A theranostic metallodrug modulates immunovascular crosstalk to combat immunosuppressive liver cancer

作者全名："Luo, Ying; Wang, Junrui; Xu, Lian; Du, Qianying; Fang, Ni; Wu, Hongyun; Liu, Fan; Hu, Liu; Xu, Jie; Hou, Jingxin; Zhong, Yixin; Liu, Yun; Wang, Zhigang; Ran, Haitao; Guo, Dajing"

作者地址："[Luo, Ying; Wang, Junrui; Xu, Lian; Du, Qianying; Fang, Ni; Wu, Hongyun; Hu, Liu; Xu, Jie; Zhong, Yixin; Liu, Yun; Guo, Dajing] Chongqing Med Univ, Dept Radiol, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Luo, Ying; Wang, Junrui; Xu, Lian; Du, Qianying; Fang, Ni; Liu, Fan; Hu, Liu; Xu, Jie; Hou, Jingxin; Zhong, Yixin; Wang, Zhigang; Ran, Haitao] Chongqing Med Univ, Chongqing Key Lab Ultrasound Mol Imaging, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Luo, Ying; Wang, Junrui; Xu, Lian; Du, Qianying; Fang, Ni; Liu, Fan; Hu, Liu; Xu, Jie; Hou, Jingxin; Zhong, Yixin; Wang, Zhigang; Ran, Haitao] Chongqing Med Univ, Dept Ultrasound, Affiliated Hosp 2, Chongqing 400010, Peoples R China"

通信作者："Guo, DJ (通讯作者)，Chongqing Med Univ, Dept Radiol, Affiliated Hosp 2, Chongqing 400010, Peoples R China."

来源：ACTA BIOMATERIALIA

ESI学科分类：MATERIALS SCIENCE

WOS号：WOS:000898825700005

JCR分区：Q1

影响因子：9.7

年份：2022

卷号：154

期号：　

开始页：478

结束页：496

文献类型：Article

关键词：Metallodrug; Immunotherapy; Vessel normalization; Hepatocellular carcinoma; Magnetic resonance imaging

摘要："Hepatocellular carcinoma (HCC) is a highly malignant, fatal disease with a complex tumor microenviron-ment (TME) characterized by severe immunosuppression and malformed vascular structures, thus most advanced HCC patients do not respond well to current mainstream pharmacotherapy and T-cell-related immunotherapy. Therefore, an efficient immunovascular crosstalk modulation strategy may help combat HCC by reversing immunosuppression and vessel normalization, especially by reprogramming tumor as-sociated macrophages (TAMs). In this study, tyrosine kinase inhibitor lenvatinib (Len) was loaded into mesoporous Fe3O4 (mFe) nanoparticles (NPs), and bovine serum albumin (BSA) was attached to the NP surface to produce a metallodrug (BSA-mFe@Len NPs). In acidic TME, BSA allowed pH-responsive Len re-lease and mFe exposure. Len directly triggered HCC apoptosis and changed the abnormal TME via vessel normalization, cytotoxic T-lymphocyte recruitment, and regulatory T-cell elimination at tailored dosages. After TAM phagocytosis, mFe NPs reprogrammed TAMs into M1 phenotypes to synergistically amplify an-titumor immunity. The metallodrug achieved significant tumor growth inhibition, induced tumor vessel normalization effects, and acquired instant antitumor immunity as well as long-term immune memory in vivo . Furthermore, it displayed good T 2 weighted magnetic resonance imaging performance, indicat-ing potential theranostic applications. Collectively, this research provides new insights for unleashing the multifaceted potential of current pharmaceuticals in synergy with metallic nanomedicine for treating in-tractable liver cancer. Statement of significance Current pharmacotherapy and immunotherapy have limited success in treating advanced hepatocellular carcinoma (HCC) due to its complex tumor microenvironment (TME). Hence, this work first put forward a theranostic metallodrug by loading lenvatinib (Len) into mesoporous Fe3O4 (mFe) nanoparticles (NPs) and coating a pH-degradable bovine serum albumin corona onto the surface. The metallodrug was able to modulate immunovascular TME for combating HCC via metalloimmunotherapy induced by the mFe NPs and Len's multiple functions (direct triggering of tumor apoptosis, vessel normalization, cytotoxic T-lymphocyte recruitment, and regulatory T-cell elimination). In vivo experiments showed that the met-allodrug could significantly inhibit HCC growth and evoke long-term antitumor immune memory, paving a new avenue for treating advanced HCC patients.(c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved."

基金机构："National Natural Science Foundation of China [81971608, 82271970]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University [CQYC2020030389, 2020-7]; Chongqing Talents Program [cstc2021ycjh-bgzxm0168]; General program of Chongqing Natural Science Foundation [cstc2020jcyj-msxmX1017]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (81971608 , 82271970) , and the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (CQYC2020030389 , 2020-7) . The authors also appre- ciate the Chongqing Talents Program (cstc2021ycjh-bgzxm0168) , the General program of Chongqing Natural Science Foundation (cstc2020jcyj-msxmX1017) ."