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化学进展 2022, Vol. 34 Issue (1): 178-197 DOI: 10.7536/PC210346 前一篇   后一篇

• 综述 •

循环肿瘤细胞及细胞外囊泡的纳米检测技术

王嘉莉1, 朱凌2, 王琛2,*(), 雷圣宾1,*(), 杨延莲2,*()   

  1. 1 天津大学 天津 300350
    2 中国科学院纳米标准与检测重点实验室 中国科学院纳米生物效应与安全性重点实验室 国家纳米科学中心 北京 100190
  • 收稿日期:2021-03-29 修回日期:2021-05-06 出版日期:2022-01-20 发布日期:2021-07-29
  • 通讯作者: 王琛, 雷圣宾, 杨延莲
  • 基金资助:
    中国科学院战略性先导科技专项(B类)(XDB36000000); 国家重点研发项目(2017YFA0205000); 国家自然科学基金项目(51861135103); 国家自然科学基金项目(31971295); 国家自然科学基金项目(21773042); 关键前沿科学研究项目(QYZDJ-SSW-SLH048); 中国科学院青年创新促进会(2018048)
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Nanotechnology for Detection of Circulating Tumor Cells and Extracellular Vesicles

Jiali Wang1, Ling Zhu2, Chen Wang2(), Shengbin Lei1(), Yanlian Yang2()   

  1. 1 Tianjin University,Tianjin 300350, China
    2 CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China
  • Received:2021-03-29 Revised:2021-05-06 Online:2022-01-20 Published:2021-07-29
  • Contact: Chen Wang, Shengbin Lei, Yanlian Yang
  • Supported by:
    Strategic Priority Research Program of the Chinese Academy of Sciences(XDB36000000); Key R&D Project(2017YFA0205000); National Natural Science Foundation of China(51861135103); National Natural Science Foundation of China(31971295); National Natural Science Foundation of China(21773042); Key Frontier Science Research Project(QYZDJ-SSW-SLH048); Youth Innovation Promotion Association of Chinese Academy of Sciences(2018048)

肿瘤液体活检通过对体液中生物标志物的检测实现疾病的精准诊断,对于恶性肿瘤的早期诊断和动态监测至关重要。循环肿瘤细胞(CTC)是肿瘤组织释放到血液中的肿瘤细胞,细胞外囊泡(EV)是由细胞分泌的膜囊泡,二者都携带肿瘤分子信息,并与肿瘤进展和转移密切相关,是重要的液体活检生物标志物,并且在检测方法和临床意义方面也有很多共性。纳米材料由于其高比表面积、独特的光、电、磁等物理化学特性以及易于功能化修饰等特点,被广泛用于CTC和EV的检测,以提高检测灵敏度和特异性,提供肿瘤形成、进展、转移和治疗反应的信息,具有很好的应用前景。本文回顾了在CTC和EV的特异性识别、高效捕获或分离、目标CTC或EV的鉴定等三方面的纳米技术进展,包括提高分子识别特异性的纳米材料表面识别探针功能化修饰以及捕获、鉴定的纳米材料和纳米技术的最新进展,总结了基于功能化纳米材料的液体活检技术的优势及挑战,为液体活检纳米技术的发展提供信息。

关键词： 液体活检, 细胞外囊泡, 循环肿瘤细胞, 功能化纳米材料, 肿瘤体外诊断

Tumor liquid biopsy achieves accurate diagnosis of disease by detecting biomarkers in the body fluids which are of great importance for early diagnosis and dynamic monitoring of malignant tumors and are essential biomarkers for liquid biopsies. Circulating tumor cells (CTC) are tumor cells released into the blood from tumor tissue, and extracellular vesicles (EV) are membrane vesicles secreted by cells. Both of them carry tumor molecular information and are closely related to tumor progression and metastasis. Nanomaterials are widely used to detect CTCs and EVs due to their high specific surface area, unique optical, electrical, magnetic and other physical and chemical characteristics that can improve the detection sensitivity and specificity. Nanomaterial-based detection of CTCs and EVs has provided important information for tumor formation, progression, metastasis, and treatment response, and holds great potential in the clinical application. This article reviewes the progress of nanotechnology in three aspects: specific recognition, efficient capture or isolation, and identification of CTC and EV. It includes the functionalization of recognition probes on the surface of nanomaterials to improve the detection specificity and the latest advances in capture and identification of nanomaterials and nanotechnology. It may provide information for the development of liquid biopsy nanotechnology by discussing the advantages and challenges of liquid biopsy technology based on functionalized nanomaterials.

Contents

1 Introduction

2 Functionalized modification of CTC and EV recognition probes

3 Efficient capture of CTC and EV by nanomaterials

4 Identification and detection of CTC and EV

4.1 Signal amplification technology based on functional nanomaterials

4.2 Signal conversion technology based on functional nanomaterials

5 Integration technology of capture and detection of nanomaterials and microchips

6 POCT

7 Conclusion and prospect

Key words: liquid biopsy, extracellular vesicles, circulating tumor cells, functionalized nanomaterials, in vitro diagnosis of tumor
()
图1 CTC与EV的产生过程以及液体活检纳米检测技术:(a)EV的形成;(b) 循环肿瘤细胞及其在肿瘤转移中的作用;(c)表面增强拉曼技术;(d)微流控芯片技术;(e)纳米颗粒捕获技术;(f)荧光纳米技术:红色为纳米棒,黄色为金纳米颗粒,绿色为量子点
Fig. 1 (a) Biogenesis of extracellular vesicles; (b) Circulating tumor cells and their role in tumor metastasis; (c) Surface enhanced Raman; (d) Microfluidic chip; (e) Nanoparticles trapping; (f) Fluorescence nanotechnology: red represents nanorods, yellow are gold nanoparticles, and green are quantum dots.
图2 (a)HER2靶向肽的筛选和(b)通过Pep@MNPs进行CTC分离示意图
Fig. 2 (a)Schematic diagram of HER2-targeted peptide screening and (b)CTC isolation via Pep@MNPs.
图3 基于AgNPR和SPION(a,b)的CTC分析系统及其在CTC捕获、富集、检测和释放方面的应用[61]
Fig. 3 CTC analysis system based on AGNPR and SPION (a, b) and its application in CTC capture, enrichment, detection and release[61]
图4 醛基化乳胶微球辅助流式细胞术分析通过超速离心法从细胞培养上清或人血清中提取的EV[71]
Fig.4 Flow cytometry analysis of EV extracted by hypercentrifugation from cell culture supernatant or human serum using aldehyde latex microbeads[71]
图5 多价适配体网络结构捕获检测MCF-7细胞原理图[85]
Fig. 5 Illustration of multivalent aptamer network for capture and electrochemical detection of CTCs in whole blood[85]
图6 利用二价铜介导的信号扩增方法直接捕获和快速检测EV原理图[99]
Fig. 6 Working principle of the proposed method for extracellular vesicles detection based on a copper(Ⅱ)-mediated signal amplification strategy[99]
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