摘要
质谱成像(MSI)作为一种无标记的分子成像技术,弥补了传统液质联用等分析技术空间分辨能力的不足,已被广泛应用于小分子代谢物、脂质、多肽及蛋白质的组织分布研究。随着MSI技术灵敏度和空间分辨率的不断提高,该技术在精确定位药物组织分布、可视化药物代谢过程、追踪药物递送等研究领域备受关注,为药物临床前研究提供了新技术和新方法。本文介绍了多种常见MSI技术的基本原理、技术关键参数、技术优势与不足,重点综述了近年来MSI技术在药物有效性及安全性评价、药物组织分布研究、药物递送、中药分析等领域的应用,以期拓展MSI技术在药物研发中的应用,推动药物研发进程。
药物效应的强弱主要取决于药物分子与靶点的结合强度以及机体对药物的处置。药物分子在靶器官/组织的分布浓度和区域与药物效应直接相关。药物研发中通常依据药物在血浆中的浓度评估其在体内的暴露程度。然而,受药物转运蛋白以及生理性屏障(如血脑屏障)等因素的影响,组织中药物浓度存在不同于血药浓度的情况。此外,药物在组织中的分布受血流量大小、药物溶解性、体液pH以及膜通透性等因素的影响,呈现区域特异性分布,仅依据药物在血浆中的浓度无法全面评估药效强弱以及药物在机体暴露所引发的潜在风险。因此,阐明药物在组织中的分布对于评价药物效应、监测药物安全性、优化给药策略以及指导制剂设计等方面具有重要意义。
分子成像技术能够将机体内复杂的生理过程转化为直观的图像,从分子水平上阐明疾病的发生机制以及药物的治疗机制,广泛应用于药物筛选和疗效评估。常用的分子成像技术包括荧光成像、红外成像和拉曼成像等,具有高灵敏度、高分辨率、实时性和非侵入性等优点。荧光成像是一种利用荧光探针标记目标分子并观察其发出的荧光信号的技术,具有较高的灵敏度和空间分辨率,并可以选择不同发射波长的荧光探针实现多通道多色成像。然而,荧光成像技术也存在自发荧光、荧光淬灭、光致漂白和组织渗透深度偏小等问题,且由于荧光标签的尺寸较大,因此该技术主要用于蛋白质、核酸等生物大分子的成
质谱成像(MSI)是一种基于质谱分析技术的分子成像方法,具有直观、高灵敏度与高分子特异性等优势,能够在较高空间分辨率下对组织切片或特定组织微观结构中的内、外源性分子如小分子代谢物、蛋白质、多肽、脂质、药物及其代谢物等进行无标记成像,是研究药物分子和内源性生物分子时空异质性的有力工
MSI采用多种原位离子化技术使样本表面的化合物离子化,传输入质谱中获得离子的质荷比(m/z)和离子强度,并利用质谱成像软件将含有空间位置信息的质谱数据集合转换为离子分布图像,从而可视化待测物的空间分布特征。依据离子化技术的不同,目前常见的3种MSI技术分别是:次级离子质谱成像技术(SIMS-MSI)、基质辅助激光解吸质谱成像技术(MALDI-MSI)以及解吸电喷雾电离质谱成像技术(DESI-MSI)。
SIMS-MSI技术利用聚焦的一次离子束轰击样品表面,溅射产生正、负二次离子。初级离子束能量较高,脂质、多肽、蛋白质等生物大分子容易碎裂,故通常用于元素分
MALDI-MSI技术利用能够吸收特定波长激光的基质与样本表面的分子形成共结晶,通过激光照射实现对待测物的原位解吸和离子化,具有质量范围宽、灵敏度高、空间分辨率高(5 ~ 50 μm)以及抗杂质干扰能力强等特
DESI技术将气动辅助电喷雾形成的带电液滴束喷射到样本表面,液滴中的溶剂立即与样本表面的待测物发生萃取、溶解过程,液滴从表面反弹后形成更加细小的次级液滴,伴随溶剂快速蒸发,电荷转移至待测物分子中,实现样本表面分子的解吸与离子化。DESI-MSI是敞开式质谱成像技术,操作简便,样品处理过程简单,常用于低相对分子质量范围内的小分子检测(m/z < 1 000),但该技术空间分辨率较低(约100 μm)。此外,萃取电喷雾电离技术(EESI)、电喷雾辅助激光解吸电离技术(ELDI)、低温等离子体技术(LTP)、空气动力辅助解吸电喷雾离子化技术(AFADESI)以及解吸电喷雾电离/二次光电离技术(DESI-PI)等常压敞开式离子化技术相继问世,拓展了敞开式质谱(ambient MS)技术的应用范
