基于巨噬细胞免疫激活协同的高效光动力学疗法用于抗肿瘤研究

The efficiency of photodynamic therapy (PDT) is greatly limited due to poor tumor targeting character of photosensitizer and tumor hypoxia. What’s worse, the tumor microenvironment aggravates tumor progression and recurrence by further regulating the immune cells in the immune-suppressed state. Based on these, it is proposed to use manganese dioxide nanosheets to load tumor cell CD47 targeting peptide-modified photosensitizers and macrophage activators to construct a highly efficient PDT system with synergistic macrophage immune activation for tumor elimination and recurrence inhibition. Upon acid/hydrogen peroxide triggering in tumor tissue, the vector disintegrates with the release of oxygen, CD47-targeted photosensitizers, and macrophage activators. On the one hand, the photosensitizer is activated in situ in the tumor and precisely targets tumor CD47 while improves tumor hypoxia, which could realize tumor efficient PDT under light irradiation. On the other hand, the activator promotes the polarization of the immunosuppressive M2 macrophage to the immune-activated M1 macrophage, activating the immune response. At the same time, CD47-targeted PDT causes destruction of CD47, further enhancing the phagocytosis of macrophage against tumor cells. Complemented by both, the effect of immunotherapy amplifies, reducing tumor recurrence rate. The system is expected to achieve synergistic immune therapy and efficient PDT through one-step triggering, providing a new strategy for constructing an efficient PDT system for tumor therapy.

光动力学治疗（PDT）因光敏剂肿瘤靶向性差和肿瘤缺氧，极大限制了其抗肿瘤效率。此外，肿瘤微环境调节相关免疫细胞处于免疫抑制状态，加重肿瘤恶化和复发。基于此，拟用二氧化锰纳米片负载肿瘤CD47靶向肽修饰的光敏剂和巨噬细胞激活剂，构建巨噬细胞免疫激活协同的高效PDT体系用于消除肿瘤和抑制复发。在肿瘤微酸/过氧化氢触发下，载体解体并伴随氧气、CD47靶向光敏剂和巨噬细胞激活剂的释放。一方面，实现光敏剂肿瘤原位激活并精确靶向到肿瘤CD47以及改善肿瘤缺氧，在光照条件下实现肿瘤高效PDT。另一方面，激活剂促进肿瘤相关巨噬细胞由免疫抑制M2型向免疫激活M1型转化，激活免疫应答，于此同时，CD47靶向PDT导致CD47被破坏，增强巨噬细胞对肿瘤细胞的免疫识别，两者相辅，放大免疫治疗效果，降低肿瘤复发率。该体系有望通过一步触发实现免疫治疗协同的高效PDT，为构建高效PDT系统用于抗肿瘤提供了新策略。

光动力学治疗（PDT）因光敏剂肿瘤靶向性差和肿瘤缺氧，极大限制了其抗肿瘤效率。此外，肿瘤微环境调节相关免疫细胞处于免疫抑制状态，加重肿瘤恶化和复发。在本项目实施过程中，我们筛选并制备出两种肿瘤细胞靶向光动力学治疗系统（M@P@HA 和 CP@mRBC-PpIX），成功实现高效光动力学治疗协同免疫治疗的目的，并阐明纳米递送系统的免疫微环境调节机制。实验结果表明，我们制备纳米递送系统的方案可行，制备出的纳米递送系统具有稳定的肿瘤微环境调节性能。其中，M@P@HA通过PDT联合Mn2+的免疫调节性质，实现了级联放大STING信号通路，激活固有免疫；而CP@mRBC-PpIX通过调节肿瘤的缺氧微酸环境，激活了抗肿瘤的M1型巨噬细胞，协同光动力学治疗，实现了增强的抗肿瘤效果。本项目证实，通过功能化递送系统本身的肿瘤微环境调节功能结合光动力学治疗可以实现更高效的肿瘤治疗效果并扩大患者的受益率，实现递送系统的最大化利用。此外，同类型递送系统与化疗药物结合，也可实现更高效的化疗、免疫治疗协同的抗肿瘤效果。得益于本项目的研究，实现了化学、生物学、材料学以及医学的融合，把纳米递送系统本身的功能最大化，对开发可应用的抗肿瘤新策略有十分重要的意义。