活性氧输运复合功能材料及其肿瘤放疗增敏性研究

Tumor hypoxia is a negative prognostic factor in cancer radiotherapy, due in part to its role in causing resistance to radiotherapy. It has attracted extensive critical attention to radiation sensetizers to improve radiotherapy outcome with an optimal therapeutic ratio. Active oxygen delivery functional materials as promising candidates to transport reactive oxygen species (ROS) to tumor cells, are important biomedical functional materials. The project will study and create new active oxygen delivery functional materials to load ROS by using inorganic mesoporous materials as carriers, delivery and controlled release ROS to tumor cells by synergistic action of functional molecules. (1) Multifunctional hollow mesoporous silica delivery system will be designed and assembled to meet the demand of the transport activity of ROS sensitizing tumor treatment. The operation mechanism of the delivery system will be studied. (2) Reactive oxygen species will be designed and synthesized; their sensitizing mechanism, loading and transport method will be researched. The physical and chemical mechanisms of the generation of reactive oxygen cluster from reactive oxygen species in the radiation effect will be studied. Study will also carried out on the quenching and interaction of reactive oxygen clusters with cells. (3) Biological safety evaluation model for reactive oxygen transport system will be established to elucidate the biological effect of sensitizing radiotherapy. Finally, get applicable active oxygen delivery functional materials, providing the scientific foundation and key techniques for the clinical applications.

氧缺失是临床肿瘤放疗效果降低的关键因素之一，针对放疗过程中氧缺失引起的肿瘤细胞放疗抗拒问题，研究活性氧输运功能材料作为放疗增敏剂，是生物医用功能材料领域的一个重要课题。本项目拟以无机介孔材料为载体，设计合成活性氧物质并与载体材料复合，通过功能分子材料与载体协同作用，实现活性氧的靶向输运和控制释放，为肿瘤组织放疗提供活性氧。（1）针对肿瘤治疗增敏输运活性氧需求，进行多功能中空介孔二氧化硅输运体系的功能化设计、组装和运行机制研究。（2）研究活性氧物质的设计、合成和增敏机制及负载输运方法；研究活性氧物质在放射线作用下活性氧蔟产生和猝灭的物理和化学机制，以及活性氧蔟与机体物质的相互作用。（3）建立活性氧输运体系生物安全性评价模型，阐明其增敏放疗作用及其关联的生物学效应，建立活性氧化放疗增敏协同治疗肿瘤的方法。获得满足体内应用要求的活性氧输运复合功能材料，为肿瘤放疗增敏临床实际应用研究奠定科学基础。

氧缺失是临床肿瘤放疗效果降低的关键因素之一，针对放疗过程中氧缺失引起的肿瘤细胞放疗抗拒问题，研究活性氧输运功能材料作为放疗增敏剂具有重要意义。本项目研究以介孔氧化硅纳米材料为载体，设计合成一系列活性氧物质并与载体材料复合，通过功能分子材料与载体协同作用，实现活性氧的靶向输运和控制释放，为肿瘤组织放疗提供活性氧。（1）研究并制备了中空介孔二氧化硅纳米粒子为功能载体，装载活性氧物质过碳酸钠或过碳酰胺后包覆一层聚丙烯酸，得到活性氧输运功能材料。该材料能够控制释放活性氧物质，与低能X-射线联用后可以显著提高细胞内的ROS水平并体现出明显的细胞杀伤力，在临床放射治疗中具有潜在的应用前景。（2）制备了溶酶体响应中空介孔氧化硅基活性氧输运体系，该复合纳米粒子利用溶酶体特殊的弱酸性环境以及富含的多种水解酶代谢产生游离的铁离子，进而与释放出来的青蒿素相互作用产生大量活性氧自由基并进一步诱发细胞损伤和细胞凋亡。（3）研究并制备了中空介孔氧化硅/过碳酰胺/壳聚糖活性氧输运体系，该体系释放的H2O2能在软X射线辐照下产生自由基，并能够发生自催化的自由基链式反应进一步产生大量的活性氧（ROS）。同时本项目还研究了具有靶向功能的双效介孔氧化硅载药体系，该体系具有靶向识别肿瘤细胞的能力，一方面增强了低能超声的空化效应，产生大量活性氧自由基，同时又可控制抗癌药物紫杉醇的释放，进一步拓展了活性氧输运功能材料的临床应用范围。