肿瘤病理可视化纳米探针的研究进展※

doi:10.6023/A21120609

化学学报 ›› 2022, Vol. 80 ›› Issue (6): 805-816.DOI: 10.6023/A21120609 上一篇下一篇

所属专题：中国科学院青年创新促进会合辑

综述

肿瘤病理可视化纳米探针的研究进展^※

张沛森^*(), 荆莉红^*()

中国科学院化学研究所胶体、界面与化学热力学院重点实验室北京 100190

投稿日期:2021-12-31 发布日期:2022-07-07
通讯作者: 张沛森, 荆莉红

作者简介:

张沛森, 北京化工大学研究助理, 于2020年在中科院化学研究所获得博士学位. 主要从事纳米生物材料在恶性肿瘤及心脑血管等重大疾病的分子影像学诊断及联合治疗. 主持国家自然科学基金青年项目1项. 以第一/通讯作者在Angew. Chem. Int. Ed., Adv. Mater., Nano Today, Small, Adv. Health. Mater., J. Mater. Chem. B等国际期刊发表SCI论文14篇, 累计发表SCI论文20多篇. 2019年荣获博士研究生国家奖学金, 中科院化学所青年科学奖特别优秀奖.

荆莉红, 博士, 中国科学院青年创新促进会会员, 2011年于中国科学院化学研究所获得理学博士学位, 同年留所工作至今, 期间先后前往香港城市大学及美国麻省理工学院开展研究工作. 主要研究方向包括: (1)量子点光电功能纳米材料的设计合成及性质; (2)肿瘤等恶性生物学事件相关纳米影像探针的构建; (3)重大传染病相关医疗大数据管理及高通量生物信息分析. 截止目前, 主持国家级项目4项、省部级项目3项, 在Sci. Transl. Med., J. Am. Chem. Soc., Adv. Mater., ACS Nano, Nano Today, Chem. Rev., Biomaterials等重要刊物上发表学术论文50多篇.

^※ 庆祝中国科学院青年创新促进会十年华诞.

基金资助:
中国科学院青年创新促进会(2018042); 国家重点研发计划项目(2018YFA0208800); 国家自然科学基金(22177115); 国家自然科学基金(81720108024); 国家自然科学基金(82102679)

Nanoprobes for Visualization of Cancer Pathology in Vivo^※

Peisen Zhang(), Lihong Jing()

Department Key Laboratory of Colloid Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190

Received:2021-12-31 Published:2022-07-07
Contact: Peisen Zhang, Lihong Jing
About author:
^※ Dedicated to the 10th anniversary of the Youth Innovation Promotion Association, CAS.
Supported by:
Youth Innovation Promotion Association CAS(2018042); National Key Research and Development Program of China(2018YFA0208800); National Natural Science Foundation of China(22177115); National Natural Science Foundation of China(81720108024); National Natural Science Foundation of China(82102679)

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摘要/Abstract

癌症的发生和发展伴随着一系列复杂的分子病理学变化, 具有极大的个体差异性. 因此, 实现肿瘤的精准诊断, 尤其是分子病理学的诊断尤为重要. 在临床检测中, 传统影像学检查可以反映肿瘤的位置和解剖学结构, 却难以对其分子病理做出判定; 而病理活检虽然可以获取肿瘤的分子学特征, 但需通过创伤性手段获取样本, 且具有时空局限性. 相比之下, 借助于特异性探针成像的肿瘤分子影像学, 直接以肿瘤病理分子标志物作为成像对比度的来源, 旨在从分子层面对肿瘤进展中的病理学特征进行在体定量化分析, 在肿瘤的精准诊断中具备独特的优势. 近年来, 纳米材料由于优越的理化性质, 已经成为构建高灵敏肿瘤分子影像探针的重要信号载体之一. 基于此, 本综述从基本的纳米靶向探针, 到光、磁学智能响应型纳米探针, 系统总结归纳了基于纳米材料的分子影像技术对肿瘤病理在体可视化的研究进展, 并对未来临床环境中实施该纳米探针技术进行了展望.

