CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment
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 resist...
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| Format: | Article |
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KeAi Communications Co., Ltd.
2022-11-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X22000032 |
| _version_ | 1797203471349317632 |
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| author | Yuehua Wang Zhenjie Wang Fei Jia Qing Xu Zhilin Shu Junlin Deng Aimin Li Meng Yu Zhiqiang Yu |
| author_facet | Yuehua Wang Zhenjie Wang Fei Jia Qing Xu Zhilin Shu Junlin Deng Aimin Li Meng Yu Zhiqiang Yu |
| author_sort | Yuehua Wang |
| collection | DOAJ |
| description | 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 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 PFH@LSLP could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification. |
| first_indexed | 2024-04-24T08:19:51Z |
| format | Article |
| id | doaj.art-f8656dea4bb549669a8c9579e02a33c4 |
| institution | Directory Open Access Journal |
| issn | 2452-199X |
| language | English |
| last_indexed | 2024-04-24T08:19:51Z |
| publishDate | 2022-11-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj.art-f8656dea4bb549669a8c9579e02a33c42024-04-17T02:10:11ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2022-11-0117147161CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatmentYuehua Wang0Zhenjie Wang1Fei Jia2Qing Xu3Zhilin Shu4Junlin Deng5Aimin Li6Meng Yu7Zhiqiang Yu8Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University. Guangzhou, 510315, PR China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR ChinaThe People's Hospital of Gaozhou, Maoming, 525200, PR ChinaCAS 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 ChinaGuangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR ChinaGuangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR ChinaGuangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR ChinaCancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University. Guangzhou, 510315, PR China; Corresponding author.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China; Corresponding author.Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University. Guangzhou, 510315, PR China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China; Corresponding author. Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University. Guangzhou, 510315, PR China.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 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 PFH@LSLP could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification.http://www.sciencedirect.com/science/article/pii/S2452199X22000032Hepatocellular carcinomaSorafenib resistanceHypoxia reliefImmunotherapyTumor targeting regulation |
| spellingShingle | Yuehua Wang Zhenjie Wang Fei Jia Qing Xu Zhilin Shu Junlin Deng Aimin Li Meng Yu Zhiqiang Yu CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment Bioactive Materials Hepatocellular carcinoma Sorafenib resistance Hypoxia relief Immunotherapy Tumor targeting regulation |
| title | CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment |
| title_full | CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment |
| title_fullStr | CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment |
| title_full_unstemmed | CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment |
| title_short | CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment |
| title_sort | cxcr4 guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib resistant tumor treatment |
| topic | Hepatocellular carcinoma Sorafenib resistance Hypoxia relief Immunotherapy Tumor targeting regulation |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X22000032 |
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