靶向肿瘤微环境的非小细胞肺癌个体化放疗探索

The individual variation of radiotherapy effect in non-small cell lung cancer is significant. We engaged in individualized radiotherapy characterized by the precise positioning and functional molecular images more than 10 years. We noticed some patients with lung cancer suffered from radiotherapy resistance originated from the hypoxic, acid and immunosuppressive tumor microenvironment. The required dose was much higher than the dose limited by normal tissue in these patients. Taking advantage of the enrichment of tumor-associated macrophages in the ischemic hypoxic region of the tumor, we intended to design and optimize the albumin manganese dioxide nanoparticles targeting tumor associated macrophages to improve the microenvironment. The nanoparticles will be delivered to the tumor hypoxic region to release oxygen, decrease acid, enhance immunity, and realize multi-mode accurate imaging such as MRI/PET/SPECT. The radio-sensitivity changes from the microenvironment adjustment and the best mode to match microenvironment adjustment and individualized radiotherapy were explored. The individualized radiotherapy targeted micro-environment for non-small cell lung cancer will be established and clinically transformed.

非小细胞肺癌放疗效果个体差异显著，课题组长期致力于以功能分子影像的精准定位和预测实施“按需照射”的个体化生物精准放疗，也是业界公认的改进路径。但是，部分进展期肺癌患者因乏氧、酸性及免疫抑制的肿瘤微环境造成放疗抵抗，实现控制的“所需剂量过高”，受限于肿瘤负荷过大和正常组织剂量限制而难以实现。课题组利用肿瘤相关巨噬细胞在肿瘤缺血乏氧区域富集的特点，拟设计优化靶向肺癌微环境的白蛋白二氧化锰纳米粒子，通过靶向肿瘤相关巨噬细胞，将纳米粒子靶向递送到肿瘤乏氧区域释放氧气、纠酸、增强免疫，并实现MRI/PET/SPECT等多模态精准成像；探索靶向调节微环境对放疗敏感性的影响并建立同步影像预测方法；探索靶向微环境和生物精准放疗的最佳模式，建立靶向微环境的非小细胞肺癌个体化放疗技术并临床转化。

按照任务书的计划要求，课题组以靶向肿瘤微环境、提升个体化放疗为目标，全面执行了课题计划：（1）不断进行靶向肺癌微环境纳米粒子的优化和验证，并探索其通过靶向调节肺癌微环境对放疗敏感性的影响。（2）通过靶向肺癌微环境成像、肿瘤干细胞的新型黑磷磁共振成像新方法，探索肺癌放疗靶区划定新方法，提高肿瘤放疗的精准度和治疗的有效性。（3）通过靶向肿瘤肿瘤微环境间质细胞18F-FAPI成像为肿瘤个体化治疗实施提供了初步的理论基础和实用技术，18F-FAPI在识别晚期肺癌患者的转移病灶和鉴别病理类型方面有很好的应用价值，并可预测放化疗的疗效和放射性肺损伤。（4）通过靶向肿瘤微环境新生血管生成的18F-RGD分子影像，发现其在不同临床病理特征中的诊断价值，可基线预测局部晚期NSCLC的放化疗预后和肿瘤抗血管生成治疗的毒性。（5）通过靶向肿瘤微环境糖代谢的18F-FDG分子影像，建立了个体化自适应放疗技术，大幅度提高了NSCLC患者的生存并在全国开展了多中心的临床验证。