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：
9061734
负责人：
Peisheng Xu
金额：
$ 22.4万
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/9061734
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 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 Pharmacotherapy Physiological Polyethylene Glycols Polymers Property Research Residual state SJL Mouse Senile Plaques Signal Transduction Structure System Tg2576 Therapeutic Effect Transferrin Treatment Efficacy Tumor Tissue Water base brain tissue cancer cell comparative efficacy crosslink density dityrosine efficacy testing ethylene glycol extracellular imaging system in vivo inhibitor/antagonist macromolecule mutant nanocarrier nanoparticle overexpression receptor reduce symptoms small molecule success systemic toxicity targeted delivery targeted treatment

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)，超过 98% 的现有分子无法进入脑组织。结果，可用于治疗中枢神经系统疾病的药物无法有效地到达其目标并且无法表现出可接受的治疗效果。拟议研究的目标是开发一种高选择性和高效的系统，用于将药物输送到大脑中，并将其应用于金属离子螯合剂，该螯合剂可以溶解AB聚集物并抑制与阿尔茨海默病相关的AB斑块形成。我们假设，通过将两个靶向部分合并到 pH 和氧化还原电位双响应纳米凝胶中，金属离子螯合剂、D-青霉胺 (PA) 和氯碘羟喹 (CQ) 可以选择性地靶向脑组织并减弱 AB 聚集。目标1是开发pH和氧化还原电位双响应纳米凝胶，并探索聚合物结构和纳米凝胶性能之间的关系。在目标 2 中，我们将螯合剂或荧光染料加载到具有两个脑靶向部分（转铁蛋白和谷胱甘肽）的双靶向双响应纳米凝胶 (DTDR) 中，并使用 Transwell 模型测量 DTDR 功效和体外 BBB 渗透。负载螯合剂的 DTDR 的神经保护作用将与游离药物对应物进行比较，并通过调整转铁蛋白、谷胱甘肽和聚乙二醇的密度来优化。目标 3 将评估荧光染料或负载螯合剂的脑靶向 DTDR 的体内功效和 BBB 渗透性。脑靶向荧光DTDR的成分将通过IVIS成像进行优化，以实现对小鼠脑组织的高选择性。脑靶向 PA 或 CQ 负载 DTDR 的治疗效果将通过在 Tg2576 小鼠体内使用体内微透析 (IVM) 测量细胞外脑 AB 来量化，并与它们的游离药物对应物进行比较。将分析从 IVM 获得的 PA 和 CQ 浓度、脑组织中残留的 Zn 和 Cu、免疫组织化学的淀粉样蛋白斑沉积以及脑组织中残留的 AB 之间的相关性。还将评估 DTDR 纳米凝胶的药代动力学特性和全身毒性。这项研究的成功将大大增加可用于治疗中枢神经系统疾病的药物范围。