兼具巨噬细胞靶向和超顺磁性的纳米胶束用于MR淋巴成像的研究

Early detection and accurate evaluation of lymph node is very important for cancer stage and treatment planning. However, the value of conventional medical imaging technology is still difficult to satisfactory. In the past several years, the applicant carried out a lot of work about multifunctional polymeric micelles which have many advantage including small size, long half-life, and easy to realize the targed function. So, polymeric micelles can be used as the carrier of MR contrast agents and drugs. In the current research, Ultrasmall superparamagnetic iron oxide (USPIO) were accommodated in the core of polymeric micelles self-assembled from amphiphilic block copolymer of poly(ethylene glycol)(PEG) and poly(ε-caprolactone)(PCL) , ultra MRI sensitivity was obtained through the group cluster effect. The purpose of this study is to structure superparamagnetic polymer micelle(SPPM), combined macrophages targeted and superparamagnetic, for MR lymphatic imaging. The in vitro and in vivo experiments were carried out to evaluate the targeting property and MRI sensitivity. The relationship between MRI strengthening characteristics and pathological ultrastructure of lymph nodes were analyzed by comparative study. In this study, the new developmental tendency of molecular imaging was fully considered. SPPM is expected as a powerful multifunctional platform for targeted diagnosis and targeted therapy of lymph node disease. There are important theory research significance and potential application value.

早期检出和准确评判淋巴结的良恶性是进行肿瘤分期和制定治疗计划的关键，常规影像技术诊断价值有限。本项目在申请者前期聚合物纳米胶束研究基础上，利用其尺寸小、半衰期长、易实现被动和主动靶向，可作为MR对比剂和药物优良载体的特点，通过控制粒径获得巨噬细胞靶向性，通过在其内核高效负载超小型超顺磁性氧化铁（USPIO）产生"团簇效应"获得超磁敏感性，构建兼具巨噬细胞靶向及MR可见的超顺磁性聚合物胶束（SPPM），分别从细胞和动物水平考察其对巨噬细胞和良恶性淋巴结的靶向性，定量分析其MR敏感性，并与组织病理学对照，考察淋巴结强化特征与超微结构的关系。本研究充分考虑分子影像学发展的新趋势，通过纳米生物技术和分子影像学等多学科交叉，研制具巨噬细胞靶向、MR超敏感"两位一体"的SPPM，探索其作为诊断探针用于MR淋巴成像的可行性，同时有望为转移淋巴结靶向治疗提供新策略，具有较大理论研究意义及潜在应用价值。

早期检出和准确判断淋巴结的良恶性是进行肿瘤分期和制定治疗计划的关键要素之一，常规影像技术诊断价值有限。本项目在申请者前期聚合物纳米胶束研究基础上，利用其尺寸小、半衰期长、易实现被动和主动靶向，可作为MR对比剂和药物优良载体的特点，通过控制粒径获得巨噬细胞靶向性，通过在其内核高效负载超小型超顺磁性氧化铁（USPIO）产生“团簇效应”获得超磁敏感性，构建兼具巨噬细胞靶向及MR可见的超顺磁性聚合物胶束（SPPM），分别从细胞和动物水平考察其对巨噬细胞和良恶性淋巴结的靶向性，定量分析其MR敏感性，并与组织病理学对照，考察淋巴结强化特征与超微结构的关系。研究结果显示：所合成SPPM粒径小、T2弛豫率显著高于水溶性SPIO（P<0.05）；体外细胞毒性实验（MTT）显示合成的SPPM毒性极低；激光共聚焦和普鲁士蓝染色检测结果显示该SPPM可迅速被巨噬细胞（Raw264.7）摄取，并均匀分布于胞浆内；体外MRI显示该SPPM和巨噬细胞Raw264.7共培养后T2WI信号不同程度的明显降低；在体动物实验结果表明该纳米探针对转移性淋巴结具有靶向效应，且生物安全性高。总之，本研究通过纳米生物技术和分子影像学等多学科交叉，研制具巨噬细胞靶向、MR超敏感“两位一体”的SPPM，探索其作为诊断探针用于MR淋巴成像的可行性，同时有望为转移淋巴结靶向治疗提供新策略，具有较大理论研究意义及潜在应用价值。