不同的MSI技术在灵敏度、分子特异性和空间分辨率等方面具有各自的优势。因此,研究人员应根据实际需求,参考不同技术的特点,选择最适合的MSI策略。例如,SIMS-MSI技术在空间分辨率方面具有明显优势,但检测生物大分子的能力较弱。DESI-MSI等敞开离子化技术适用于小分子分析,操作简便,但空间分辨率较低。MALDI-MSI技术适用于分析多种生物分子,但存在基质峰干扰等问
提升空间分辨率至单细胞/亚细胞水平是MSI技术的发展方向之一。然而,空间分辨率越高,采样面积越小,导致检测灵敏度显著降低。MALDI-MSI激光光斑大小一般设置为100 µm,相比从整个组织匀浆中提取富集待测物,从组织切片表面原位检测待测物的难度更高,如果采用更高的空间分辨率,可能导致组织药物浓度低于检测
MSI技术不涉及复杂的样品前处理和色谱分离过程,化合物鉴定的准确性高度依赖质谱的质量分辨率和质量精度。因此,将MSI离子源与高分辨质量分析器相串联是提高原位分子鉴定可靠性、准确性的重要保障。SIMS/DESI/MALDI-MSI串联高分辨质谱如Orbitrap、傅里叶变换离子回旋共振质谱(FTICR),实现了对组织中整数质量相同,而结构不同的同重分子的分辨。此外,将MSI与离子迁移质谱(IMS)串联,赋予了MSI技术对同分异构体的分辨能力,但IMS分辨率有待进一步提高。Unsihuay
MSI技术可以定量分析组织切片中的药物浓度,为药代动力学、药效及药物安全性评价等研究提供重要参考。MSI定量策略主要包括标准曲线法,将一系列不同浓度的标准品溶液滴加在空白对照组织切片或组织匀浆切片的不同位置上,干燥后测定各个浓度标准品点所在区域的峰强度,归一化后绘制峰强度与标品浓度的标准曲线,定量分析组织切片中待测物的含
MSI技术的发展实现了对多种分子的可视化分析,在药物有效性及安全性评价、药物组织分布研究、药物递送及中药分析等研究中发挥了重要作用,为药物研发提供关键参考信息(

Figure 1 Mass spectrometry imaging and its application in pharmaceutical research
利用MSI技术分析药物及候选药物在组织中的分布情况,可以为药物效应评价提供重要参考依据。Torok
药物的肝、肾毒性与药物的理化性质、体内ADME特性以及个体遗传背景等多方面因素密切相关,是药物安全性评价研究中的重要组成部分。对乙酰氨基酚(APAP)是一种常见的易引起肝损伤的药物。当APAP服用过量,体内的还原型谷胱甘肽(GSH)不足以中和过量的毒性代谢产物N-乙酰苯醌亚胺(NAPQI)时,蓄积的NAPQI将导致急性药物性肝损
药代动力学通常基于动力学模型定量研究血药浓度的变化,进而探究药物的吸收、分布、代谢以及排泄(ADME)过程。然而,血药浓度在某些情况下无法准确地反映药物在靶组织中的暴露情
药物递送研究的目的是将药物更好地递送至病灶部位,增加药物在靶部位的累积,改善药物ADME,提高治疗效果,降低不良反应。在抗肿瘤药物递送研究中,纳米药物可以通过高渗透长滞留效应(EPR)增加药物在肿瘤组织中的累积从而提高疗
MSI技术被广泛用于中药研究,包括药用植物空间代谢、中药质量评价、中药活性成分体内过程等研
MSI技术在中药活性成分体内过程分析中也得到应用。Meng
MSI作为一种免标记、高特异性、高灵敏度的可视化技术,已经成为药物研究的重要分析技术手段之一。MSI所提供的崭新的空间化学信息将在药动学-药效学、细胞药代动力学、药物递送,以及类器官、3D细胞模型等药物体内、体外评价研究中发挥重要作用。近10年,MSI技术在检测灵敏度、定量能力、分析通量、数据分析速度等方面都得到了极大提升。随着未来进一步的发展和完善,MSI技术必将在药物研究中展现更多的可能性和更广阔的应用前景。
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