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

作　　者：Yuehua Wang Zhenjie Wang Fei Jia Qing Xu Zhilin Shu Junlin Deng Aimin Li Meng Yu Zhiqiang Yu 

机构地区：[1]Cancer Center,Integrated Hospital of Traditional Chinese Medicine,Southern Medical University.Guangzhou,510315,PR China [2]Guangdong Provincial Key Laboratory of New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou,510515,PR China [3]The People’s Hospital of Gaozhou,Maoming,525200,PR China [4]CAS Key Laboratory of Standardization and Measurement for Nanotechnology,CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety,CAS Center for Excellence in Nanoscience,National Center for Nanoscience and Technology of China,Beijing,100190,PR China

出　　处：《Bioactive Materials》2022年第11期147-161,共15页生物活性材料（英文）

基　　金：This research was financially supported by GDNRC[Guangdong nature resource center](2020)037;the National Natural Science Foundation of China(81773642,52073139);the Natural Science Foundation of Guangdong Province(2019A1515011619 and 2019A1515011498);Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety,National Center for Nanoscience and Technology,CAS(NSKF201819);Project of Traditional Chinese Medi-cine Bureau of Guangdong Province,China(NO.20203006);Science and Technology Program of Guangzhou,China(NO.202002030075).

摘　　要：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 PFH@LSLP)for sorafenib-resistant HCC treatment.The PFH@LSLP was developed to overcome sorafenib resistance by syner-gistic 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-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 PFH@LSLP could overcome sorafenib resistance by synergistic effect of hypoxia attenuation,resistance-related gene regulation,and immune-microenvironment modification.

关 键 词：Hepatocellular carcinoma Sorafenib resistance Hypoxia relief Immunotherapy Tumor targeting regulation 

分 类 号：R73[医药卫生—肿瘤] R318[医药卫生—临床医学]