3D Mass Spectrometry Imaging Reveals a Very Heterogeneous Drug Distribution in Tumors

Abstract

Mass Spectrometry Imaging (MSI) is a widespread technique used to qualitatively describe in two dimensions the distribution of endogenous or exogenous compounds within tissue sections. Absolute quantification of drugs using MSI is a recent challenge that just in the last years has started to be addressed. Starting from a two dimensional MSI protocol, we developed a three-dimensional pipeline to study drug penetration in tumors and to develop a new drug quantification method by MALDI MSI. Paclitaxel distribution and concentration in different tumors were measured in a 3D model of Malignant Pleural Mesothelioma (MPM), which is known to be a very heterogeneous neoplasm, highly resistant to different drugs. The 3D computational reconstruction allows an accurate description of tumor PTX penetration, adding information about the heterogeneity of tumor drug distribution due to the complex microenvironment. The use of an internal standard, homogenously sprayed on tissue slices, ensures quantitative results that are similar to those obtained using HPLC. The 3D model gives important information about the drug concentration in different tumor sub-volumes and shows that the great part of each tumor is not reached by the drug, suggesting the concept of pseudo-resistance as a further explanation for ineffective therapies and tumors relapse.

Quantitative Mass Spectrometry Imaging Reveals Mutation Status-independent Lack of Imatinib Penetration into Liver Metastases of Gastrointestinal Stromal Tumors

“…The observed apparent lack of drug also confirms the clinical practice for GIST patients with liver metastases that the best treatment option is a multidisciplinary one with continued TKI drug therapy and possibly surgical intervention (37). This result based on a small cohort of patient-derived tissues is in line with results from several MALDI-qMSI mouse studies on various chemotherapeutic drug agents in different cell line-based and patient-derived xenograft models (18,19,21,(38)(39)(40).…”

“…However, tumor heterogeneity and the poorly understood spatial organization of the tumor microenvironment present major challenges for drug uptake and, hence, effective cancer treatment (15,16). This challenge has prompted qMSI studies of drug disposition and of pharmacological/toxic effects in tumor tissues and their surroundings in mice (17,18). Most mouse studies and pioneering qualitative MSI studies of the tyrosine kinase inhibitor (TKI) erlotinib in patient tissue report high degrees of variability and intratumor heterogeneity as well as highly heterogeneous drug distribution (19)(20)(21).…”

Fabrication of homogenous three‐dimensional biomimetic tissue for mass spectrometry imaging

“…However, the tissue heterogeneity and anisotropy cannot guarantee the parallel of serial sections in histological structure. With respect to drugs or other exogenous analytes, “on‐tissue” or “under‐tissue” micropipetting strategies are also difficult to accurately reflect the similar drug status within native tissue, where desorption/ionization is being processed under the complicated suppression by cells and extracellular matrix (ECM). Apart from parallel cryo‐sections, tissue homogenate is another type of surrogate used for representing the analyte's surrounding environment .…”

A Nanostructured Matrices Assessment to Study Drug Distribution in Solid Tumor Tissues by Mass Spectrometry Imaging

“…In particular, the literature reports some examples of the use of this material for the determination of carbohydrates [32] and antitumor drugs [22,33]. …”