基于老年性痴呆复杂发病机制的高协同效应纳米递药系统的构建

Against Aβ aggregation therapy method and acetylcholinesterase inhibitor (AchE inhibitor) therapy method for the clinical treatment of AD have a series of defects such as low capacity to across the membrane for against Aβ aggregation agent (Zinc chelating agent), side effects for AchE inhibitor (donepezil) via oral administration, unsatisfying therapy effect with single drug treatment due to complicated pathogenesis of AD and so on. A new kind of nano-drug delivery system with good synergistic effect is constructed by the self-assemble of transmembrane peptide (TAT), nasal mucosa targeting agent (Ulex Europaeus agglutinin I), Zinc chelating agent (5-amino-8-hydroxyquinoline), AchE inhibitor (donepezil) with linoleic acid modified dextran polymeric liposome in our group. Combining the benefits of the above-mentioned therapy methods and the benefits of nanobiotechnology and intranasal administration, the construction is expected to combine efficient transmembrane capacity, enhanced targeting function, drug controlled release, against Aβ aggregation therapy method and AchE inhibitor therapy method together perfectly. The actual efficacy of the construction was extensively studied by stability test, chelating ability test, drug controlled release test, cytotoxicity, targeting ability in vitro and treatment experiment in vivo based on the Tg2576 transgenic mice AD model, all of which provide important evidence for mostly improving the treatment of AD.

老年性痴呆(Alzheimer's disease,AD)发病机制复杂，目前临床多采用抗Aβ聚集或抑制乙酰胆碱酯酶（AchE）等治疗方法，但存在抗Aβ聚集锌离子螯合剂跨膜（鼻粘膜及细胞膜）能力低、AchE抑制剂口服给药副作用大、单一用药疗效差等科学问题。本项目拟联合抗Aβ聚集和抑制AchE两种治疗方法，将纳米生物技术与鼻腔给药技术相结合，采用自主研发的亚油酸改性葡聚糖纳米高分子脂质体与跨膜肽（TAT）、嗅粘膜靶向制剂（荆豆凝集素）、锌离子螯合剂（5-氨基-8-羟基喹啉）、AchE抑制剂（多奈哌齐）等组分进行组装，构建一种同时具有跨膜、靶向、缓释、抗Aβ聚集和抑制AchE治疗等功能的高协同效应纳米递药系统。并通过一系列体外稳定性、螯合性、释药性、安全性、靶向性实验及体内Tg2576转基因小鼠AD模型治疗实验，验证该纳米递药系统的实际协同功效，为最大程度地提高AD的治疗效果提供科学依据。

老年痴呆（AD）是最普遍的神经退行性疾病，目前尚无有效的治疗方法。据报道，金属离子引发的淀粉样蛋白-β（Aβ）肽聚集交联和乙酰胆碱失衡可能是AD的发病机理。因此，针对上述问题，本课题设计了氯喹醇（金属离子螯合剂）和多奈哌齐（AChE抑制剂）共包裹的人血清白蛋白（HSA）纳米颗粒，并用TAT肽和单唾液酸四己糖基神经节苷脂（GM1）进行了修饰，构建出集脑部靶向、药物缓释和多机制协同治疗治疗功能于一体的新型多功能人血清白蛋白高效协同药物递送系统。通过体外细胞实验及体内动物实验验证，我们成功构建了集脑部靶向、药物缓控释和多机制协同治疗治疗功能于一体的新型多功能人血清白蛋白高效协同药物递送系统，这一药物递送系统在诊疗一体化的应用过程中具有显著优势。在本课题的支持下取得了一系列成果，以第一作者和通讯作者在国际顶级材料期刊如Advanced Materials, Advanced Functional Materials，ACS nano，ACS Applied Materials & interfaces 等发表SCI 论文共28 篇，其中25篇论文IF 均>3，申请中国发明专利8 项。在本项目实施过程中，共培养硕士及博士研究生20名。针对阿兹海默症复杂的机制，本项目的实施为拓宽高效协同药物递送系统的构建思路，研制新一代阿兹海默高效协同药物递送系统提供重要科学依据。