Brain targeted nanoparticle for Alzheimer's disease therapy

项目总结 阿尔茨海默病(AD)在2015年消耗了约226亿美元的医疗费用，与 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 AD的发展。我们的初步研究开发了一种双靶向双响应性纳米颗粒 (DTDRN)可以有效地穿透血脑屏障(BBB)，并在大脑中释放其有效载荷。 此外，N-乙酰半胱氨酸(NAC)负载DTDRN的治疗效果明显优于游离NAC 脂多糖诱导的脑炎性动物模型。这项研究的目的是开发一种有针对性的大脑 合理利用血脑屏障和脑组织的特点，建立治疗AD的系统。在目标1中，我们 将开发一种NAC-DTDRN，并在体外表征其血脑屏障渗透效率。目标2将评估 NAC-DTDRN体外抗炎、抗氧化作用及体内药代动力学研究。 目的3将在AD动物模型上测试NAC-DTDRN的有效性并评估其毒性。总而言之， 通过建议的DTDRN系统提供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，建议的 DTDRN系统可以携带其他治疗分子(疏水和亲水)到大脑和 应用于帕金森等其他中枢神经系统疾病的检测和治疗 疾病、创伤性脑损伤和多发性硬化症。

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.