基底样乳腺癌的靶向多模态分子影像研究

Basal-like breast cancer (BLBC) is a serious disease threatening to the women’s health with easily metastasis and poor prognosis. Until now, there have no efficicy imaging methods to diagnose BLBC. In this study, two antigens, EGFR and CK5/6, which are highly expressed in BLBC, will be chosen as molecular targets, while, ER, PR and Her-2 will be used to exclude the diagnosis of BLBC. Several molecular probes will be prepared, and upconversion luminescence (UCL), PET and multimodality imagings will be performed in order to early, specificly diagnosis and differencial diagnosis of BLBC. .Three parts will be included in this project. Firstly, four different nanoparticles will be prepared for triplet-triplet energy transfer (TTET) UCL. With different and simple color recognition, different molecular markers of breast cancer will be visulized noninvasively. Secondly, radionuclide labelled probe targeting EGFR and CK5/6 will be constructed for PET imaging. The primary and matastasis lesions will be evaluated in vivo. Lastly, nanoparticles for UCL will be labelled with radionuclide for nuclide and UCL multimodality imaging to precise diagnosis of BLBC. .The construction of different nanoparticles for molecular imaging in this study is not only for the diagnosis and differencial dignosis of breast cancer, but also could be extended to the application for other malignant tumors. Most importantly, an innovation TTET UCL platform makes it possible that different molecular markers could be identified by color visually, noninvasively and simply. This could share a totally new light on the conventional diagnostic methods, and must play an important role in molecular imaging.

基底样乳腺癌(BLBC)恶度高、预后差，至今没有有效影像学诊断方法。本研究以BLBC多表达的两种抗原(EGFR、CK5/6)为分子靶标，以ER、PR、Her-2表达阳性为排除诊断，制备多个分子探针，实现上转换发光、核素及多模态显像，达到早期、特异诊断和鉴别BLBC的目的。首先创新应用三重态上转换发光显像，构建不同纳米上转换分子探针，将近红外光转化为四种不同颜色可见光，以颜色识别，实现无创、在体、可视化鉴别乳腺癌不同分子标记物表达；然后构建核素双靶标分子探针，以PET显像评估其对BLBC原发及转移灶诊断效能；最后通过核素标记纳米粒子，实现核素-上转换发光双模态、多靶点显像精确诊断BLBC。本研究构建纳米分子探针平台的思路，将可拓展用于多种恶性肿瘤的诊断和鉴别。需特别指出，研究应用三重态上转换发光显像，以不同颜色可见光识别不同分子标志物，颠覆常规影像诊断方式，必定在未来分子影像中起重要作用。

基底样乳腺癌（BLBC）恶性程度高、预后差，至今没有有效影像学诊断方法。本项目的主要目标是通过多模态显像实现早期、特异诊断和鉴别BLBC的目的。项目围绕无创显示BLBC分子分型及精准诊断，分别通过三个方面进行探索。.第一部分，以BLBC高表达的特异性抗原（EGFR、Nectin-4、CK14）为分子靶标，进行核素标记相应的单克隆抗体、抗体片段及双靶点（CD13和整合素ανβ3）显像；单靶的单克隆抗体及抗体片段在动物模型成像效果佳，有望成为BLBC放射免疫显像剂；双靶点探针具有更高的亲和力和更长的肿瘤滞留时间，并可以探测微小的肺部转移灶，探测效果优于单靶点。.第二部分，创新性地应用上转换稀土纳米粒联合仿生材料的多模态显像，应用红细胞膜包覆上转化纳米粒，可以增加纳米粒生物相容性，并减少肝脾摄取，成功实现了PET、MR和上转化发光多模态显像；采用癌细胞包覆时，可将源细胞表面的多样性抗原进行几乎完全复制，具有同源结合特性，极大提升纳米粒对肿瘤的靶向特异性；同时具有免疫逃避能力，增加生物相容性，修饰后可进行多模态显像，肿瘤显影清晰、肝脾摄取明显减少。这些研究实现了BLBC的诊断和分子分型。.第三部分，本项目开发了一系列新型乳腺癌分子探针；研发了泛PI3K小分子抑制剂GDC-0941正电子显像剂，并对探针进行了11C和18F的标记与优化，在体显像效果佳；合成了一种新型硫代吡啶盐XB1034，可用于近红外二区成像，量子产率高、光稳定性好，是一种理想的近红外二区和PET靶向显像，可用于乳腺癌实时精准切除和前哨淋巴结定位。.综上，本项目从核素多靶点成像、上转化纳米材料及分子探针研发三个方面出发，本项目最终实现了乳腺癌的分子分型，成功为BLBC的早期精准诊断提供了良好的多模态分子影像手段。