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

• 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
• 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' 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

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）的存在，超过98%的现有分子无法进入脑组织。因此，可能对中枢神经系统疾病有用的药物不能有效地到达目标，不能表现出可接受的治疗效果。该研究的目标是开发一种高选择性和高效的药物输送系统，并将其应用于金属离子螯合剂，可以溶解AB聚集体并抑制与阿尔茨海默病相关的AB斑块形成。我们假设，通过在pH和氧化还原电位双响应纳米凝胶中加入两个靶向部分，金属离子螯合剂d -青霉胺（PA）和氯喹诺（CQ）可以选择性地靶向脑组织并减弱AB聚集。目的1：制备pH和氧化还原电位双响应的纳米凝胶，探讨聚合物结构与纳米凝胶性能之间的关系。在目标2中，我们将把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的疗效和体外血脑屏障渗透。通过调整转铁蛋白、谷胱甘肽和聚乙二醇的浓度，将负载螯合剂的DTDR与游离药物的神经保护作用进行比较。目的3将在体内评估荧光染料或螯合剂负载的脑靶向DTDR的疗效和血脑屏障穿透性。利用IVIS成像优化脑靶向荧光DTDR的组成，以实现对小鼠脑组织的高选择性。通过体内微透析（IVM）测量Tg2576小鼠的细胞外脑AB，并与游离药物进行比较，量化脑靶向PA或cq负载DTDR的治疗效果。我们将分析IVM测定的PA和CQ浓度、脑组织中Zn和Cu残留、免疫组化测定的淀粉样斑块沉积以及脑组织中AB残留之间的相关性。还将评估DTDR纳米凝胶的药代动力学性质和全身毒性。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的范围。