靶向乳腺癌微钙化特异性双功能分子探针的制备及PET/NIR显像研究

Breast cancer is one of the most common malignant tumors in women, and microcalcification is the only sign of the incipient breast tumor. Therefore, early detection and screening of microcalcification can provide important information and basis for the early diagnosis of breast tumor. At present, the early diagnosis of breast tumor mainly relies on the X-ray mammography. However, X-ray mammography has relatively poor sensitivity and specificity, and the diagnostic accuracy is still low. So, it is urgent to develop novel multimodal molecular probes with targeting and specificity ability for imaging with high selectivity and sensitivity. Then, the detection accuracy of tumor will be improved. Based on our preliminary experiments, we intend to design and synthesize a novel dual-modality molecular probe based on positron emission tomography (PET) and near-infrared (NIR) fluorescence imaging for detecting the microcalcification of early breast cancer. The probe will be constructed by the bisphosphonate as the microcalcification-targeting ligand, IRDye800CW as the NIR fluorescence imaging group, and the positron nuclide 68Ga as the nuclear of PET imaging tracer agent, respectively. Imaging studies will be carried out on the animal models bearing breast cancer microcalcifications. The complement PET/NIR imaging technology can reflect the distribution, size, shape and density of microcalcifications more accurately than one imaging technology. This will help to achieve more precise results for the early diagnosis of tumors. It also can provide important information for identifying the benign and malignant tumors. Thus, this research has important clinical value and great practical needs.

乳腺癌是女性最常见的恶性肿瘤之一，微小钙化是早期隐性乳腺癌的唯一征象，尽早发现和甄别微小钙化可为乳腺癌的早期确诊提供重要依据。临床上通常使用钼靶X线检查进行乳腺癌的早期诊断，但由于该技术的特异选择性无法达到期望，故诊断准确率仍较低。因此，急需发展具有靶向特异性的多功能分子影像探针进行高选择性、高灵敏度地成像，有效提高肿瘤检测的准确性。本研究拟利用双膦酸盐作为靶向配体，将正电子核素68Ga和近红外荧光基团IRDye800CW分别作为正电子发射断层成像和光学成像基团，构建一种靶向肿瘤微钙化的PET/NIR双功能分子探针，通过对乳腺癌微小钙化动物模型进行PET/NIR融合成像，利用不同影像技术的优势互补，确定微钙化的分布、大小、形态和密度等异常表现，从而使获取的结果更为精确可靠，实现肿瘤特别是微小肿瘤的早期确诊，同时也为鉴别肿瘤的良、恶性提供重要依据，因而具有重要的临床意义和实际需求。

乳腺癌是女性最常见的恶性肿瘤之一，其发病率呈年轻化和逐年上升趋势。乳腺癌如果能够早期发现和早期治疗，对提高患者生存率有重要作用。应用高敏感的正电子发射型计算机断层成像(PET)以及高灵敏的近红外荧光成像(NIR)可为乳腺癌的明确诊断提供更加精确和全面的信息。本项目通过设计合成系列靶向特异性地PET/NIR分子影像探针、通过对其同位素标记条件和分离纯化方法的探索，脂水分配系数、稳定性、靶向结合率、细胞毒性、药物体内分布和代谢等性质的测定，以及模型动物的 PET 和 NIR 显像研究，筛选出了具有靶向特异性强的分子探针，为乳腺癌等肿瘤疾病的检测与分析提供更为准确的信息，因而具有重要的临床应用潜力与价值。受本项目资助，现共发表SCI收录研究论文17篇；发表会议论文8篇；申请国家发明专利8项，其中1项现已获得了授权；获得科技奖励2项；培养硕士研究生7名。