Wei Jiaojie, Long Yang, Guo Rong, Liu Xinlei, Tang Xian, Rao Jingdong, Yin Sheng, Zhang Zhirong, Li Man, He Qin
Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Acta Pharm Sin B. 2019 Jul;9(4):819-831. doi: 10.1016/j.apsb.2019.01.018. Epub 2019 Jan 31.
Immunotherapy has become a highly promising paradigm for cancer treatment. Herein, a chemo-immunotherapy was developed by encapsulating chemotherapeutic drug doxorubicin (DOX) and Toll-like receptor 7 agonist imiquimod (IMQ) in low molecular weight heparin (LMWH)-d--tocopheryl succinate (TOS) micelles (LT). In this process, LMWH and TOS were conjugated by ester bond and they were not only served as the hydrophilic and hydrophobic segments of the carrier, but also exhibited strong anti-metastasis effect. The direct killing of tumor cells mediated by DOX-loaded micelles (LT-DOX) generated tumor-associated antigens, initiating tumor-specific immune responses in combination with IMQ-loaded micelles (LT-IMQ). Furthermore, the blockade of immune checkpoint with programmed cell death ligand 1 (PD-L1) antibody further elevated the immune responses by up-regulating the maturation of DCs as well as the ratios of CD8 CTLs/T and CD4 T/T. Therefore, such a multifunctional strategy exhibited great potential for inhibiting the growth of orthotopic and metastatic breast cancer.
免疫疗法已成为一种极具前景的癌症治疗模式。在此，通过将化疗药物阿霉素（DOX）和Toll样受体7激动剂咪喹莫特（IMQ）封装在低分子量肝素（LMWH）-d-α-生育酚琥珀酸酯（TOS）胶束（LT）中，开发了一种化学免疫疗法。在此过程中，LMWH和TOS通过酯键连接，它们不仅作为载体的亲水和疏水部分，还表现出强大的抗转移作用。载有DOX的胶束（LT-DOX）介导的肿瘤细胞直接杀伤产生肿瘤相关抗原，与载有IMQ的胶束（LT-IMQ）联合引发肿瘤特异性免疫反应。此外，用程序性细胞死亡配体1（PD-L1）抗体阻断免疫检查点，通过上调DC的成熟以及CD8 CTLs/T和CD4 T/T的比例进一步增强免疫反应。因此，这种多功能策略在抑制原位和转移性乳腺癌生长方面显示出巨大潜力。
