McCrorie Phoebe, Rowlinson Jonathan, Scurr David J, Marlow Maria, Rahman Ruman
Children's Brain Tumour Research Centre, Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK.
Advanced Materials and Healthcare Technologies, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
Pharmaceutics. 2022 Mar 5;14(3):571. doi: 10.3390/pharmaceutics14030571.
Historically, pre-clinical neuro-oncological drug delivery studies have exhaustively relied upon overall animal survival as an exclusive measure of efficacy. However, with no adopted methodology to both image and quantitate brain parenchyma penetration of label-free drugs, an absence of efficacy typically hampers clinical translational potential, rather than encourage re-formulation of drug compounds using nanocarriers to achieve greater tissue penetration. OrbiSIMS, a next-generation analytical instrument for label-free imaging, combines the high resolving power of an OrbiTrapTM mass spectrometer with the relatively high spatial resolution of secondary ion mass spectrometry. Here, we develop an ex vivo pipeline using OrbiSIMS to accurately detect brain penetration of drug compounds. Secondary ion spectra were acquired for a panel of drugs (etoposide, olaparib, gemcitabine, vorinostat and dasatinib) under preclinical consideration for the treatment of isocitrate dehydrogenase-1 wild-type glioblastoma. Each drug demonstrated diagnostic secondary ions (all present molecular ions [M-H]− which could be discriminated from brain analytes when spiked at >20 µg/mg tissue. Olaparib/dasatinib and olaparib/etoposide dual combinations are shown as exemplars for the capability of OrbiSIMS to discriminate distinct drug ions simultaneously. Furthermore, we demonstrate the imaging capability of OrbiSIMS to simultaneously illustrate label-free drug location and brain chemistry. Our work encourages the neuro-oncology community to consider mass spectrometry imaging modalities to complement in vivo efficacy studies, as an analytical tool to assess brain distribution of systemically administered drugs, or localised brain penetration of drugs released from micro- or nano-scale biomaterials.
从历史上看，临床前神经肿瘤学药物递送研究一直完全依赖动物的总体生存期作为疗效的唯一衡量标准。然而，由于没有采用对无标记药物的脑实质渗透进行成像和定量的方法，疗效不佳通常会阻碍临床转化潜力，而不是鼓励使用纳米载体重新配制药物化合物以实现更大的组织渗透。OrbiSIMS是一种用于无标记成像的下一代分析仪器，它将OrbiTrapTM质谱仪的高分辨率与二次离子质谱相对较高的空间分辨率结合在一起。在此，我们开发了一种使用OrbiSIMS的离体流程，以准确检测药物化合物的脑渗透情况。针对一组在临床前被考虑用于治疗异柠檬酸脱氢酶-1野生型胶质母细胞瘤的药物（依托泊苷、奥拉帕利、吉西他滨、伏立诺他和达沙替尼）获取了二次离子光谱。每种药物都显示出诊断性二次离子（所有均存在分子离子[M-H]−，当以>20μg/mg组织的浓度加样时可与脑分析物区分开来）。奥拉帕利/达沙替尼和奥拉帕利/依托泊苷的双重组合作为OrbiSIMS同时区分不同药物离子能力的示例展示。此外，我们展示了OrbiSIMS的成像能力，可同时说明无标记药物的位置和脑化学情况。我们的工作鼓励神经肿瘤学界考虑将质谱成像方式作为一种分析工具，以补充体内疗效研究，用于评估全身给药药物的脑分布或从微米或纳米级生物材料释放的药物的局部脑渗透情况。
