新型长循环“双靶点”双模态分子探针对乳腺癌的可视化活体成像研究

Early diagnosis is important for the treatment and prognosis of breast cancer. Multimodal molecular imaging provides a new platform for the early diagnosis of breast cancer. Molecular imaging depends on the sensitive and specific molecular probe. Traditional molecular probes targeting single target has the disadvantages of low intake and undesirable pharmacokinetic properties, due to unstable expression of tumor cell receptors . Considering the breast cancer tumor with high expression of integrin αvβ3 and GRPR, it is superior to design RGD-BBN dual-receptor targeting molecular probe. In our previous basic research, we have synthesized SPIO coated with long circulating liposomes, and the experimental results showed that it was with the proper physical properties, particle sizes, uniform distribution and of anti-macrophage function in vitro and in vivo. Based on the results, we intend to use the long-circulating liposomes with excellent biological properties as a carrier, coating SPIO@QD800(InAs/InP/ZnSe) nanoparticles, and then coupling dual-receptor targeting RGD-BBN heterodimer for tumor, in order to prepare new long-circulating, dual-receptor targeting, magneto-optical dual-mode nanoparticles. Magnetic resonance and fluorescence imaging were performed on the animal models with breast cancer with the molecular porbe, and the advantages and feasibilities were evaluated in the early diagnosis of breast cancer. If successful, it may also be applicable to multimodal molecular imaging for other tumors.

早期诊断对乳腺癌的治疗及预后具有重要意义。多模态分子影像为乳腺癌的早期诊断提供了新的视角。分子影像诊断依赖于灵敏度及特异性高的分子探针。由于肿瘤细胞表面受体表达不稳定，传统针对某单一靶点的分子探针面临肿瘤摄取低、体内药代动力学特性不佳等缺点。鉴于乳腺癌肿瘤高表达GRPR及integrin αvβ3，设计针对这两个肿瘤特异性受体的RGD-BBN双靶点分子探针具有独特优势。我们前期合成了长循环SPIO脂质体纳米颗粒，实验显示其物理性能较好，粒径小，分布均匀及体内外均具抗巨噬细胞吞噬功能。本课题在此基础上，将其核心SPIO与无镉量子点QDs组装，再在脂质体表面与肿瘤双靶向功能特异性受体RGD-BBN偶联，制备长循环肿瘤双靶点磁性/荧光脂质体双模态纳米分子影像探针，在乳腺癌动物模型上行磁共振及荧光成像研究，评价其对乳腺癌早期诊断的优势和可行性。一旦成功，对其他肿瘤受体多模态成像也有重要的借鉴作用。

早期诊断对乳腺癌的治疗及预后具有重要意义。鉴于乳腺癌肿瘤高表达整合素受体（αvβ3） 和（或）胃泌素释放肽受体（GRPR），本课题申请者在前期对长循环SPIO脂质体研究的基础上，设计针对上述两个肿瘤特异性受体RGD及BBN的长循环肿瘤“双靶点”磁性/荧光脂质体双模态纳米分子影像探针RGD@BBN-lipo(QDs)-SPIO；我们测定了该探针的理化性质，并优化制备工艺，着重考察探针的生物稳定性及安全性，实验结果表明，本课题所构建的“双靶点”磁性/荧光双模态分子探针制备方法简便，具有优良的理化性质及稳定性、生物安全性好、T2弛豫率高；同时，我们评价了该探针对乳腺癌细胞的体外靶向成像能力，我们通过普鲁士蓝和荧光成像显示该探针可以灵敏地靶向整合素αvβ3和GRPR任何一个受体高表达的乳腺癌细胞；最后，我们通过成功建立裸鼠乳腺癌皮下移植瘤动物模型，采用临床型MR成像系统及小动物活体成像仪浅探该探针在乳腺癌动物模型双模态磁共振/荧光成像中的应用。通过本课题的开展，为下一步的研究工作打下了坚实的基础。本课题所构建的“双靶点”、磁性／荧光双模态分子探针较单一成像模式而言，提高了对乳腺癌的检出能力，具有较大的理论研究意义及潜在的应用价值。已发表“标注受本项目资助”论文6篇，其中SCI收录论文3篇，申请国家级专利1项。