MALDI-MS imaging for the study of tissue pharmacodynamics & toxicodynamics Perspective
inflammation were visualized. This work clearly dem- onstrates the potential for visualizing TD responses. Taverna et al. [48] reported an interrogation of the pro- teome for protein signatures in human skin and Hart et al. [49] performed the analysis of ex vivo human skin exploiting ion-mobility as a tool for the improvement of yield and specificity of peptides. In each of these studies mass spectrometry imaging was used to give multiple images of protein distribution where con- ventional procedures were unable to do so. To further improve the confidence in peptide localization, multi- variate statistical analyses were performed that high- lighted differences in peptide expression within com- partment layers of the tissue. Enthaler et al. [50] have shown the versatility of on-tissue digestion protocols applied to ex vivo mammalian skin for protein imag- ing. In this study, various choices of digestive enzymes and matrices were trialed to discern differences in peptide abundance. A true PD study in skin was reported by Marshall
et al. [51]. In this study, MALDI-MSI and liquid extrac- tion surface analysis combined with nano-electrospray ionization MS were used to investigate skin blanching (paling of the skin) occurring as a response to the topi- cal administration of glucocorticoid receptor agonists. A correlation between the depth of skin penetration of the glucocorticoid receptor agonist and both the degree and time of onset of skin blanching postapplication of the three compounds was found.
Discussion of prior work Examination of the literature indicates that the first paper suggesting the possibility of obtaining PD/TD information by MALDI-MSI was produced by Cap- rioli’s group in 2006 [16], who used MALDI-MSI to investigate the localization of administered drugs. In their study, they compared images of proteins in con- secutive whole body rat sections to those showing the distribution of the drug and its corresponding metabo- lites. The authors clearly demonstrated a future avenue to link proteomic changes to drug localization and pharmacological/toxicity response. A careful scrutiny of the literature shows that this possibility has not been fully embraced. On the subject of MALDI-MSI, Lietz et al. commented that: “It can give relative pharmaco- kinetic (PK) and pharmacodynamic (PD) information, as well as allow the identification of novel metabolites that could help elucidate metabolic mechanisms” [52]. However, this was not preceded or followed up by any citations to previously published work on PD investi- gations by MALDI-MSI. Indeed, while the majority of the published studies on the use of MALDI-MSI in pharmaceutical analysis concern the localization and quantification of the drug in specific tissues or
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in the whole body, often within time course experi- ments (PK), surprisingly, very few actually focus on the PD/TD response to the administered drug in skin, lungs and tumors, and none are reported for other tissues/organs. These drug localization/quantification experiments
may be very useful in PK studies, however, they lack information on the underlying biomolecular changes induced by the drug and by the drug at different dos- ages; therefore, they do not provide a link to associ- ated toxicological damage or pharmacological activity. Often, the preliminary reading of the abstract and the introduction of papers might lead the reader to believe that authors have indeed investigated the tissue PD/TD response. For example, Nilsson and coworkers attracted our attention with the promise of MALDI- MSI being able to “detect underlying biomolecular changes” in kidney sections upon drug administration [53]. These authors had undertaken a study involving the administration of two microsomal prostaglandin E synthase 1 inhibitors (mPGES-1) and assessed the toxi- cological damage (resulting from the dosing regimens) to the kidney (accumulation of bisulphonamide crystal deposits) through a multidisciplinary approach involv- ing histopathology, LC–MS, NMR and MALDI-MSI. Although their findings suggest, in our view, that no one technique can provide all the answers and paint the complete picture, MALDI-MSI was crucial in revealing the distribution of the drug and localiza- tion of the crystals within the kidneys as well as in the in situ detection and mapping of PEG400. Disappoint- ingly, no tissue TD response was investigated as the bisulphonamide crystals are considered a metabolite of the parent drug and PEG400. They were detected as a ‘change’ in the dosed animal; however, they were, in fact, used in the formulation of the two compounds. Therefore, care must be taken when describing the achievements of one’s own research in papers to avoid to accidentally misleading the readers. There are in reality very few reports of the study of
PD/TD responses in tissue investigated by MALDI- MSI other than the work on tumor response to anti- vascular agents carried out by ourselves [35] or the skin blanching work carried out by Marshall et al. [51]. Goodwin et al. [54] hinted at the opportunity to map a tissue response to the administration of the drug com- pound
4-bromophenyl-1,4-diazabicyclo(3.2.2)non-
ane-4-carboxylic acid, monohydrochloride (BDNC), showing that two lipid distributions changed in dosed mice brains (target organ for BDNC). Although this was an indication that tissue response to a drug could be detected, it is not clear if the lipid distribution changes correlate with the presence of the drug in the same anatomical regions or if these changes are to be
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