关键词: 病理, 肿瘤, 纳米探针, 分子影像, 可视化检测

Cancer progression is often accompanied by a series of complicated variations of molecular pathology, varying enormously between individuals. Therefore, it is necessary to achieve precise diagnosis of tumor, especially at the molecular pathology level. In clinical trials, the traditional medical imaging can identify the position and the anatomical structure of tumors, but it is difficult to reveal their molecular pathology. Although the molecular details of tumors can be obtained later through the pathological analysis of biopsies, this approach is invasive and has spatiotemporal limitations. Unlike these strategies, the pathological biomarkers of tumors can be directly imaged in vivo through the probe-based molecular imaging technology, which aims to quantitatively study the real-time tumorous pathological features at a molecular level. This technology holds huge potentials in the clinical application of precise tumor diagnosis. In recent years, nanomaterials that possess superior optical or magnetic physicochemical properties have become one of the important signal carriers for constructing highly sensitive molecular imaging probes. In this review, the development of nanoprobe-based molecular imaging and the in vivo visualization of tumor molecular pathology are summarized. Specifically, the construction of the pathology responsive nanoprobes is highlighted. The current challenges and perspectives on the future steps needed to implement this nanotechnology in a clinical setting are also discussed.

Key words: pathology, tumor, nanoprobe, molecular imaging, visualization

引用此文

张沛森, 荆莉红. 肿瘤病理可视化纳米探针的研究进展^※[J]. 化学学报, 2022, 80(6): 805-816.

Peisen Zhang, Lihong Jing. Nanoprobes for Visualization of Cancer Pathology in Vivo^※[J]. Acta Chimica Sinica, 2022, 80(6): 805-816.

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图/表 5

图1. (a)叶酸受体靶向NaErF4@NaYbF4@NaYF4光学纳米探针结构示意图; (b)注射探针不同时间点记录的腹腔转移瘤的上转换(上)及下转换(下)光学成像(图中标尺对应长度为3 mm); (c)肿瘤相邻切片的H&E染色, 波形蛋白、叶酸受体免疫组化染色显微图片(图中标尺对应长度为500 μm). 上/下转换发光的肿瘤成像分辨率可以通过体内肿瘤区域的线谱进行比较(右)[39]

Figure 1. (a) Schematic illustration of the folate receptor (FR)-targeting NaErF4@NaYbF4@NaYF4 nanoprobe; (b) up-conversion (top) and down-conversion (bottom) luminescence images of intraperitoneal tumors in vivo recorded at different time points post-injection of nanoprobe, together with microscopic images of adjacent slices of intraperitoneal tumor extracted (c) upon H&E staining or immunohistochemical staining through anti-vimentin antibody and anti-FR, respectively. The resolution of up-/down-conversion luminescence imaging can be compared through the line spectra drown across the tumorous regions in vivo (right). The scale bars in frame (b) and (c) correspond to 3 mm and 500 µm, respectively[39]

图2. (a)通过氢键连接模拟Ir-BTPHSA与β-环糊精最可能的空间位置关系示意图; (b) Ir-BTPHSA/CD-NH2的二维ROESY谱图; (c) Ir-BTPHSA/CD-Cy7在不同氧分压下的Ir-BTPHSA和Cy7的发射光谱(插图: Ir-BTPHSA和Cy7在不同氧分压下发射峰的强度); (d) I0'/I'的比值与氧气浓度的线性关系(I0'和I'分别是在氧气浓度为0%和特定氧气浓度下Ir-BTPHSA与Cy7的发射强度比)(插图: Ir-BTPHSA与Cy7在不同氧气浓度下的发射强度比); (e)探针通过瘤内及皮下对应部位注射后氧分压分布定量成像[56]

