Multipoint Costriking Nanodevice Eliminates Primary Tumor Cells and Associated-Circulating Tumor Cells for Enhancing Metastasis Inhibition and Therapeutic Effect on HCC.
Multipoint Costriking Nanodevice Eliminates Primary Tumor Cells and Associated-Circulating Tumor Cells for Enhancing Metastasis Inhibition and Therapeutic Effect on HCC.
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多点共击纳米装置消除原发肿瘤细胞和相关循环肿瘤细胞，增强肝癌转移抑制和治疗效果
DOI：
10.1002/advs.202101472
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Zhang N
中科院分区：
文献类型：
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作者：
Mu W;Chu Q;Yang H;Guan L;Fu S;Gao T;Sang X;Zhang Z;Liang S;Liu Y;Zhang N
消除原发性肿瘤（“根源”）和抑制相关循环肿瘤细胞（相关CTC，“种子”）是癌症治疗中迫切需要解决的重要问题。相关CTC，包括单个CTC、CTC簇和CTC-中性粒细胞簇，是癌症患者转移的重要执行者和转移相关死亡的原因。在此，开发了“根和种子”多点共击纳米装置（GV‐Lipo/索拉非尼（SF）/洋地黄毒苷（DT）），以消除原发性肿瘤并抑制相关CTC的扩散，从而增强对肝细胞癌（HCC）的转移抑制和治疗效果。GV‐Lipo/SF/DT通过SF的作用消除原发性肿瘤细胞，从而从根本上减少CTC的产生，提高对HCC的治疗效果。GV‐Lipo/SF/DT通过增强磷脂酰肌醇蛋白聚糖-3和/或血管细胞粘附分子1（VCAM 1）靶向的识别和捕获效应，使用DT解离CTC簇，使用抗VCAM 1单克隆抗体阻断CTC-中性粒细胞簇的形成，并使用SF杀死CTC，有效抑制相关CTC。已成功验证GV‐Lipo/SF/DT可提高体内CTC清除效率，从而有效预防转移，并在H22荷瘤模型和原位HCC模型中均显示出增强的抗肿瘤功效。总的来说，“根和种子”多点共击策略可能为临床开辟一种新的癌症治疗模式。获得了具有消除原发性肿瘤细胞和相关循环肿瘤细胞（CTC）的能力的多点共打击纳米装置（GV‐Lipo/SF/DT），用于增强对HCC的转移抑制和治疗效果。GV‐Lipo/SF/DT可特异性靶向肿瘤细胞并捕获CTC，解离CTC簇，阻断CTC-中性粒细胞簇的形成，最终杀死CTC和原发性肿瘤细胞。
Eliminating primary tumor (“roots”) and inhibiting associated‐circulating tumor cells (associated‐CTCs, “seeds”) are vital issues that need to be urgently addressed in cancer therapy. Associated‐CTCs, which include single CTCs, CTC clusters, and CTC–neutrophil clusters, are essential executors in metastasis and the cause of metastasis‐related death in cancer patients. Herein, a “roots and seeds” multipoint costriking nanodevice (GV‐Lipo/sorafenib (SF)/digitoxin (DT)) is developed to eliminate primary tumors and inhibit the spread of associated‐CTCs for enhancing metastasis inhibition and the therapeutic effect on hepatocellular carcinoma (HCC). GV‐Lipo/SF/DT eliminates primary tumor cells by the action of SF, thus reducing CTC production at the roots and improving the therapeutic effect on HCC. GV‐Lipo/SF/DT inhibits associated‐CTCs effectively via the enhanced identification and capture effects of glypican‐3 and/or vascular cell adhesion molecule 1 (VCAM1) targeting, dissociating CTC clusters using DT, blocking the formation of CTC–neutrophil clusters using anti‐VCAM1 monoclonal antibody, and killing CTCs with SF. It is successfully verified that GV‐Lipo/SF/DT increases the CTC elimination efficiency in vivo, thus effectively preventing metastasis, and shows enhanced antitumor efficacy in both an H22‐bearing tumor model and orthotopic HCC models. Overall, the “roots and seeds” multipoint costriking strategy may open a new cancer treatment model for the clinic. A multipoint costriking nanodevice (GV‐Lipo/SF/DT) with the capability of eliminates primary tumor cells and associated‐circulating tumor cells (CTCs) is obtained for enhancing metastasis inhibition and therapeutic effect on HCC. GV‐Lipo/SF/DT can specifically target tumor cells and capture CTCs, dissociate CTC clusters, block the formation of CTC–neutrophil clusters, finally kill CTCs and primary tumor cells.