基于钆金属富勒烯的多功能分子影像探针的设计及在肿瘤早期诊断的应用研究

Molecular imaging has become a booming area because of its non-invasive, real time and three dimensions imaging of the physiological and pathological changes in biological organisms at molecular level.Molecular imaging is crucial to understand the occurrence and development mechanism of tumor,especially in early diagnosis and assessment of curative effect of disease, where molecular imaging probes are fundamental.This project aims to develop new MRI contrast agent based on gadofullerenes with low-toxicity and high-efficiency. The new fabricated molecualr imaging probes will be further modified by various types of bioactive molecules for targeting specific disease sites through molecular recognition,such as aptamer. The research content includes: the design of biocompatible, high efficient MRI contrast agent based on gadofullerenes; the assembly of MRI/optical molecular imaging probe with molecular recognition part-aptamer; the evaluation of biocompatibility,stability,tumor cell specificity and sensitivity and the visual analysis of the optimized molecular imaging probe in vivo.The achievement obtained herein will not only provide fundamental evidence for the occurrence, development and metastasis of tumor, but also establish a foundation for the theranostics of tumor.

通过分子影像学手段对恶性肿瘤细胞进行标记、显像，将为阐明肿瘤发生发展机制、早期诊断和疗效判定奠定基础。发展肿瘤细胞靶向性的多功能分子探针是实现肿瘤细胞分子成像及治疗的基础和关键。本课题将围绕严重威胁人类生命健康的恶性肿瘤(肺癌)，以其表面高表达的肿瘤标志物为靶标，筛选得到能特异性识别肿瘤细胞的核酸适体，构建靶向肿瘤的磁共振/荧光分子影像探针。主要研究内容包括筛选靶向肺癌肿瘤细胞的核酸适体，研制生物相容性好的、高灵敏钆基内嵌金属富勒烯造影剂，将肿瘤细胞单抗或核酸适体分别与钆基内嵌金属富勒烯偶联，构建适用于肿瘤特异性识别的磁共振/荧光成像分子探针。对这些分子探针的生物相容性、灵敏性、特异性、稳定性等进行评价和优化，实现模型荷瘤鼠体内肿瘤细胞的特异性识别与标记，提高检测灵敏度，为深入研究肿瘤发生、发展和转移规律提供依据，为实现早期诊疗一体化奠定基础。

首先以富勒烯C60为模型分子，制备了两种磁共振成像造影剂，初步研究了其在体外的理化性质和小鼠体内的成像效果，并拓展到金属富勒烯Gd@C82目标分子的研究上。探索了Gd@C82羟基衍生物弛豫率影响因素及聚集特性，发现了半缩酮结构对其聚集行为以及弛豫效率有重要影响，为优化钆金属富勒烯分子影像探针提供理论基础。开发了一种钆金属富勒烯的新型衍生化方法，构建出高弛豫率的Gd@C82造影剂，制备了一种基于钆基金属富勒烯的新型碳纳米材料诊疗剂。研制了一种具有近红外光发射、高单线态氧产率以及独特的磁学性质的Gd@C82的衍生物，作为一种由荧光成像和磁共振成像双模态成像介导的无毒副作用的抗肿瘤试剂，具有高效的抗肿瘤效果。通过以上研究，为深入研究肿瘤发生、发展和转移规律提供依据，为开发高效低毒、可代谢纳米光诊疗剂奠定基础。