米颗粒不仅可以作为将螯合剂送入大脑的载体，还可以将铁（和一些其他金属）-螯合剂复合物带出大脑，从而防止过量金属相关的脑损伤。该假设基于1）纳米颗粒可以模拟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，形成的颗粒有可能通过模拟脂蛋白进入大脑。更重要的是，与纳米颗粒缀合的螯合剂保留了金属结合能力，并且金属-螯合剂-纳米颗粒复合物能够模拟一些可以离开大脑的脂蛋白颗粒。为了证明我们的假设，提出了具体的目标。1.合成铁螯合剂并将其与纳米粒子结合，然后测试所形成的系统的金属结合能力。铜螯合剂也将用于结合和测试，以深入了解不同金属在AD中的作用。合成和缀合的方法已经由我们或根据文献开发。2.表征形成的系统和与金属络合的系统上的血浆蛋白吸收模式（PPAP）。PPAP将通过二维凝胶分析确定，并指示系统模拟脂蛋白的能力。将使用体外共培养血脑屏障（BBB）模型进行颗粒递送系统双向穿过BBB的动力学研究。3.使用体内动力学研究和改良程序检查系统进入和离开大脑的能力。分别采用色谱法、石墨炉原子吸收光谱法（GFAAS）测定小鼠脑中纳米颗粒和金属离子的含量。还将检查其他器官、血液和排泄物中的这些内容物。4.证明该系统是否从阿尔茨海默氏症转基因小鼠和帕金森氏症大鼠的大脑中去除铁或其他金属，并防止大脑氧化损伤。除了大脑之外，还将检查目标3中的其他隔室的纳米颗粒、金属和氧化损伤水平。这些终点将通过生物、组织和免疫化学方法以及仪器分析（如GFAAS）确定。 本研究不仅为探讨过量金属离子导致AD的发病机制提供了新的思路，同时也为AD的治疗提供了新的思路。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。