CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment

作者：Wang, Yuehua; Wang, Zhenjie; Jia, Fei; Xu, Qing; Shu, Zhilin; Deng, Junlin; Li, Aimin^*; Yu, Meng^*; Yu, Zhiqiang^*

来源：Bioactive Materials, 2022, 17: 147-161.

DOI：10.1016/j.bioactmat.2022.01.003

• Hepatocellular carcinoma
• Sorafenib resistance
• Hypoxia relief
• Immunotherapy
• Tumor targeting regulation

Clinical sorafenib treatment could activate C-X-C receptor type 4 (CXCR4)/stromal source factor-1 alpha (SDF-1 alpha) axis to aggravate intra-tumoral hypoxia of hepatocellular carcinoma (HCC), which further leads to progression, invasion, metastasis, and immunosuppression of tumors and in return causes resistance to sorafenib therapy. Therefore, a multi-functional oxygen delivery nanoplatform was rationally constructed based on an oxygen-saturated perfluorohexane (PFH)-cored liposome, with the CXCR4 antagonist LFC131 peptides modifying on the surface to simultaneously deliver sorafenib and the CSF1/CSF1R inhibitor PLX3397 (named PFH@LSLP) for sorafenib-resistant HCC treatment. The PFH@LSLP was developed to overcome sorafenib resistance by synergistic effects of the following 3 roles: 1) the O-2-saturated PFH core could alleviate the tumor hypoxia by O-2 supply; 2) the LFC131 peptide recognized the hypoxia-related overexpressed CXCR4 and then blocked SDF-1 alpha/CXCR4 axis to re-sensitize the HCC cells to sorafenib; 3) PLX3397 activated the immune responses via inhibiting the CSF1/CSF1R pathway in TAMs, further enhanced CD8(+) T cell infiltration to reverse immunosuppression in tumors. Antitumor performance on H22 tumor-bearing mice and HCC patient-derived tumor xenograft (PDX) model showed that PFH@LSLP could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification.

• 单位
  中国科学院; 南方医科大学; 国家纳米科学中心