高压氧增敏基于纳米闪烁晶体的深部肿瘤光动力协同放疗研究

The lack of effective energy accumulation in tumor region and the radioresistance of tumor cells caused by tumor microenvironment often lead to inefficient radiotherapy. To solve these clinical challenges, X-ray excitable nanocomposites (ScNPs-PSs) with synergistic photodynamic therapy and radiotherapy will be constructed with the combination of hyperbaric oxygen (HBO) for deep tumor treating, based on our previous work. The relationships between ScNPs-PSs’ structure characteristics and photodynamic performance, ROS quantum yield, radiotherapy dose enhancement effect will be elucidated in detail by in vitro functional test and corresponding cytological evaluation. The effect of HBO on enhancing tumor targeting, reversing tumor hypoxia and increasing radiotherapy sensitivity of tumor cells will be explored by testing the changes of tumor tissue microenvironment after HBO treating. The therapy efficacy and mechanism of synergistic photodynamic therapy and radiotherapy based on ScNPs-PSs and HBO sensitization will be revealed at cellular level and in animals. This project bears great potential to provide a novel view and an efficient comprehensive therapy strategy for deep tumor treating.

针对肿瘤放疗过程中如何特异性增强肿瘤组织放射性损伤、提高肿瘤细胞放疗敏感性等临床挑战，采用我们前期具有良好工作基础的纳米闪烁晶体，结合高压氧治疗策略，构建可被X射线激发用于深部肿瘤光动力治疗协同增敏放疗的纳米复合体系（ScNPs-PSs）。通过体外性能测试及相关细胞评价，阐明ScNPs-PSs的结构特征与光动力效应活性氧量子产率以及放疗剂量增强效应的关系；研究高压氧对肿瘤组织微环境的改变，明确高压氧提高ScNPs-PSs肿瘤靶向性、改善肿瘤组织乏氧、增强肿瘤细胞放疗敏感性的作用；从细胞水平和动物水平揭示高压氧增敏基于纳米闪烁晶体的光动力协同放疗的效果和作用机制。该项目的研究有望为深部肿瘤治疗提供一种新的思路和有效的综合治疗策略。

肿瘤放疗过程中对正常组织的放射性损伤以及实体瘤乏氧微环境导致的肿瘤细胞放疗不敏感一直以来广受研究者的关注，本项目拟探索通过改善肿瘤组织乏氧微环境以及联合治疗协同效应，增强肿瘤放疗敏感性、提高放疗“效剂比”、降低放疗副作用。在前期工作基础上，我们构建了一种可直接响应高能射线产生活性氧的NaCeF4:Gd,Tb纳米闪烁晶体，可以实现深部肿瘤在X射线激发下的同步光动力治疗和放疗增敏，达到协同治疗的效果，并深入阐明了该纳米闪烁晶体的X射线敏化机制，为深部肿瘤光动力治疗提供了新思路。为了增强活性氧杀伤肿瘤细胞效果，我们从肿瘤组织独特生化微环境出发，构建了具有两种拟酶性质的PtCu3纳米笼，一方面可作为类芬顿试剂催化H2O2产生羟基自由基，同时具有谷胱甘肽过氧化物酶性质催化氧化肿瘤组织高表达的还原性谷胱甘肽增强ROS肿瘤细胞杀伤损伤。为进一步改善肿瘤组织乏氧微环境增强肿瘤放疗效果，我们以牛血清白蛋白（BSA）为模板，通过生物矿化的方法制备了Bi2Se3-MnO2@BSA复合纳米颗粒，利用MnO2拟酶性质催化H2O2分解产生氧气以改善肿瘤组织乏氧微环境，同时利用Bi2Se3的强X射线阻挡能力增强肿瘤局部放射剂量，达到肿瘤放疗协同增敏效果。