肿瘤微环境触发的Fe基智能诊疗试剂的构筑及其在癌症诊疗上的应用

Smart theranostics that integrated the molecular imaging, minimally invasive therapy, nanomedicine and tumor microenvironment can effectively overcome the shortcomings of conventional diagnosis and treatment method for cancer, which can improve the treatment effect and reduce the suffering of patients. Therefore, based on clinical needs for tumor diagnosis and treatment and Fe-based nano-theranostic platform that is easy to be clinically applied, development of smart theranostic agents triggered by tumor microenvironment and exploration of the law of tumor diagnosis and treatment have important clinical transformation prospects. Hence, the applicant intends to carry out the following work: (1) though the tumor microenvironment triggering self-assembly strategy, to construct Fe-based nanomaterials that can self-assemble in the tumor, and develop smart theranostic agents for MRI-guided magnetic-Hyperthermia therapy; (2) according the strategy of increasing the reaction site, to develop MRI-guided chemodynamic therapy smart theranostic agents by changing the surrounding environment of Fe ions and increasing the chemical kinetics treatment reaction sites; (3) using Fe-MOF loaded hydrogen sulfide donor, to prepare MRI-guided photothermal therapy smart agents based on the FeS generated by reaction of Fe ion and hydrogen sulfide which is released from hydrogen sulfide donor triggered by tumor acidity. By evaluating the diagnostic and therapeutic effects for tumor of the developed smart theranostic agents explore the new materials and new theories based on Fe-based smart theranostic agents.

将分子影像、微创治疗、纳米医学以及肿瘤微环境有机结合起来的智能纳米诊疗一体化技术能有效克服传统癌症诊断和治疗的弊端，提高治疗效果，降低患者的痛苦。因此，基于肿瘤临床诊疗需求和易于临床应用的Fe基纳米诊疗平台，开发相应的肿瘤微环境触发的智能诊疗试剂，并探索对肿瘤诊疗规律，具有重要的临床转化前景。基于此，申请人拟开展以下工作：（1）利用肿瘤微环境触发自组装策略，构建能够在瘤内自组装的Fe基纳米材料，开发MRI介导的磁热治疗的智能诊疗试剂；（2）利用增加反应位点策略，通过改变Fe离子的周围环境和增加化学动力学治疗反应位点，开发MRI介导的化学动力学治疗智能诊疗试剂；（3）通过Fe基有机框架结构担载硫化氢供体，经肿瘤微酸性触发释放硫化氢，并和Fe反应生成硫化铁，开发MRI介导的光热治疗智能诊疗试剂。通过评估开发的智能诊疗试剂对癌症的诊断和治疗效果，探索基于Fe基智能纳米诊疗试剂的新材料、新理论。

本项目围绕Fe基智能诊疗试剂，开展了三个方面的研究工作：（I）通过改变Fe基纳米材料的配位聚合物及粒径和表面配体构建不同的Fe基核磁共振成像造影剂，并开展其在核磁共振成像性能方面的研究；（II）将Fe基纳米材料的核磁共振成像功能与肿瘤微环境响应结合起来，构建硫化氢或谷胱甘肽响应的智能造影剂，并开展其在T1/T2成像模式转变上的相关研究。（III）将肿瘤微环境响应的Fe基纳米粒子运用到诊疗一体化中，探究了其在肿瘤微环境响应后引起的光热/磁热增强，金属离子价态转变，化学动力学效果增强等对肿瘤治疗效果的影响。本工作的开展，为肿瘤的智能诊断和精准医疗提供了新的试剂，同时建立了肿瘤智能诊断和精准治疗的新理论。.