质谱成像新基质及其在分析生物样本方面的研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2022-0158

摘要/Abstract

摘要：

作为一门新兴的分子成像技术，质谱成像（mass spectrometry imaging，MSI）不仅能保留生物组织的空间结构信息，还能够在原位无标记地检测组织中的生物分子，包括蛋白质、多肽、氨基酸、脂类、药物及其代谢产物等物质的表达水平，实现对生物样本的原位检测。随着电离技术、基质材料、分析仪器和软件的不断开发与优化，MSI技术在近年来被越来越多地应用到生物学、医学、药物研究等诸多领域。本综述总结了近几年基质辅助激光解吸电离（matrix-assisted laser desorption ionization，MALDI）质谱成像技术在应用到生物样本时开发出的各类新型基质，并对以往涌现的新型MSI技术的最新应用和进展，以及出现的数据处理新方法进行了综述。最后，展望了MSI技术的发展方向——单细胞水平化、绝对定量化、仪器便携化。

关键词: 质谱成像, MALDI, 基质, 离子化, 二次离子质谱技术, 解吸电喷雾电离技术, 定量MSI

Abstract:

As a new molecular imaging technology，mass spectrometry imaging（MSI）can not only retain the spatial structure information of biological tissues，but also detect the expressions of biomolecules in tissues without labeling in situ，including proteins，peptides，amino acids，lipids，drugs and their metabolites，thus in situ detection of biological samples can be achieved. With the continuous development and optimization of ionization technology，matrix materials，analytical instruments and software，MSI technology has been increasingly applied to biological research，medical research，drug research and many other fields in recent years. In this review，a variety of novel matrixes developed by matrix-assisted laser desorption（MALDI）imaging technology for biological samples are summarized. The latest application and progress of new MSI technology and new data processing methods are summarized. Finally，the development direction of MSI technology，single cell horizontal，absolute quantification，and portable instrument，is prospected.

Key words: mass spectrometry imaging, MALDI, matrix, ionization, secondary ion mass spectroscopy, desorption electrospray ionization, quantitative MSI

苗玉娇, 朱龙佼, 许文涛. 质谱成像新基质及其在分析生物样本方面的研究进展[J]. 生物技术通报, 2022, 38(12): 156-167.

MIAO Yu-jiao, ZHU Long-jiao, XU Wen-tao. Novel Matrixes for Mass Spectrometry Imaging and Research Progress of It in Analyzing Biological Samples[J]. Biotechnology Bulletin, 2022, 38(12): 156-167.

