基于Her2受体靶向性磁共振纳米探针的乳腺癌诊疗一体化影像学研究

Breast cancer is a highly heterogeneous tumor, with different genetic phenotypes in imaging findings. This nature results in significant differences on tumor treatment response and prognosis among various subtypes of breast cancer, especially for breast cancer with human epidermal growth factor receptor 2 (Her2)–positive receptor. The diagnosis and treatment of Her2-positive breast cancer has been a tough problem due to its strong invasiveness and poor prognosis. To achieve early diagnosis and individualized treatment of Her2-positive breast cancer, it is essential to explore new approaches for targeted imaging and targeted treatment, as well as adequate assessment of curative effect on breast cancer with Her2 receptors. This research project is proposed on the basis of our previous extensive works on successful synthesis of rare earth polymer nanoparticles as dual-mode imaging contrast agents. First, we have designed hybrid block copolymer nanoparticles of Poly(4-(3-oxo-3-phenyl -propanoyl) phenyl methacrylate)-b-Poly (Oligo (ethylene glycol) methyl ether methacrylate) (PDKMA-b-POEGMA, DbO) with simultaneous loading of gadolinium (Gd) as a magnetic resonance (MR) T1 contrast agent, europium (Eu) as a fluorescence imaging contrast agent, paclitaxel (PTX) as a chemotherapy drug, and Her2 single antibody fragment (ScFv) as a target molecule to achieve multifunctional theranostic nanoprobes for breast cancer. Second, through serial in vitro and in vivo experiments, we will evaluate the mechanism and theranostic capability of these unique nanoparticles specifically targeting breast cancer cells using a fusion of MR imaging and fluorescence imaging, which will be subsequently confirmed by quantitative analysis with different laboratory correlations. Finally, we will determine the distribution, transportation, and toxicity of these nanoprobes in more pre-clinical reality with mouse models. We strongly believe that the success of this project should enable us to establish the “proof-of-principle” of the concept on targeted hybrid diagnostic imaging and chemotherapy of breast cancers using the novel theranostic nanoprobes, which should open the new avenues for early diagnosis and individualized treatment of breast cancer.

乳腺癌属于高度异质性肿瘤，不同表型的影像学表现以及对肿瘤治疗的反应与预后存在显著个体差异，其中人表皮生长因子受体2（Her2）阳性乳腺癌侵袭性强、预后差，至今仍是诊治难题。针对乳腺癌Her2受体集靶向影像诊断、治疗及疗效评价于一体的诊疗一体化有望实现乳腺癌精准及个性化诊疗。本课题组近期成功制备了可用于双模态成像的稀土纳米探针。本项目拟在前期工作的基础上，通过以人工嵌段稀土聚合物为载体、钆为磁共振对比剂、铕为荧光成像剂、紫杉醇为化疗药、抗Her2单链抗体片段为靶向分子，制备Her2受体阳性乳腺癌诊疗一体化的纳米探针；通过构建磁共振融合光学的影像学评价方法和量化指标，对一种新型的纳米探针在乳腺癌诊疗一体化的在体评价及诊疗机制研究；阐明纳米探针小鼠体内分布、转运和代谢途径；通过乳腺癌的诊疗一体化影像学研究，为最终实现乳腺癌的精准及个性化诊疗提供理论依据。

本课题针对乳腺癌，尤其是Her2阳性的乳腺癌，研发集靶向影像诊断、治疗及疗效评价于一体的诊疗一体化纳米探针，以实现乳腺癌精准及个性化诊疗，取得了一系列原创性的科研成果。具体如下：1. 在乳腺癌的靶向诊断方面，通过以人工嵌段稀土聚合物为载体、钆为磁共振对比剂、铕为荧光成像剂，成功制备乳腺癌靶向双模态成像探针，实现了乳腺癌的靶向诊断。2. 在乳腺癌的靶向治疗方面，新型可降解高分子紫衫醇纳米药（PGG-PTX-iRGD与PGG-PTX-scfv）的成功研发，实现了HER-2乳腺癌的靶向治疗。3. 在乳腺癌的诊疗一体化方面，通过中空金纳米携载抑癌基因探针，实现了乳腺癌的诊疗一体化；此外，PGG-PTX-DTPA-Gd及碳酸氧铋管状组装体等两种纳米探针，介导肿瘤精准及个性化诊疗。4. 成功构建三株Her2阳性原代乳腺癌细胞系，有助于Her2阳性乳腺癌靶向诊断、治疗及诊疗一体化药物的研发。5. 本课题组还成功研发了一种新型无钆纳米载体，聚多巴氨基酸螯合三价铁离子的两亲性聚合物纳米胶束（PDOPA-b-PSar），安全、高效，有望实现临床转化。