Department of Radiology, Center for Medical Imaging, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17 South Renmin Road, Chengdu, Sichuan, 610041, China.
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
Biomaterials. 2021 Jun;273:120847. doi: 10.1016/j.biomaterials.2021.120847. Epub 2021 Apr 23.
Hypoxia is a major obstacle towards successful cancer treatment, due to the hypoxia-mediated resistance to radiotherapy and chemotherapy, as well as immunosuppression. Therefore, engineering hypoxia-sensitive cytotoxic and immunogenic nanomedicines would promote the therapeutic efficacy. In this study, we developed novel tumor-targeted polymeric micelles sensing hypoxia in tumors to activate strong cytotoxicity and immunogenic responses for effectively eradicating advanced breast cancer. The hypoxia-activatable polymeric micelles could efficiently deliver anticancer drugs and photosensitizers into cancer cells, to trigger synergistic cytotoxicity and immunogenic cell death through chemotherapy and photodynamic therapy (PDT)/photothermal therapy (PTT). The long-circulating micelles efficiently delivered drugs to triple negative 4T1 breast tumors for accurate tumor diagnosis by photoacoustic imaging (PA), and effectively eliminating primary tumors without recurrence, including hypoxic 4T1 tumors. In addition, the micelle-based eradication of primary tumors could elicit robust systemic immune responses to inhibit tumor recurrence and significantly suppress distant 4T1 tumors and lung metastasis by combining with CpG and aCTLA4. These results indicate the high performance of our innovative multifunctional micelles for synergistic therapy against tumor malignancy, bringing opportunity for effectively dealing with disseminated and metastatic tumors.
缺氧是癌症治疗成功的主要障碍，这是由于缺氧介导的对放疗和化疗的耐药性，以及免疫抑制。因此，工程缺氧敏感的细胞毒性和免疫原性纳米药物将促进治疗效果。在这项研究中，我们开发了新型的肿瘤靶向聚合物胶束，用于在肿瘤中感应缺氧，以激活强大的细胞毒性和免疫原性反应，有效地根除晚期乳腺癌。缺氧激活的聚合物胶束可以将抗癌药物和光敏剂高效递送到癌细胞中，通过化学疗法和光动力疗法（PDT）/光热疗法（PTT）触发协同细胞毒性和免疫原性细胞死亡。长循环胶束通过光声成像（PA）高效地将药物递送到三阴性 4T1 乳腺癌中，进行准确的肿瘤诊断，并有效地消除原发性肿瘤而不复发，包括缺氧的 4T1 肿瘤。此外，基于胶束的原发性肿瘤消除可以引发强烈的全身免疫反应，通过与 CpG 和 aCTLA4 结合，抑制肿瘤复发，并显著抑制远处的 4T1 肿瘤和肺转移。这些结果表明，我们创新的多功能胶束在协同治疗肿瘤恶性方面具有出色的性能，为有效治疗播散性和转移性肿瘤带来了机会。