图/表 3

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	基质名称 Name of matrix	目标分析物类别 Target analyte class	离子模式 Ion mode	特点Characteristic	沉积方法 Deposition method	参考文献 Reference
有机小分子新型基质 Novel organic small molecule matrix	N-苯基-2-萘胺（PNA） N-Phenyl-2-naphthylamine	脂质、氨基酸、抗氧化剂、	/	强紫外线吸收、低基质背景信号、强耐盐能力	喷涂 Spray	[7]
	N-（1-萘基）乙二胺二盐酸盐（NEDC）N-（1-Naphthyl）ethylenediamine dihydrochloride	葡萄糖、Na⁺、K⁺、氨基酸、核苷酸、抗氧化剂、甘油磷脂	/	强耐盐能力，基质背景信号低，提高了对分析物类别的灵敏度	喷涂 Spray	[8-9]
	3-氨基邻苯二甲酰肼（3-APH） 3-Aminophthalhydrazide	核苷酸、脂质	+，-	双极性、高灵敏度、分子覆盖范围广、低基质背景信号、真空稳定性好	喷涂 Spray	[10]
	IR-780	高分子量脂质	/	强紫外吸收、强光热能力、强耐盐能力、共结晶均匀、低背景信号、高真空稳定性	喷涂 Spray	[11]
	1,6-二苯基-1,3,5-己三烯（DPH）1,6-Diphenyl-1,3,5-hexatriene	脂肪酸、多烯结构的脂类	/	高真空稳定性、高空间分辨率	升华 Sublimation	[12]
	1,1'-联萘-2,2'-二胺（BNDM） 1,1'-Binaphthyl-2,2'-diamine	氨基酸、有机酸、核苷、核苷酸、含氮碱基、胆固醇、多肽、脂肪酸、胆碱、肉碱、多胺、肌酸、磷脂等	+，-	双极性、低基质背景信号、高灵敏度、广泛的分子覆盖范围	喷涂 Spray	[13-14]
	2,3-二氰基氢醌（DCH） 2,3-Dicyanohydroquinone	脂质	+	高真空稳定性、高空间分辨率、高化学稳定性、高灵敏度	喷涂 Spray	[15]
	DCTB（2-[（2E）-3-（4-tert-butylphenyl）-2-methylprop-2-enylidene]malononitrile）	中枢神经系统药物	+	高灵敏度，低信号抑制	喷涂 Spray	[16]
	3,4-二甲氧基肉桂酸（DMCA） 3,4-Dimethoxycinnamic acid	小分子	+	低基质背景信号、高灵敏度、分子覆盖范围广	喷涂 Spray	[17]
	1,5-二氨基萘（DAN） 1,5-Diaminonaphthalene	脂质、酚类物质如原花色素及其单体等小分子	-	低激光能量、最小化发射次数、数据采集速度快、基质沉积均匀、在细胞水平保存特定组织学信息	升华 Sublimation	[18-19]
	2-氰基-3-（2-噻吩基）丙烯酸（CTA）2-Cyano-3-（2-thienyl）acrylic acid	脂质、蛋白质、多肽、正离子模式下的糖类、天然产物（即环烯醚萜）、聚乙二醇、有机金属	+，-	高信噪比和分辨率、可以用作分析大多数类别分析物的通用基质、提供组织表面的完整轮廓	升华 Sublimation	[20]
	咖啡酸（CA）Caffeic acid	高分子量蛋白质	/	强紫外线吸收、接近20 kDa的超宽检测范围、高电离效率	升华 Sublimation	[21]
无机纳米材料新型基质 Novel inorganic nano material matrix	金纳米粒子（AuNPs） Gold nanoparticles	神经递质（单胺类或乙酰胆碱类物质）、氯虫苯甲酰胺、嘧菌酯	/	高电离效率、增强了丰度低小分子类物质的成像信号、高空间分辨率，横向分辨率达到 5 μm（单细胞水平）	喷涂 Spray	[22-23]
	银纳米粒子（AgNPs） Silver nanoparticles	脂质如脂肪酸、甘油磷脂、鞘脂、甾醇以及一些小代谢物分子	﹢	通过银的选择性阳离子化来提高含有 π 键的分析物的电离效率	喷涂 Spray	[24]
	氧化石墨烯（GO） Graphene oxide	脂质等小分子、黄芩苷-灯盏花乙素	﹢，-	高电离效率、增强丰度低小分子类物质的成像信号、低基质背景信号	喷涂 Spray	[25]
	氧化锌纳米粒子（ZnO NPs） Zinc oxide nanoparticles	低分子量分子	﹢	在酸性pH值中溶解，定期酸洗可有效减少喷雾器喷嘴堵塞、结果高重现性	喷涂 Spray	[26]
	改性二氧化钛纳米线（TiO₂） Modified titanium dioxide nanowire	低分子量代谢物（长春花生物碱）	﹢	高选择性、高检测限、修改程序简单且具有成本效益、适用于复杂的天然生物样品	/	[27]
	硅纳米柱阵列（NAPA） Silicon nanopost array	中性脂质如甘油三酯、胆固醇酯、己糖神经酰胺和一些小代谢物；聚羟基丁酸、聚谷氨酸和多糖寡聚物	+，-	允许分离异构体、信号强度增加、均匀性好、和传统基质MALDI-MSI 平台之间实现脂质覆盖的互补性	/	[28-31]
	层状双氢氧化物（LDH） Layered double hydroxide	低分子量酚类物质	-	高稳定性、氢键促进分析物电离、优先检测以羟基为主的分析物	喷涂 Spray	[32]

