Novel Approach of MALDI Drug Imaging, Immunohistochemistry, and Digital Image Analysis for Drug Distribution Studies in Tissues
Novel Approach of MALDI Drug Imaging, Immunohistochemistry, and Digital Image Analysis for Drug Distribution Studies in Tissues
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DOI：
10.1021/ac502177y
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发表时间：
2014-11-04
影响因子：
7.4
通讯作者：
Walch, Axel
中科院分区：
文献类型：
--
作者：
Huber, Katharina;Feuchtinger, Annette;Walch, Axel
药物疗效强烈依赖于靶部位药物的存在。由于血管化是药物在组织中分布的重要因素，我们分析了药物在肿瘤组织中的血管定位功能。为了探索抗癌药物阿法替尼、厄洛替尼和索拉非尼的分布，应用了基质辅助激光解吸/电离（MALDI）药物成像和免疫组织化学血管染色的联合方法，并通过数字图像分析进行了检查。研究了以下两种异种移植物模型：（1）携带鳞状细胞癌（FaDu）异种移植物的小鼠（（n）肿瘤= 13）接受阿法替尼或厄洛替尼治疗，（2）携带肉瘤（A673）异种移植物的小鼠（（n）肿瘤= 8）接受索拉非尼治疗。MALDI药物成像显示所有抗癌药物的分布不均匀。与无药物信号的区域相比，含有高药物水平的肿瘤区域与更高程度的血管化相关（p < 0.05）。当在肉瘤模型中将血管大小的影响与药物丰度相关联时，与具有低药物水平的肿瘤区域相比，在具有高药物水平的肿瘤区域中检测到更高量的小血管（p < 0.05）。通过数字图像分析，对共配准的MALDI成像和CD 31免疫组化数据进行分析，我们首次证明了MALDI药物成像和免疫组化相关性的潜力。本文介绍了一种在微观水平上将药物的组织学特征与药代动力学特性联系起来的具体而精确的方法，这将为药物设计、给药配方或治疗方案的改进提供信息。
Drug efficacy strongly depends on the presence of the drug substance at the target site. As vascularization is an important factor for the distribution of drugs in tissues, we analyzed drug distribution as a function of blood vessel localization in tumor tissue. To explore distribution of the anticancer drugs afatinib, erlotinib, and sorafenib, a combined approach of matrix-assisted laser desorption/ionization (MALDI) drug imaging and immunohistochemical vessel staining was applied and examined by digital image analysis. The following two xenograft models were investigated: (1) mice carrying squamous cell carcinoma (FaDu) xenografts ((n)tumor = 13) were treated with afatinib or erlotinib, and (2) sarcoma (A673) xenograft bearing mice ((n)tumor = 8) received sorafenib treatment. MALDI drug imaging revealed a heterogeneous distribution of all anticancer drugs. The tumor regions containing high drug levels were associated with a higher degree of vascularization than the regions without drug signals (p < 0.05). When correlating the impact of blood vessel size to drug abundance in the sarcoma model, a higher amount of small vessels was detected in the tumor regions with high drug levels compared to the tumor regions with low drug levels (p < 0.05). With the analysis of coregistered MALDI imaging and CD31 immunohistochemical data by digital image analysis, we demonstrate for the first time the potential of correlating MALDI drug imaging and immunohistochemistry. Here we describe a specific and precise approach for correlating histological features and pharmacokinetic properties of drugs at microscopic level, which will provide information for the improvement of drug design, administration formula or treatment schemes.