多模态诊疗一体化纳米探针用于HER-2阳性乳腺癌转移灶受体定量、成像监测与克服耐药的研究

Human epidermal growth factor receptor 2 (HER-2) positive breast cancer is characterized by strong invasiveness, frequent relapse, metastasis, and short disease-free survival. In HER-2 positive breast cancer treatment, the patients’ responses to HER-2 targeting drugs such as antibodies largely depend on the HER-2 expression levels of metastatic tumors. Thus, it is of great therapeutic relevance to quantify HER-2 in HER-2 positive breast cancers, which would provide instructive information for targeted therapy and prognosis. In this project, we aim to construct a multi-modal theranostic nanoprobe that might overcome several disadvantages of current therapies for HER-2 positive breast cancers. Using nanotechnology, we would extend the retention time and enhance the antigen recognition capabilities of HER-2 antibodies labeled by radionuclide, and then establish a quantitative relationship between PET/MR imaging signals and HER-2 expression levels. Moreover, the nanoprobe with tumor environment-responsive MR signal is of important significance to monitor the tumor staging, guide the treatment, and improve the prognosis. Furthermore, the nanoprobe could kill tumor cells via multiple mechanisms and consequently overcome drug resistance in HER-2 positive breast cancers. In summary, this multi-modal theranostic nanoprobe could achieve real-time visualization of targeted therapy via intergrated PET/MR imaging techniques to optimize overall treatment, reduce the mortality, and improve the life quality of HER-2 positive breast cancer patients.

人类表皮生长因子受体-2（HER-2）阳性乳腺癌浸润性强，易复发转移，且无病生存期短。在转移性HER-2阳性乳腺癌治疗中，极易产生靶向治疗耐药，转移灶HER-2表达水平很大程度决定患者对靶向药物的反应性。因此，如何确定HER-2阳性乳腺癌转移灶受体表达情况及肿瘤发展状态以指导靶向治疗和克服耐药具有重大研究意义。本项目拟构建一种多模态诊疗一体化纳米探针，利用纳米化策略提高HER-2抗体在转移灶的滞留时间及其与肿瘤表面受体的结合能力，并通过PET/MR双模态成像信号互补等影像学手段建立成像信号与受体表达间的定量关系，同时利用微环境响应性磁共振成像功能监测肿瘤发展状态，指导治疗方案。此外，该纳米探针可以通过多重机制杀伤肿瘤细胞，克服耐药。综上，该多模态诊疗一体化纳米探针有望利用分子影像学技术，实现靶向治疗的可视化，优化治疗方案并提升治疗效果，从而降低HER-2阳性乳腺癌患者死亡率，改善生存质量。

乳腺癌具有浸润性强、易复发转移等特点，确定肿瘤发展状态以指导靶向治疗具有重大研究意义。多模态诊疗一体化纳米探针是乳腺癌可视化治疗的有效工具。在本项目支持下，在纳米诊疗探针的制备与性能调控、以及微小肿瘤的精准诊断、乳腺癌的可视化治疗等方面取得了一系列具有自主知识产权、国际领先水平的创新成果，主要在以下三个方面取得重要进展：1) 磁性纳米成像探针用于肿瘤诊断：基于磁共振成像原理，设计合成了一系列高性能磁性纳米成像探针，有效提高了肿瘤早期诊断效率，包括通过超高场磁共振成像在活体内分辨出小于0.6 mm的原位肿瘤以及小于0.2 mm的极微小转移灶；2）多功能纳米酶用于肿瘤治疗：利用不同纳米酶的催化特性，实现了光声成像指导下的肿瘤特异性杀伤作用，以及肿瘤化疗引发肾损伤的缓解作用，为高效安全的肿瘤治疗提供了新策略；3）高性能诊疗一体化纳米探针用于乳腺癌特异性治疗：针对乳腺癌，构建了一系列诊疗一体化纳米探针，实现了磁共振成像、光声成像等模式指导下的可视化治疗，并结合化学动力学疗法、光热疗法、化学疗法等多重手段提高治疗效果，如结合三阴性乳腺癌细胞中铁代谢异常的微环境特点实现了近红外光控的特异性高效协同治疗。以上工作为新型诊疗一体化纳米探针的构建提供了基础，为实现乳腺癌的高效诊断与治疗提供了新工具。