	基质名称 Name of matrix	目标分析物类别 Target analyte class	离子模式 Ion mode	特点Characteristic	沉积方法 Deposition method	参考文献 Reference
有机小分子新型基质 Novel organic small molecule matrix	N-苯基-2-萘胺（PNA） N-Phenyl-2-naphthylamine	脂质、氨基酸、抗氧化剂、	/	强紫外线吸收、低基质背景信号、强耐盐能力	喷涂 Spray	[7]
	N-（1-萘基）乙二胺二盐酸盐（NEDC）N-（1-Naphthyl）ethylenediamine dihydrochloride	葡萄糖、Na⁺、K⁺、氨基酸、核苷酸、抗氧化剂、甘油磷脂	/	强耐盐能力，基质背景信号低，提高了对分析物类别的灵敏度	喷涂 Spray	[8-9]
	3-氨基邻苯二甲酰肼（3-APH） 3-Aminophthalhydrazide	核苷酸、脂质	+，-	双极性、高灵敏度、分子覆盖范围广、低基质背景信号、真空稳定性好	喷涂 Spray	[10]
	IR-780	高分子量脂质	/	强紫外吸收、强光热能力、强耐盐能力、共结晶均匀、低背景信号、高真空稳定性	喷涂 Spray	[11]
	1,6-二苯基-1,3,5-己三烯（DPH）1,6-Diphenyl-1,3,5-hexatriene	脂肪酸、多烯结构的脂类	/	高真空稳定性、高空间分辨率	升华 Sublimation	[12]
	1,1'-联萘-2,2'-二胺（BNDM） 1,1'-Binaphthyl-2,2'-diamine	氨基酸、有机酸、核苷、核苷酸、含氮碱基、胆固醇、多肽、脂肪酸、胆碱、肉碱、多胺、肌酸、磷脂等	+，-	双极性、低基质背景信号、高灵敏度、广泛的分子覆盖范围	喷涂 Spray	[13-14]
	2,3-二氰基氢醌（DCH） 2,3-Dicyanohydroquinone	脂质	+	高真空稳定性、高空间分辨率、高化学稳定性、高灵敏度	喷涂 Spray	[15]
	DCTB（2-[（2E）-3-（4-tert-butylphenyl）-2-methylprop-2-enylidene]malononitrile）	中枢神经系统药物	+	高灵敏度，低信号抑制	喷涂 Spray	[16]
	3,4-二甲氧基肉桂酸（DMCA） 3,4-Dimethoxycinnamic acid	小分子	+	低基质背景信号、高灵敏度、分子覆盖范围广	喷涂 Spray	[17]
	1,5-二氨基萘（DAN） 1,5-Diaminonaphthalene	脂质、酚类物质如原花色素及其单体等小分子	-	低激光能量、最小化发射次数、数据采集速度快、基质沉积均匀、在细胞水平保存特定组织学信息	升华 Sublimation	[18-19]
	2-氰基-3-（2-噻吩基）丙烯酸（CTA）2-Cyano-3-（2-thienyl）acrylic acid	脂质、蛋白质、多肽、正离子模式下的糖类、天然产物（即环烯醚萜）、聚乙二醇、有机金属	+，-	高信噪比和分辨率、可以用作分析大多数类别分析物的通用基质、提供组织表面的完整轮廓	升华 Sublimation	[20]
	咖啡酸（CA）Caffeic acid	高分子量蛋白质	/	强紫外线吸收、接近20 kDa的超宽检测范围、高电离效率	升华 Sublimation	[21]
无机纳米材料新型基质 Novel inorganic nano material matrix	金纳米粒子（AuNPs） Gold nanoparticles	神经递质（单胺类或乙酰胆碱类物质）、氯虫苯甲酰胺、嘧菌酯	/	高电离效率、增强了丰度低小分子类物质的成像信号、高空间分辨率，横向分辨率达到 5 μm（单细胞水平）	喷涂 Spray	[22-23]
	银纳米粒子（AgNPs） Silver nanoparticles	脂质如脂肪酸、甘油磷脂、鞘脂、甾醇以及一些小代谢物分子	﹢	通过银的选择性阳离子化来提高含有 π 键的分析物的电离效率	喷涂 Spray	[24]
	氧化石墨烯（GO） Graphene oxide	脂质等小分子、黄芩苷-灯盏花乙素	﹢，-	高电离效率、增强丰度低小分子类物质的成像信号、低基质背景信号	喷涂 Spray	[25]
	氧化锌纳米粒子（ZnO NPs） Zinc oxide nanoparticles	低分子量分子	﹢	在酸性pH值中溶解，定期酸洗可有效减少喷雾器喷嘴堵塞、结果高重现性	喷涂 Spray	[26]
	改性二氧化钛纳米线（TiO₂） Modified titanium dioxide nanowire	低分子量代谢物（长春花生物碱）	﹢	高选择性、高检测限、修改程序简单且具有成本效益、适用于复杂的天然生物样品	/	[27]
	硅纳米柱阵列（NAPA） Silicon nanopost array	中性脂质如甘油三酯、胆固醇酯、己糖神经酰胺和一些小代谢物；聚羟基丁酸、聚谷氨酸和多糖寡聚物	+，-	允许分离异构体、信号强度增加、均匀性好、和传统基质MALDI-MSI 平台之间实现脂质覆盖的互补性	/	[28-31]
	层状双氢氧化物（LDH） Layered double hydroxide	低分子量酚类物质	-	高稳定性、氢键促进分析物电离、优先检测以羟基为主的分析物	喷涂 Spray	[32]

离子源 Ion source	基质辅助激光解吸电离质谱成像 MALDI MSI	二次离子质谱成像 SIMS MSI	解吸电喷雾电离质谱成像 DESI MSI
电离类型Ionization type	软	硬	软
是否需要基质Need matrix or not	是	否	否
可检测物质类型 The type of substance that can be detected	小分子代谢物和药物、生物大分子如多肽、蛋白质、核酸、聚糖等	元素、小分子代谢物和药物、脂类	小分子代谢物和药物、脂类、多肽
质量范围Mass range/Da	300-100 000	<2 000	100-2 000
空间分辨率Spatial resolution/μm	5-100	0.1-1	40-200
扫描深度Depth of the scanning/μm	0.1-20	0.5-10	1-50

离子源 Ion source	基质辅助激光解吸电离质谱成像 MALDI MSI	二次离子质谱成像 SIMS MSI	解吸电喷雾电离质谱成像 DESI MSI
电离类型Ionization type	软	硬	软
是否需要基质Need matrix or not	是	否	否
可检测物质类型 The type of substance that can be detected	小分子代谢物和药物、生物大分子如多肽、蛋白质、核酸、聚糖等	元素、小分子代谢物和药物、脂类	小分子代谢物和药物、脂类、多肽
质量范围Mass range/Da	300-100 000	<2 000	100-2 000
空间分辨率Spatial resolution/μm	5-100	0.1-1	40-200
扫描深度Depth of the scanning/μm	0.1-20	0.5-10	1-50