Selectively targeting tumor-associated macrophages and tumor cells with polymeric micelles for enhanced cancer chemo-immunotherapy
Selectively targeting tumor-associated macrophages and tumor cells with polymeric micelles for enhanced cancer chemo-immunotherapy
复制标题
用聚合物胶束选择性靶向肿瘤相关巨噬细胞和肿瘤细胞以增强癌症化学免疫治疗
DOI：
10.1016/j.jconrel.2019.09.021
复制
发表时间：
2019-11-10
影响因子：
10.8
通讯作者：
Zhou, Shaobing
中科院分区：
文献类型：
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作者：
Wei, Xiao;Liu, Lingqiao;Zhou, Shaobing
肿瘤相关巨噬细胞（TAM）相关的免疫治疗是一种非常有前途的策略，涉及使用免疫调节剂咪喹莫特（R837）改变免疫抑制肿瘤微环境以增强癌症治疗。然而，由于R837水溶性差且缺乏靶向能力，其功能受到严重限制。在这里，我们开发了两种类型的靶向聚合物胶束，分别通过瘤内注射和静脉注射将R837和抗癌药物阿霉素（DOX）分别递送至TAM和肿瘤细胞，以增强针对乳腺癌的癌症化学免疫治疗。这些胶束在肿瘤组织中积累后，免疫刺激胶束释放出R837，R837与TAM内溶酶体膜上的TLR-7受体结合，刺激TAM成熟，从而引起抗肿瘤免疫反应，解除肿瘤微环境中的免疫抑制作用。同时，化疗胶束在肿瘤细胞的细胞质中释放DOX，直接诱导细胞死亡。结果，通过这些纳米药物实现了化疗和免疫疗法的协同组合，分别激活抗肿瘤免疫反应并抑制肿瘤细胞生长。因此，该策略为开发针对恶性癌症的联合化学免疫疗法的靶向纳米药物提供了新途径。
Tumor-associated macrophage (TAM)-related immunotherapy is a greatly promising strategy that involves altering the immunosuppressive tumor microenvironment with the immunomodulator imiquimod (R837) for enhanced cancer therapy. However, the function of R837 is seriously limited due to poor water solubility and a lack of targeting ability. Here, we developed two types of targeting polymer micelles to separately deliver R837 and the anticancer drug doxorubicin (DOX) to TAMs and tumor cells via intratumoral injection and intravenous injection, respectively, for enhanced cancer chemo-immunotherapy against breast cancer. After these micelles accumulated in the tumor tissues, the immunostimulating micelles released R837, which bound to the TLR-7 receptor on the lysosomal membrane within the TAM, stimulating the maturation of the TAM, thereby causing an antitumor immune response and relieving the immunosuppressive effect in the tumor microenvironment. Simultaneously, the chemotherapeutic micelles released DOX in the cytoplasm of the tumor cells, directly inducing cell death. As a result, a synergistic combination of chemotherapy and immunotherapy was achieved through these nanomedicines, which separately activated the antitumor immune response and inhibited tumor cell growth. Therefore, this strategy is a new avenue for the development of targeting nanomedicines for combination chemo-immunotherapy against malignant cancer.