内嵌钆金属富勒烯通过抑制氧化还原介导的内皮细胞迁移诱导肿瘤血管正常化并增强化疗疗效  

Inhibiting redox-mediated endothelial migration by gadofullerenes for inducing tumor vascular normalization and improving chemotherapy

作　　者：孙梓豪 周悦 李蕾 周辰 贾旺 刘阳 曹欣然 苏升娥 赵中普 甄明明 王春儒 Zihao Sun;Yue Zhou;Lei Li;Chen Zhou;Wang Jia;Yang Liu;Xinran Cao;Shenge Su;Zhongpu Zhao;Mingming Zhen;Chunru Wang(Beijing National Laboratory for Molecular Sciences,Key Laboratory of Molecular Nanostructure and Nanotechnology,CAS Research/Education Center for Excellence in Molecular Sciences,Institute of Chemistry,Chinese Academy of Sciences,Beijing 100190,China;University of Chinese Academy of Sciences,Beijing 100049,China)

机构地区：[1]Beijing National Laboratory for Molecular Sciences,Key Laboratory of Molecular Nanostructure and Nanotechnology,CAS Research/Education Center for Excellence in Molecular Sciences,Institute of Chemistry,Chinese Academy of Sciences,Beijing 100190,China [2]University of Chinese Academy of Sciences,Beijing 100049,China

出　　处：《Science Bulletin》2023年第15期1651-1661,M0004,共12页科学通报（英文版）

基　　金：supported by the Major Research Project of National Natural Science Foundation of China(92061123);the Key Research Program of the Chinese Academy of Sciences(QYZDJ-SSW-SLH01);the Youth Innovation Promotion Association of CAS(2022036)。

摘　　要：肿瘤血管正常化(TVN)可以通过逆转异常的肿瘤血管,从而增强抗癌效率,特别是增加药物的瘤内输送.内皮细胞在血管生成中起着至关重要的作用,但持续调控内皮细胞迁移以改善TVN是巧妙而具有挑战性的.本文提出了一种基于具有纳米尺寸和抗氧化能力的富勒烯纳米颗粒(FNPs)抑制内皮细胞迁移的可能策略来实现TVN.本研究证明FNPs在体外通过其抗氧化作用抑制细胞迁移.丙氨酸修饰的钆富勒烯(GFA)表现出优异的TVN效果,并在体内抑制肿瘤生长.在蛋白质微阵列的帮助下,确认GFA在机制上是通过抑制粘着斑通路,从而抑制内皮细胞的迁移.随后,得益于GFA的血管正常化效应,显著增强了化疗疗效.总之,本文证明了富勒烯纳米材料在肿瘤血管正常化中的应用潜力,并拓展了其在癌症纳米医学材料设计中应用的可能性.Tumor vascular normalization(TVN)reverses abnormal tumor vasculatures,which could boost anticancer efficiency and especially increase drug intratumoral delivery.Endothelial cells play a vital role in angiogenesis,yet continuous modulating endothelial cell migration to improve TVN is ingenious but challenging.Here we propose a potential strategy for TVN based on inhibiting endothelial migration using antioxidative fullerene nanoparticles(FNPs).We demonstrate that FNPs inhibit cell migration upon their anti-oxidation effects in vitro.The optimized alanine-modified gadofullerene(GFA)exhibits superior TVN ability and inhibits tumor growth in vivo.Mechanically,facilitated with the protein microarray,we confirm that GFA could suppress the focal adhesion pathway to restrain endothelial migration.Subsequently,remarkable anti-tumor efficacy of chemotherapy synergy was obtained,which benefited from a more normalized vascular network by GFA.Together,our study introduces the potential of FNPs as promising TVN boosters to consider in cancer nanomedicine design.

关 键 词：Gadofullerene Reactive oxygen species Endothelial migration Tumor vascular normalization Protein microarray 

分 类 号：R730.53[医药卫生—肿瘤]