Dual responsive nanoparticle for brain targeted drug delivery

用于大脑靶向药物输送的双响应纳米颗粒

基本信息

批准号：
8885856
负责人：
Peisheng Xu
金额：
$ 21.98万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8885856
关键词：
Adverse effects Alkanes Alzheimer&apos s Disease Amyloid beta-Protein Precursor Attenuated Blood - brain barrier anatomy Blood Circulation Brain Brain Diseases Cells Central Nervous System Agents Central Nervous System Diseases Chelating Agents Clioquinol Deposition Development Disease Drug Delivery Systems Drug Kinetics Encapsulated Endothelial Cells Ensure Environment Ethylene Glycols Exhibits Fluorescent Dyes Glioblastoma Glutathione Goals Hepatolenticular Degeneration Image Immunohistochemistry In Vitro Ions Kinetics Length Malignant Neoplasms Measures Metals Microdialysis Modeling Molecular Target Multiple Sclerosis Mus NanoGel Neurodegenerative Disorders Neurons Oxidation-Reduction Parkinson Disease Particle Size Penetration Penicillamine Pharmaceutical Preparations Physiological Polyethylene Glycols Polymers Property Research Residual state SJL Mouse Senile Plaques Signal Transduction Structure Symptoms System Tg2576 Therapeutic Effect Toxic effect Transferrin Treatment Efficacy Tumor Tissue Water base brain tissue cancer cell comparative efficacy crosslink density dityrosine drug development efficacy testing ethylene glycol extracellular imaging system in vivo inhibitor/antagonist macromolecule mutant nanocarrier nanoparticle overexpression receptor small molecule success targeted delivery therapeutic target

项目摘要

More than 98% of existing molecules cannot access the brain tissue because ofthe blood brain barrier (BBB). As a result, drugs that could be useful for central nervous system diseases cannot reach their targets efficiently and fail to exhibit acceptable therapeutic effect. The goal of the proposed research is to develop a highly selective and efficient system for drug delivery into the brain and to apply it to metal ion chelators that can solubilize AB aggregates and inhibit AB plaque formation associated with Alzheimer's disease. We hypothesize that by incorporating two targeting moieties into a pH and redox potential dual responsive nanogel, metal ion chelators, D-penicillamine (PA) and clioquinol (CQ) can be selectively targeted to the brain tissue and attenuate AB aggregation. Aim 1 is to develop a pH and redox potential dual responsive nanogel and explore the relationship between polymer structure and nanogel properties. In aim 2, we will load chelators or fluorescent dyes into dual targeted dual responsive nanogel (DTDR) with two braintargeting moieties (transferrin and glutathione) and measure DTDR efficacy and BBB penetration in vitro using a Transwell model. The neuroprotective effect of chelator-loaded DTDR will be compared with free drug counterparts and optimized by adjusting the densities of transferrin, glutathione, and polyethylene glycol. Aim 3 will assess the efficacy and BBB penetration of fluorescent dye or chelator-loaded brain-targeting DTDR in vivo. The composition of brain-targeted fluorescent DTDR will be optimized with IVIS imaging to achieve high selectivity for brain tissue in mice. The therapeutic efficacy of the brain-targeted PA or CQ-loaded DTDR will be quantified by measuring extracellular brain AB using in vivo microdialysis (IVM) in Tg2576 mice and compared with their free drug counterparts. Correlations between PA and CQ concentrations obtained from IVM, Zn and Cu residual in the brain tissue, amyloid plaque deposition from immunohistochemistry, and the residual AB in the brain tissue will be analyzed. Pharmacokinetic properties and systemic toxicity ofthe DTDR nanogel will also be evaluated. The success of this study should drastically increase the spectrum of drugs that can be developed for central nervous system diseases.

由于血脑屏障（BBB），现有分子中有98％以上无法进入脑组织。结果，可能对中枢神经系统疾病有用的药物无法有效地达到其靶标，并且无法表现出可接受的治疗作用。拟议的研究的目的是开发一种高度选择性，有效的系统，用于将药物输送到大脑中，并将其应用于可以溶解AB聚集体并抑制与阿尔茨海默氏病相关的AB斑块形成的金属离子螯合剂。我们假设通过将两个靶向部分纳入pH和氧化还原潜在的双重响应纳米凝胶，金属离子螯合剂，D-苯胺氨基胺（PA）和clioquinol（CQ）可以选择性地靶向脑组织并降低AB聚集。目的1是开发pH和氧化还原潜在的双重响应纳米凝胶，并探索聚合物结构与纳米凝胶性能之间的关系。在AIM 2中，我们将使用两个BraintArgenting部分（转铁蛋白和谷胱甘肽）加载螯合剂或荧光染料，并使用Transwell模型在体外测量DTDR功效，并测量DTDR的功效和BBB渗透。螯合剂负载的DTDR的神经保护作用将与游离药物对应物进行比较，并通过调节转铁蛋白，谷胱甘肽和聚乙烯乙二醇的密度来进行优化。 AIM 3将评估体内荧光染料或螯合剂的脑靶向DTDR的功效和BBB渗透。通过IVIS成像，将对脑靶向荧光DTDR的组成进行优化，以实现小鼠脑组织的高选择性。通过在TG2576小鼠中使用体内微透析（IVM）测量细胞外脑AB来测量细胞外脑AB的治疗疗效，并与其自由药物对应物进行比较。将分析从IVM，Zn和Cu在脑组织中残留的PA与CQ浓度之间的相关性，免疫组织化学中的淀粉样蛋白斑块沉积以及脑组织中的残留AB。还将评估DTDR纳米凝胶的药代动力学特性和全身毒性。这项研究的成功应大大增加可用于中枢神经系统疾病的药物谱。