Brain targeted nanoparticle for Alzheimer's disease therapy

用于治疗阿尔茨海默病的脑靶向纳米颗粒

• 批准号: 9329544
• 负责人: Peisheng Xu
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329544
• 关键词: Acetylcysteine; Alpha Cell; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Disease Models; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Base of the Brain; Biodistribution; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; C57BL/6 Mouse; Cause of Death; Cells; Central Nervous System Diseases; Characteristics; Chronic; Coculture Techniques; Cysteine; Detection; Development; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Endothelium; Environment; Exhibits; Fluorescent Probes; Frequencies; Gamma counter; Glutathione; Health Care Costs; Human; Hydrophobicity; Immune response; Immunotherapy; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; Kinetics; Learning; Ligands; Lipopolysaccharides; Maximum Tolerated Dose; Memory; Microglia; Mission; Modeling; Modification; Molecular Target; Multiple Sclerosis; Mus; NanoGel; Nervous system structure; Organ; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Particle Size; Patients; Penetration; Pharmaceutical Preparations; Physiological; Polymers; Property; Reporting; Research; System; TNF gene; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; Traumatic Brain Injury; United States; United States National Institutes of Health; base; brain tissue; cost; crosslink; cytokine; density; hydrophilicity; hyperphosphorylated tau; imaging system; in vivo; in vivo imaging system; inhibitor/antagonist; macromolecule; morris water maze; mouse model; nanoparticle; neglect; public health relevance; receptor; reduce symptoms; small molecule; stimulus sensitivity; success; systemic toxicity; targeted delivery; tau Proteins; therapy development

PROJECT SUMMARY Alzheimer’s disease (AD), which consumed ~$226 billion in health care costs in 2015, is associated with nervous system chronic inflammation. Recent research revealed that the malfunction of microglia is critical for the development of AD. Our preliminary study developed a dual targeted dual responsive nanoparticle (DTDRN) which can effectively penetrate the blood brain barrier (BBB) and release its payload in the brain. Furthermore, N-acetyl cysteine (NAC)-loaded DTDRN showed much better therapeutic effect than free NAC in a LPS-induced brain inflammatory animal model. The objective of this study is to develop a brain targeted system for AD therapy by rationally utilizing the characteristics of both BBB and the brain tissue. In Aim 1, we will develop a NAC-DTDRN and characterize its BBB penetration efficiency in vitro. Aim 2 will evaluate the anti-inflammatory and anti-oxidant effects of the NAC-DTDRN in vitro and study its pharmacokinetics in vivo. Aim 3 will test the efficiency of the NAC-DTDRN in an AD animal model and evaluate its toxicity. In summary, NAC delivery via the proposed DTDRN system which can effectively penetrate the BBB and exhibit anti- inflammatory effects has potential to benefit AD patients. Due to the versatility of DTDRN, the proposed DTDRN system can carry other therapeutic molecules (both hydrophobic and hydrophilic) to the brain and to be applied for the detection and treatment of other central nervous system diseases such as Parkinson disease, traumatic brain injury, and multiple sclerosis.

项目摘要 阿尔茨海默病（AD）在2015年消耗了约2260亿美元的医疗保健费用， 神经系统慢性炎症。最近的研究表明，小胶质细胞的功能障碍是关键， AD的发展。我们的初步研究开发了一种双靶向双响应纳米颗粒， （DTDRN），其可以有效地穿透血脑屏障（BBB）并在脑中释放其有效载荷。 此外，N-乙酰半胱氨酸（NAC）负载的DTDRN显示出比游离NAC更好的治疗效果。 LPS诱导的脑炎症动物模型。这项研究的目的是开发一种针对 合理利用血脑屏障和脑组织的特点，建立AD治疗系统。目标1： 将开发NAC-DTDRN并在体外表征其BBB穿透效率。目标2将评估 体外抗炎和抗氧化作用，并研究其体内药代动力学。 目的3：在AD动物模型中检测NAC-DTDRN的有效性并评价其毒性。总的来说， 通过所提出的DTDRN系统递送NAC，该系统可以有效地穿透BBB并表现出抗- 炎症作用有可能使AD患者受益。由于DTDRN的多功能性，建议 DTDRN系统可以将其他治疗分子（疏水性和亲水性）携带到大脑， 可用于检测和治疗其他中枢神经系统疾病，如帕金森病 疾病、创伤性脑损伤和多发性硬化症。