分级靶向超小锰铁氧体纳米磁热疗剂的构建及其转移性前列腺癌诊疗一体化应用研究

As the prevailing biomedical magnetic nanoplatform, iron oxide nanoparticles usually show negative magnetic resonance (MR) T2 enhancement and low-effecient magnetic hyperthermia, which hinder their application as a high-performance theranostic nanoagent in cancer medicine. Herein, we propose to construct an innovative, tumor cell and mitochondria hierarchical-targeting hyperthermia nanoagent based on novel ultrasmall manganese ferrite nanoparticles (UMFNPs) and glutathione-responsive mesoporous silica for high-performance metastatic prostate cancer theranostics. The UMFNPs employed could play the multiple roles as both highly sensitive MRI T1 contrast agent and highly efficient subcellular organelle-targeting hyperthermia nanoagent. We will study the structure and composition of nanoagent as a function of thernoastic properties, and the key factors for hierarchical targeting strategy; establish prostate cancer primary- and metastatic-tumor mice models to evaluate the curative effect of single- and hierarchical-targeting hyperthermia nanoagent; elucidate the underlying mechanism of hierarchical-targeted MRI diagnosis and magnetic hyperthermia therapy as well as the dose-response relationship. The results obtained from this study will not only provide a general strategy to construct a variety of high efficient UMFNPs based theronostic nanoagents that rely on subcellular organelle-directed heat induction, but also enable a safe and efficacious diagnostics and therapeutics for metastatic prostate cancer in the future.

针对当前生物医用磁性氧化铁纳米颗粒存在的磁共振负增强造影特性限制和低效磁热疗导致以其开发的纳米磁热疗剂在恶性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、具有高灵敏T1正增强造影和高效亚细胞定向磁热疗的超小锰铁氧体纳米颗粒为诊疗平台，谷胱甘肽还原敏感的介孔二氧化硅为载体，构建全新的、可实现肿瘤细胞靶向和线粒体靶向的分级靶向高效纳米磁热疗剂并用于转移性前列腺癌诊疗一体化。研究其多组分复合结构和诊疗功能之间的构效关系以及针对肿瘤还原性微环境响应的分级靶向关键技术；建立前列腺癌裸鼠模型，对单一靶向热疗和分级靶向热疗进行比较研究，明确分级靶向磁热疗剂的诊疗机制和治疗过程的量效关系，评估其一体化诊疗效果。本研究的开展可为高效纳米磁热疗剂的构建提供理论和方法基础，为基于纳米制剂的转移性前列腺癌诊疗一体化多学科综合治疗提供一个新的选择。

针对当前小分子线粒体调控工具存在的在体线粒体富集效率低及调控线粒体能力弱等问题，本项目以新型的、具有类过氧化氢酶和高效亚细胞定向磁响应的超小锰铁氧体纳米颗粒为平台，谷胱甘肽还原敏感的支化聚乙二醇（八臂）为载体，构建全新的、可实现肿瘤细胞靶向和线粒体靶向的分级靶向高效线粒体调控工具并用于三阴乳腺癌的治疗。本项目将分级靶向与主动靶向相结合实现了纳米颗粒在体内肿瘤细胞线粒体的高效富集，将超小猛铁氧体的类酶活性与交变磁场响应性结合实现了在体肿瘤细胞线粒体功能的有效调控。此外，本项目揭示了其多组分复合结构和线粒体调控功能之间的构效关系以及针对肿瘤还原性微环境响应的分级靶向关键技术；建立三阴乳腺癌裸鼠模型，对单一靶向和分级靶向线粒体调控工具进行比较研究，明确了分级靶向线粒体调控工具的治疗机制和治疗过程的量效关系，并评估了其治疗效果。本研究的开展可为在体高效线粒体调控工具的构建提供理论和方法基础，为基于纳米制剂的三阴乳腺癌治疗提供一个新的选择。