Administration of cytotoxic agents like doxorubicin (DOX) is restrained by the effects on different non-targeted/non-cancerous tissues, which instigates the development of nano-enabled drug delivery systems, among others. In this study, imaging mass spectrometry (IMS) was selected to examine the effects of DOX nanoformulations on non-targeted tissues. Chemical alterations induced by liposomal (LPS) and poly (lactic-co-glycolic acid) (PLG) nanoformulations were assessed against the ones induced by the conventional (CNV) formulation. Kidney cryosections of the treated and control Wistar rats were used as a model of the non-targeted tissue and analyzed by MALDI TOF IMS in the 200–1000 Da m/z range. Principal component analysis (PCA) and Volcano plots of the average mass spectra demonstrated a large overlap between treatments. However, the Venn diagram of significant m/z values revealed a nanoformulation-specific fingerprint consisting of 59 m/z values, which set them apart from the CNV formulation characterized by the fingerprint of 22 significant m/z values. Fingerprint m/z values that were putatively annotated by metabolome database search were linked to apoptosis, cell migration and proliferation. In CNV and PLG cases, false discovery rate adjusted ANOVA showed no differences in the spatial distribution of fingerprint m/z values between the histological substructures like glomeruli and convoluted tubules indicating their tissue-nonselective effect. LPS caused the least significant changes in m/z values and some of the LPS-specific fingerprint m/z values were primarily distributed in the glomeruli. The IMS based procedure successfully differentiated the effects of DOX formulations on the model non-targeted tissue, thus indicating the importance of IMS in effective drug development.

中文翻译：

---

成像质谱法区分阿霉素制剂对非靶向组织的影响

像阿霉素 (DOX) 这样的细胞毒剂的给药受到对不同非靶向/非癌组织的影响的限制，这促进了纳米药物输送系统等的发展。在这项研究中，选择成像质谱 (IMS) 来检查 DOX 纳米制剂对非靶向组织的影响。由脂质体 (LPS) 和聚 (乳酸-共- 乙醇酸) (PLG) 纳米制剂诱导的化学改变与常规 (CNV) 制剂诱导的化学改变相比进行了评估。将治疗和对照 Wistar 大鼠的肾脏冷冻切片用作非靶向组织模型，并通过 MALDI TOF IMS 在 200-1000 Da m / z范围。平均质谱的主成分分析 (PCA) 和火山图表明处理之间有很大的重叠。然而，显着m / z值的维恩图揭示了由 59 个m / z值组成的纳米制剂特异性指纹，这使它们与以 22 个显着m / z值指纹为特征的 CNV 制剂区分开来。指纹m / z通过代谢组数据库搜索假定注释的值与细胞凋亡、细胞迁移和增殖有关。在 CNV 和 PLG 病例中，错误发现率调整的 ANOVA 显示，在肾小球和回旋小管等组织学亚结构之间指纹m / z值的空间分布没有差异，表明它们的组织非选择性作用。LPS 引起的m / z值和一些 LPS 特有的指纹m / z的变化最小值主要分布在肾小球。基于 IMS 的程序成功区分了 DOX 制剂对模型非靶向组织的影响，从而表明 IMS 在有效药物开发中的重要性。