Distribution and quantification of irinotecan and its active metabolite SN-38 in colon cancer murine model systems using MALDI MSI
Distribution and quantification of irinotecan and its active metabolite SN-38 in colon cancer murine model systems using MALDI MSI
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DOI：
10.1007/s00216-014-8237-2
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发表时间：
2015-03-01
影响因子：
4.3
通讯作者：
Walch, Axel
中科院分区：
文献类型：
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作者：
Buck, Achim;Halbritter, Susanne;Walch, Axel
小分子药物的组织分布和定量分析是评价药物作用机制和疗效的关键。伊立替康（CPT-11）前体药物广泛用于结直肠癌的化疗治疗。CPT-11需要转化为其活性代谢产物SN-38以发挥所需的药理学作用。进行MALDI-傅里叶变换离子回旋共振（FT-ICR）和MALDI-飞行时间（TOF）质谱成像（MSI），以检测CPT-11注射后小鼠组织切片中的CPT-11和SN-38。获得了关于药物化合物在正常和肿瘤组织中的分布和数量的深入信息。肝、肾、消化道中SN-38的检测结果表明，前药被代谢。在来自结肠直肠癌遗传小鼠模型的肿瘤（Apc（1638 N/wt）x pvillin-Kras（V12 G））中，检测到CPT-11，但未检测到活性代谢物。为了将药物分布与血管形成相关联，将MALDI数据与CD 31（PECAM-1）免疫组织化学叠加。该分析表明，CPT-11的肿瘤内进入主要通过微血管外渗发生。本研究利用MALDI MSI在药物分析中的作用，并提出了一种新的方法来监测药物分布与临床前和临床研究中血管功能的关系。
Tissue distribution and quantitative analysis of small molecules is a key to assess the mechanism of drug action and evaluate treatment efficacy. The prodrug irinotecan (CPT-11) is widely used for chemotherapeutic treatment of colorectal cancer. CPT-11 requires conversion into its active metabolite SN-38 to exert the desired pharmacological effect. MALDI-Fourier transform ion cyclotron resonance (FT-ICR) and MALDI-time-of-flight (TOF) mass spectrometry imaging (MSI) were performed for detection of CPT-11 and SN-38 in tissue sections from mice post CPT-11 injection. In-depth information was gained about the distribution and quantity of drug compounds in normal and tumor tissue. The prodrug was metabolized, as proven by the detection of SN-38 in liver, kidney and digestive tract. In tumors from genetic mouse models for colorectal cancer (Apc (1638N/wt) x pvillin-Kras (V12G) ), CPT-11 was detected but not the active metabolite. In order to correlate drug distribution relative to vascularization, MALDI data were superimposed with CD31 (PECAM-1) immunohistochemistry. This analysis indicated that intratumoral access of CPT-11 mainly occurred by extravasation from microvessels. The present study exploits the power of MALDI MSI in drug analysis, and presents a novel approach to monitor drug distribution in relation to vessel functionality in preclinical and clinical research.