靶向阿尔茨海默病标志物的超小铁氧体纳米探针的构建及MRI早期诊断应用研究

Alzheimer's disease (AD) is a neurodegenerative disease that is difficult to diagnose and treat. Although a large amount of money has been invested in drug research and development at home and abroad, almost all of them have failed. The main possible reason is the existing diagnostic approaches are difficult to achieve nonradiative, non-invasive and effective early diagnosis and long-term tracing for AD. Therefore, the construction of multi-mode nanoprobe based on MRI image to evaluate and intervene in the early stage of AD disease is expected to be an effective solution to the clinical diagnosis and treatment of AD. A type of phenothiazine derivatives with high affinity and specificity for amyloid plaques Aβ (pathological markers of AD) was selected in our early research, and its ability to target amyloid plaques in vivo was further demonstrated. A series of new ultrasmall ferrite nanoparticles were also constructed by dynamic thermal decomposition method in our previous research, which achieved excellent in vivo MRI contrast effect. This project is applied with chemical conjugation and click chemistry, and builds composite nanoprobe based on phenothiazine derivatives and ultrasmall ferrite nanoparticles, and then the function, safety, efficacy and capability of blood brain barrier penetration in vivo and in vitro are also be investigated, in order to achieve Aβ targeting in brain by multimodal imaging. This project also can provide technical theoretical basis for the early diagnosis of AD disease.

阿尔茨海默症(AD)是一项难以诊断和治疗的神经退行性疾病。虽然目前国内外已投入大量资金进行药物研发，但几乎均以失败告终。其中的主要原因是现有的诊断途径难以实现无辐射、非入侵的、有效的早期AD疾病诊断和长期示踪。因此，构建基于MRI影像的多模态纳米探针，对AD疾病的早期阶段进行评估和干预，有望成为AD临床诊治的有效解决途径。本课题组前期筛选出了一种对β-淀粉样斑块（AD的病理标志物,Aβ）具有高亲和性和特异性的吩噻嗪类衍生物，并进一步证明了其在体内的靶向标记能力。同时我们利用动态热分解法构建了一系列新型超小铁氧体纳米颗粒，实现了优异的活体MRI造影效果。本项目拟应用化学偶联和点击化学等手段，构建基于吩噻嗪类衍生物和超小铁氧体纳米颗粒的复合纳米探针，并对其功能、安全性、有效性、血脑屏障穿透能力进行体内外研究，以期实现Aβ的活体脑内靶向多模态影像标记和示踪，为AD疾病的早期诊断提供技术理论基础。

阿尔茨海默症(AD)临床面临的主要问题是难以实现无辐射非入侵的早期诊断和示踪，因此构建基于临床影像的靶向探针，用于标记AD疾病的生物标志物，是解决临床诊治问题的一个可能的途径。本研究前期研究合成系列吩噻嗪衍生物分子，筛选获得具有Aβ蛋白聚集体高度亲和能力的近红外区发光的分子，并通过体外实验验证了其可明显标记阿尔茨海默病小鼠模型的脑切片上的Aβ蛋白聚集体。进一步的，利用动态热分解法构建了一系列新型超小铁氧体纳米颗粒，获得了具有特异性能的MRI造影能力的纳米探针。在前期研究基础上，本研究构建了基于吩噻嗪类衍生物和超小铁氧体纳米颗粒的复合纳米探针，并对其物理化学性能进行了表征。然后通过体内外实验，验证了其对体外标记、体内靶向方面均具有良好的标记Aβ蛋白聚集体能力。最后通过对靶向纳米探针的安全性、有效性进行系统评估，验证了其在活体标记Aβ蛋白聚集体和对AD疾病的诊断方面的能力和潜在转化应用价值。