超顺磁-荧光双信号分子探针的构建及其用于乳腺癌分子标志物定量检测和乳腺癌组织成像研究

Breast cancer has the highest fatality rate of all female cancer. ER and Her-2 are the two key biomarkers of breast cancer, distribution and expression of these two biomarkers are related to the early-stage diagnosis, subtype, TNM stage and therapeutic schedule of breast cancer. Currently, to in situ mark, track and accurately quantify these biomarkers remains a challenge in early stage breast cancer diagnosis and bioanalysis research field. In this program, we develop a series of probes composed of bifunctional ER or Her-2 target peptides and the Gd doped noble metal cluster, which simultaneously possess superparamagnetism and fluorescence. The probe can target the biomarkers of breast cancer tissue of different pathological stage. Using the confocal microscopy, MRI, biological mass spectrometry, ICP-MS and combine with molecular biology technology to characterize physicochemical properties and biological effect of the nanoprobe, in situ mark and quantify the biomarkers of breast cancer. According the aforementioned researches, we will reveal the real time distribution and expression differences between the two biomarker of breast cancer at tissue-level; To guide the puncture biopsy and quantify the expression amount of biomarkers at cell-level, and understand the relationship of the biomarkers abnormal-expression and the TNM stage, subtype of breast cancer. This research results will provide the key data to judge subtype and invasion/matastasis tendency of the earlier stage breast cancer, and to assist the clinician to make clinical therapeutic schedule for patients.

乳腺癌是女性癌症相关疾病中最常见的、致死率最高的恶性肿瘤，准确地判断乳腺癌的分子分型是乳腺癌早期诊断和实施个体化治疗中亟待解决的关键问题。前期研究提示：雌激素受体（ER）和表面生长因子受体-2（Her-2）是与乳腺癌的早期诊断、分子分型和恶性程度显著相关的两种肿瘤标志物。探索能通过临床影像技术实现对活体组织中标志物的原位分子成像，同时实现乳腺癌标志物ER和Her-2的活细胞原位标记和定量检测方法，是乳腺癌早期诊断和标志物定量中极具挑战性的研究课题。本课题以ER和Her-2为研究对象，发展一系列由多肽和钆掺杂的贵金属团簇复合而成的核磁-荧光双模分子探针。利用活细胞、活体荧光和核磁共振成像技术，在组织水平实现同时对乳腺癌细胞中ER和Her-2的实时追踪，有针对性地实施活检并对标志物进行定量检测，为指导临床乳腺癌分型、治疗方案的选择提供重要依据。

肿瘤标志物的细胞原位标记和定量检测方法，是肿瘤早期诊断和标志物定量中极具挑战性的研究课题。本项目构建了Au, Ag, Cu三种金属元素为基础的团簇纳米探针，实现了细胞亚结构的标记；构建了能够特异性识别单细胞表面蛋白分子的荧光/质谱一体化分子探针，建立了在单细胞水平进行整合素空间分布和定量检测的方法；构建了活体水平荧光/CT一体化的蛋白质-金团簇纳米探针，实现了在活体水平对小鼠肾脏解剖结构的成像；在此基础上，进一步耦合稀土族钆金属元素，制备了具有超顺磁/荧光/CT一体化的分子探针，实现了对小鼠皮下肿瘤的多模态成像；