早期非小细胞肺癌剂量增强立体定向消融放疗联合肿瘤干细胞靶向治疗的基础研究与实验评估

As China is stepping into aging society, the incidence of malignant tumors in elderly populations continuously grows with non-small cell lung cancer (SCLC) dominating. Lobar resection is the current standard treatment of early-stage NSCLC. However, many elderly NSCLC patients are deemed unfit for surgical treatment due to various medical comorbidities. Stereotactic ablative radiotherapy (SABR), as an invasive and localized treatment with curative intent, provides this patient population a viable treatment alternative with excellent outcomes comparable to surgery. Generally, the efficacy of SABR is subject to two factors: radiation dose received by tumors and the amount of radioresistant tumor cells (especially tumor stem cells). In this research project, efforts will be invested into radiation dose optimization/enhancement and tumor stem cell elimination. A bi-functional (dose-enhancement and image contrast-enhancement) heavy metal-loaded nanoparticle with capability of selectively accumulating within tumors will be synthesized, characterized and assayed in vitro and in vivo. During radiation therapy, heavy metal atoms in nanoparticles will interfere with X rays, the interactions causing electron-cascade and consequently radiation dose enhancement within tumors. Meanwhile, stem cell-targeted agents, all-trans retinoid A (ATRA) and valproic acid (a histone deacetylase inhibitor, HDACi) will be investigated for stem cell elimination. Collectively, with combination of radiation dose enhancement and tumor stem cell-targeted therapy, better tumor control with noninvasive and painless SABR could be anticipated in elderly patients with early-stage NSCLC.

立体定向放疗（SABR）为不能手术治疗的早期肺癌患者提供了根治性治疗的可能，特别是老年肺癌患者。SABR的疗效（控制和复发）主要受两个因素的影响：肿瘤区剂量的高低和肿瘤内放射抵抗细胞（主要是肿瘤干细胞）的多少。针对上述两个制约因素，本项目将着重研究肿瘤内靶向放疗剂量增强效应，研发测试具有剂量增强和影像对比功能含重金属的药物（以金和稀土族元素纳米颗粒为主），以期提高肿瘤区的实际放疗剂量；同时探讨减少或根除肿瘤干细胞的策略，联合应用靶向干细胞治疗（全反式维甲酸A和组蛋白脱羧酶抑制剂）以减少干细胞的数量，从而为根治性放疗完全杀灭肿瘤（包括根除干细胞）创造条件。冀此进一步改善早期NSCLC局部控制疗效，降低远处转移率，延长患者的生存时间，为实现无创性的肺癌治疗奠定基础；此外，在医疗费用攀升的今天，本研究所探讨的治疗措施因疗程短且费用有限更突显其现实意义。

立体定向放疗（SABR）为不能手术治疗的早期肺癌患者提供了根治性治疗的可能。本项目将着重研究肿瘤内靶向放疗剂量增强效应，研发测试具有剂量增强和影像对比功能含重金属的药物（以金和稀土族元素纳米颗粒为主），以期提高肿瘤区的实际放疗剂量。本项目按计划完成了相关任务，研究工作包括：1、课题组首先评估了立体定向放疗在高龄（≥75岁）局限性肺癌患者中的疗效和安全性。结果显示对于高龄局限性肺癌患者，SBRT治疗安全和有效。2、课题组对肺部立体定向放疗急性肺损伤与血液学指标和剂量体积参数的相关性进行了研究，结果显示血浆D－二聚体对于症状性肺炎的发生具有预测价值。3、课题组比较双能CT的碘定量参数与18FDG-PET/CT的代谢定量参数用于评估肺癌放化疗疗效的相关性，结果显示基于碘定量的DECT可以从解剖和功能角度提供肺癌治疗前后整体变化信息，有可能替代18FDG-PET/CT代谢参数用于肺癌疗效评估。4、成功制备稀土纳米探针NaYbF4: 2% Tm3+，详细研究了该纳米探针的体内分布、代谢及生物相容性。通过建立MAGIC gels模型，验证了RGD多肽修饰的BaYbF5: 2% Er3+ (Tm3+) 稀土纳米探针显著提高了纳米探针周围的放射剂量和组织损伤。5、制备了一种新型“核-卫星”结构多功能诊疗剂（NaYbF4: Er3+/Gd3+@SiO2@CuS-PEG）用于CT/MR/UCL三模式成像和光热/放疗联合治疗。6、氧化钨（W18O49）纳米线作为CT成像和光热/光动力/放疗联合治疗多功能纳米诊疗剂的应用研究。细胞和活体实验结果表明，PTT/PDT和增强型放疗之间存在良好的协同作用，三模式协同治疗可以完全根除肿瘤组织，并在9个月内无复发。7、课题组合成和测试了一种分散性良好的非晶铁纳米颗粒（Amorphous iron nanoparticles，AFeNPs）。通过诱导氧化应激，增加细胞对电离辐射的敏感性。8、课题组对基于钨酸亚锡（SnWO4）和上转换纳米颗粒的杂化结构（UCNP-SnWO4）在放射治疗和光动力治疗的增敏特征的研究显示能够在肿瘤内增加氧自由基产物；增加次级电子的产生，提高局部区域内X射线能量的沉积，形成放射剂量增强的效果。