基于涡旋磁氧化铁的高性能靶向热化疗纳米制剂的构建及肝癌诊疗一体化应用研究

As the prevailing biomagnetic materials platform, superparamagnetic iron oxide (SPIO) has size limitation and weak magnetic properties, which in turn result in significantly reduced performance of SPIO based nanoagent in cancer thernoastic application. Here, we propose to construct an innovative tumor-targeting thermo-chemotherapeutic nanoagent based on novel ferrimagentic vortex-domain iron oxide (FVIO) for high performance hepatocellular carcinoma thernoastics. By rational design and optimization of interface, the FVIO is conjugated with PEI-g-PEG and VEGF/EGFR antibodies as well as loading cis-platinum as chemotherapeutic drug. We will study the structure and composition of nanoagent as a function of thernoastic properties, and the key factors for the drug loading and thermally activated release; establish hepatocellular carcinoma animal model using tumor-bearing nude mice to evaluate the enhanced efficacy of the nanoagent； understand the possible interaction and synergistic effect of chemotherapy magnetic hyperthermia and targeted therapy as well as the dose-response relationship. The results obtained from this project will not only provide a general strategy to construct a variety of high efficient FVIO based theronostic nanoagents that rely on heat induction, but also enable a safe and efficacious multimodality treatment for hepatocellular carcinoma in the future.

针对当前占主导地位的超顺磁氧化铁纳米平台中存在的尺寸限制和磁学性能损失导致以其开发的磁性靶向热化疗剂在抗肿瘤诊疗一体化应用中不能满足临床需求的问题，本项目提出以新型的、具有优异磁学性质的涡旋磁氧化铁纳米环为平台，优化界面从而结合化疗药物顺铂并偶联抗体等靶向分子，构建高效靶向热化疗纳米制剂并用于肝癌诊疗。研究其多组分复合结构和诊疗功能之间的构效关系以及药物负载与热激活释放的关键技术；建立肝癌肿瘤裸鼠模型，评估该靶向热化疗纳米制剂在肝癌诊疗中的效果和优势; 阐明化学治疗、物理磁感应热疗和靶向治疗之间的相互作用以及治疗过程中量效特性。本研究的开展可望为高效靶向热化疗纳米制剂的构建提供理论和方法基础，为基于纳米制剂的肝癌诊疗一体化多学科综合治疗提供一个新的选择。

以高生物安全性的纳米氧化铁为平台材料，将临床化疗与磁感应热疗联合、结合磁共振成像诊断，可望实现微创、高效低毒的抗肿瘤诊疗一体化综合诊疗。然而，当前占主导地位的超顺磁氧化铁纳米材料存在磁热转化效率低，导致以其开发的靶向热化疗剂在肿瘤治疗应用中不能满足临床需求的问题。本项目以高磁热性能的新型涡旋磁氧化铁纳米环为平台材料，利用温敏分子修饰并结合化疗药物如阿霉素、顺铂等，同时偶联如抗体血管内皮生长因子VEGF等靶向分子，合理的设计出高效靶向热化疗纳米制剂，评价了其在裸鼠肝癌和乳腺癌皮下瘤中的诊疗一体化效果。在材料方面，我们改进了制备工艺，优化材料尺寸，实现了40纳米涡旋磁氧化铁的合成，提高了涡旋磁氧化铁的肿瘤滞留和渗透性能。在化疗药物可控释放方面，利用温敏聚乙烯亚胺分子修饰和负载化疗药物，首次实现了纳米尺度单个纳米颗粒水平的磁热药物释放，显著增强了药物胞内有效浓度和肿瘤抑制效果，同时降低了整体药物剂量；通过进一步结合靶向抗体分子，实现了可视化的高效靶向热化疗。本研究项目揭示了关键材料参数与诊疗性能的依赖关系，明确了热/化疗模式间相互协同和增敏机制，突破了传统的组织水平磁热治疗和宏观热致药物释放，实现了精准、高效的纳米尺度靶向热化疗。研究成果为构建可磁场调控的高效靶向热化疗纳米制剂提供了理论和方法基础，为基于纳米制剂的癌症诊疗一体化多学科综合治疗提供了一个新的选择。