Figure 2. (a) The most possible binding situation between Ir-BTPHSA and β-CD by connection with hydrogen bond; (b) the ROESY spectra of Ir-BTPHSA/CD-NH2; (c) luminescence spectra of Ir-BTPHSA/CD-Cy7 recorded under various oxygen levels upon excitation at 488 nm and 747 nm for Ir-BTPHSA complex and Cy7, respectively (inset: PL intensities of Ir-BTPHSA and Cy7 against oxygen levels); (d) liner fitting of I0'/I' against the oxygen level (I0' and I' refer to PL intensities of Ir-BTPHSA recorded at 0% oxygen and specific oxygen levels, respectively, after normalized with reference PL intensity of Cy7) (inset: normalized PL intensity of Ir-BTPHSA against the oxygen level); (e) quantitative oxygen level mapping of the tumor and its control site[56]

图3. (a)“on-on”型双比率计量纳米荧光探针示意图; (b)分别在肿瘤发展中的D+0、D+2和D+4天得到的pH值与MMP-9酶活性的定量图片(伪彩的黑色到黄色标尺显示的MMP-9表达量在4.3~6.8 ng/mL, 每一个小格代表0.25个浓度单位)以及对应荷瘤小鼠持续观察4天的照片; (c) H&E染色的组织切片照片以及两个相邻切片对E-钙粘蛋白(红色)和MMP-9(绿色)表达量的免疫荧光染色叠加照片. 图中标尺长度为200 μm. 橘色箭头指示了正常组织与肿瘤组织的边界(MMP-9高表达区域)[58]

Figure 3. (a) Schematic illustration of the dual-ratiometric fluorescent nanoprobe; (b) quantified pH and MMP-9 expression mapping of tumors obtained at D+0, D+2, and D+4 (in color bar shading from black to yellow for reading MMP-9 expression ranging from of 4.3 to 6.8 ng/mL, each step thus corresponds to 0.25 units), together with the photographs of tumor-bearing mice for 5 d; (c) microscopic image of a tissue slide stained with H&E and merged immunofluorescence microscopic image of two adjacent slides stained for E-cadherin expression (red) and MMP-9 expression (green), respectively (scale bar corresponds to 200 μm). The orange arrows indicate the boundaries between healthy tissue and the tumor where MMP-9 is highly expressed[58]

图4. (a)可激活磁共振探针UCNP@GA-Fe(III)对肿瘤MRI成像及多途径联合治疗示意图; (b)静脉注射探针前后不同时间点荷瘤小鼠的T1加权像; (c)基于上转换发光I475/I800比例成像的Fe3+释放分布图谱; (d)通过上述光学通道所显示肿瘤部位Fe3+释放的综合信号强度随时间变化规律[70]

Figure 4. (a) Illustration to demonstrate the activatable function of UCNP@GA-Fe(III) probe for MRI and its therapeutic function involving multiple pathways; (b) T1-weighted MR images of tumor-bearing mice acquired at different time points pre- and post-injection of nanoprobe; (c) mapping of Fe3+ release based on I475/I800 ratio of upconversion luminescence; (d) the ratio of the integrated signal intensities through above channels for showing Fe3+ release at tumor site against time[70]

图5. (a) GSH诱导响应型磁共振探针聚集的分子机制示意图; 静脉注射探针前后不同时间点原位脑胶质瘤荷瘤小鼠的颅脑T1 (b)及T2 (c)加权像; (d)相邻肿瘤切片谷胱甘肽还原酶(GR)和Ki 67染色; (e)根据ΔR2/ΔR1与GSH浓度之间的拟合关系, 使用注射探针后7 h的磁共振成像结果实现的瘤内GSH定量成像[78]

Figure 5. (a) Schematic drawings to show molecular mechanism of the GSH-induced agglomeration of the responsive nanoprobes; (b) T1-weighted and (c) T2-weighted MR images of mice bearing orthotopic glioblastoma xenografts acquired before and at different time points after the intravenous injections of nanoprobes; (d) glutathione reductase (GR) and Ki 67 staining of adjacent tumor tissue slices; (e) quantitative mapping of GSH according to imaging data acquired at 7 h post-injection through the correlation between ΔR2/ΔR1 and GSH concentration in vivo[78]

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肿瘤病理可视化纳米探针的研究进展^※

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肿瘤病理可视化纳米探针的研究进展※

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肿瘤病理可视化纳米探针的研究进展^※

Nanoprobes for Visualization of Cancer Pathology in Vivo^※