Sun Xu, Cao Ziyang, Mao Kuirong, Wu Chenxi, Chen Hongmei, Wang Jialiang, Wang Xin, Cong Xiuxiu, Li Yong, Meng Xianying, Yang Xianzhu, Yang Yong-Guang, Sun Tianmeng
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital, Jilin University, Changchun, Jilin, 130061, China.
Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510005, Guangzhou, China.
Biomaterials. 2020 May;240:119845. doi: 10.1016/j.biomaterials.2020.119845. Epub 2020 Feb 6.
Photodynamic therapy (PDT) can destroy local tumor cells and induce effective antitumor immune responses, and has been applied in the treatment of patients with superficial solid tumors. Numerous systemic side effects of PDT, such as pain and skin photosensitivity, however, limit this therapeutic option. In addition, the immunosuppressive tumor microenvironment has been found to be another critical barrier for the antitumor immunity induced by PDT. Therefore, effectively enhancing the cytotoxicity to tumor cells of low-dose PDT and inhibiting the tumor immunosuppressive tumor microenvironment may be a feasible strategy to overcome these drawbacks of PDT. Here, a sorafenib and chlorin e6 co-loaded reactive oxygen species (ROS)-responsive nanoparticle (NP-sfb/ce6) is developed to improve antitumor responses by intratumoral release of sorafenib at the time of PDT. Under 660-nm laser irradiation, ROS produced by chlorin e6 (ce6) destruct the nanoparticles, resulting in boosted sorafenib cascade release. The rapidly released sorafenib acts synergistically with the low-dose PDT to inhibit tumor growth by inducing strong T cell-dependent local and systemic antitumor immune responses, reprograming the tumor immune microenvironment, and limiting the interaction between cytotoxic CD8 T cells and immunosuppressive cells. This study provides new avenues for cascade-amplifying antitumor effects of photodynamic therapy.
光动力疗法（PDT）可破坏局部肿瘤细胞并诱导有效的抗肿瘤免疫反应，已应用于浅表实体瘤患者的治疗。然而，PDT的许多全身副作用，如疼痛和皮肤光敏性，限制了这种治疗选择。此外，免疫抑制性肿瘤微环境已被发现是PDT诱导的抗肿瘤免疫的另一个关键障碍。因此，有效增强低剂量PDT对肿瘤细胞的细胞毒性并抑制肿瘤免疫抑制性肿瘤微环境可能是克服PDT这些缺点的可行策略。在此，开发了一种索拉非尼和氯e6共负载的活性氧（ROS）响应纳米颗粒（NP-sfb/ce6），通过在PDT时肿瘤内释放索拉非尼来改善抗肿瘤反应。在660nm激光照射下，氯e6（ce6）产生的ROS破坏纳米颗粒，导致索拉非尼级联释放增强。快速释放的索拉非尼与低剂量PDT协同作用，通过诱导强烈的T细胞依赖性局部和全身抗肿瘤免疫反应、重新编程肿瘤免疫微环境以及限制细胞毒性CD8 T细胞与免疫抑制细胞之间的相互作用来抑制肿瘤生长。本研究为光动力疗法的级联放大抗肿瘤作用提供了新途径。
