CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment
Yuehua Wang, Zhenjie Wang, Fei Jia, Qing Xu, Zhilin Shu, Junlin Deng, Aimin Li, Meng Yu, Zhiqiang Yu
Abstract
Clinical sorafenib treatment could activate C-X-C receptor type 4 (CXCR4)/stromal source factor-1α (SDF-1α) 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 [email protected]) for sorafenib-resistant HCC treatment. The [email protected] was developed to overcome sorafenib resistance by synergistic effects of the following 3 roles: 1) the O2-saturated PFH core could alleviate the tumor hypoxia by O2 supply; 2) the LFC131 peptide recognized the hypoxia-related overexpressed CXCR4 and then blocked SDF-1α/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 [email protected] could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification.