Institute of Inorganic and Analytical Chemistry, Justus Liebig University Giessen, 35392, Giessen, Germany.
Institute of Parasitology, BFS, Justus Liebig University Giessen, 35392, Giessen, Germany.
Anal Bioanal Chem. 2021 Apr;413(10):2755-2766. doi: 10.1007/s00216-021-03230-w. Epub 2021 Mar 15.
Schistosoma mansoni is a parasitic flatworm causing schistosomiasis, an infectious disease affecting several hundred million people worldwide. Schistosomes live dioeciously, and upon pairing with the male, the female starts massive egg production, which causes pathology. Praziquantel (PZQ) is the only drug used, but it has an inherent risk of resistance development. Therefore, alternatives are needed. In the context of drug repurposing, the cancer drug imatinib was tested, showing high efficacy against S. mansoni in vitro. Besides the gonads, imatinib mainly affected the integrity of the intestine in males and females. In this study, we investigated the potential uptake and distribution of imatinib in adult schistosomes including its distribution kinetics. To this end, we applied for the first time atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) for drug imaging in paired S. mansoni. Our results indicate that imatinib was present in the esophagus and intestine of the male as early as 20 min after in vitro exposure, suggesting an oral uptake route. After one hour, the drug was also found inside the paired female. The detection of the main metabolite, N-desmethyl imatinib, indicated metabolization of the drug. Additionally, a marker signal for the female ovary was successfully applied to facilitate further conclusions regarding organ tropism of imatinib. Our results demonstrate that AP-SMALDI MSI is a useful method to study the uptake, tissue distribution, and metabolization of imatinib in S. mansoni. The results suggest using AP-SMALDI MSI also for investigating other antiparasitic compounds and their metabolites in schistosomes and other parasites.
曼氏血吸虫是一种寄生扁形动物，可引起血吸虫病，这是一种影响全球数亿人口的传染病。血吸虫雌雄同体，与雄性配对后，雌性开始大量产卵，从而引起病变。目前唯一使用的药物是吡喹酮（PZQ），但它存在固有耐药风险。因此，需要替代品。在药物再利用的背景下，测试了癌症药物伊马替尼，结果表明它在体外对曼氏血吸虫具有很高的疗效。除了生殖腺外，伊马替尼主要影响雌雄虫的肠道完整性。在这项研究中，我们研究了伊马替尼在成年血吸虫中的潜在摄取和分布，包括其分布动力学。为此，我们首次应用大气压扫描微探针基质辅助激光解吸/电离质谱成像（AP-SMALDI MSI）对配对曼氏血吸虫中的药物进行成像。我们的结果表明，伊马替尼在体外暴露后 20 分钟即可在雄性的食道和肠道中检测到，表明存在口服摄取途径。一个小时后，该药物也在配对的雌性体内被发现。主代谢物 N-去甲基伊马替尼的检测表明药物发生了代谢。此外，成功应用了一种雌性卵巢的标记信号，有助于进一步得出关于伊马替尼器官趋向性的结论。我们的结果表明，AP-SMALDI MSI 是一种研究伊马替尼在曼氏血吸虫中的摄取、组织分布和代谢的有用方法。这些结果表明，AP-SMALDI MSI 也可用于研究其他抗寄生虫化合物及其在血吸虫和其他寄生虫中的代谢物。
