基质金属蛋白酶依赖性MR双向衬度增强多模态纳米探针实现结直肠癌早期及微小肝转移靶向诊断

Colorectal cancer is among the most prevalent malignancies in the world, which develops through the well-recognized classic pathway from adenoma to adenocarcinoma with a high incidence of hepatic metastases. It is still an unsolved clinical problem to diagnose colorectal cancer and its hepatic micrometastatic foci at early stage. The continuous upregulation and expression of matrix metalloproteinase (MMP) plays an important role throughout the process of colorectal cancer development from adenoma to adenocarcinoma, and it is highly associated with the prognosis. Therefore, MMP may be an ideal diagnostic target for colorectal cancer. An emerging novel concept of inverse contrast-enhancement, which involves the conjugation of tumor microenvironment-responsive nanoprobes targeting MMPs, is expected to pave the way to achieve the goal of early diagnosing colorectal cancer and its micrometastatic foci in livers. This project is designed to construct an inverse contrast enhanced nanoparticle assembly that crosslinks MMP-cleavable polypeptide on the surface of 3nm iron oxide nanoparticles on the basis of previous work. The MMP-dependent bimodal nanoparticles loaded with fluorescent imaging agent, Alexa647, can instantly disintegrate by specifically responding to the MMP in tumor microenvironment, functioning as a multimodal imaging probe. We will investigate the metabolism, transport, and distribution of the nanoparticles in mice models with colorectal cancers and use the multimodal probe-based MR imaging/optical imaging techniques to evaluate the development pathway of mouse colorectal cancers. The success of this study is expected to elucidate the mechanism of colorectal cancer germination, growth and metastasis in vivo, which may be valuable for establishing the basis for achieving the ultimate goal of early diagnosis on colorectal cancer and its hepatic micrometastases.

结直肠癌是全球高发且易肝转移的恶性肿瘤，大多由结直肠腺瘤恶变而来，但结直肠癌和微小肝转移瘤早期诊断仍是当今临床难题。金属基质蛋白酶MMP-2/9从腺瘤到腺癌发展过程中稳定持续增高且与预后相关，故是理想的分子诊断靶点。利用MMP特异性剪切肽链，引入磁共振双向衬度增强新理念，设计肿瘤微环境响应型多模态纳米探针，有望实现结直肠癌和微小肝转移瘤早期靶向诊断。本项目拟在前期工作基础上，首先将MMP-2/9特异剪切肽链与3nm氧化铁纳米粒子交联，构建对MMP响应解体的纳米粒子组装体并负载荧光成像剂Alexa647，制备出MMP依赖磁共振双向衬度增强多模态纳米探针；然后建立多模态影像学评价方法和量化指标，对该新型纳米探针进行在体评价及诊断机制研究，以确定其小鼠体内分布、转运和代谢途径；另进行结直肠腺瘤、早期癌和微小肝转移瘤多模态成像研究，最终实现早期结直肠癌及微小肝转移瘤精准靶向诊断并提供理论依据。

结直肠癌是全球高发且易肝转移的恶性肿瘤，大多由结直肠腺瘤恶变而来，但结直肠癌和微小肝转移瘤的早期诊断仍是当今临床难题。本项目针对结直肠癌和肝转移的早期诊断，设计并合成了多种新型磁共振成像纳米探针，实现对结直肠癌和肝转移的精准靶向磁共振成像。此外，研发了具有结直肠癌诊疗一体化效果的纳米探针，达成结直肠癌的精准和个性化治疗。主要研究成果如下：1.在结直肠癌及肝转移精准靶向磁共振成像方面，成功合成了由载铁两亲性聚合物聚多巴氨基酸自组装成的磁共振T1加权成像纳米探针，实现结直肠癌和肝转移的精准靶向诊断，有望取代传统钆系对比剂成为新一代安全、高效的磁共振对比剂，具有良好的临床转化前景；此外，成功制备了一种铁基固体脂质纳米粒，实现了溃疡性结肠炎和原位结肠癌的精准磁共振成像。2.在结直肠癌诊疗一体化方面，研发了一种负载SN38的硅酸锰纳米输送系统，实现结直肠肿瘤部位的T1增强磁共振成像和化疗/化学动力学联合治疗；研发了一种具有光热和磁共振增强效果的锰掺杂普鲁士蓝纳米粒子，实现结直肠癌磁共振成像下热消融术后进一步清除消融残余灶，降低肿瘤复发的风险。