Perspective Patel, Cole, Bradshaw et al.
conducted on compounds targeting the lung. Com- pounds studied include bronchodilators [23,36], tyrosine kinase inhibitors [37] and fluoroquinolones [38]. MALDI-MSI has been successfully applied to deter-
mine the uniformity of two drug delivery modes (neb- ulized aerosol and intratracheal administration) in the study of pulmonary inhaled drugs [39]. Investigating the distribution patterns of a compound upon admin- istration remains imperative in understanding which drug delivery method provides greater permeation into the upper and lower parenchyma of the lung, thus max- imizing therapeutic effects. Comparison of MS images from both delivery modes showed that with intratra- cheal administration tiotropium bromide (a musca- rinic receptor antagonist) was concentrated around the central airways whereas animals dosed with nebulizers produced a more uniform drug distribution in the MS and MS/MS images. Detecting tiotropium bromide at pharmacological dosages, as first successfully demon- strated by Nilsson et al. [23], and differentiating drug distribution based on administration mode illustrates the great potential of MALDI-MSI [39] in PK studies. To facilitate accurate localization of therapeutic
compounds, sample preparation remains crucial in pulmonary studies. Optimized lung dissection proto- cols prevent the lung parenchyma collapsing, therefore enabling the alveolar substructures to remain intact. In addition to providing localization information
on drug compounds, the ability to obtain quantitative information from MS images would be of great ben- efit, as it would allow the determination of the actual amount of drug or metabolite present in the tissue at a particular point. As previously mentioned, ion sup- pression effects are a major concern with MALDI-MSI analysis. Tissue morphology alone can impact ana- lyte extraction and the way the matrix crystallizes; a homogenous application of matrix may not result in homogenous crystallization across the entire tissue surface. In order to quantify the distribution of the bronchodilators tiotropium and imipramine, drug standards were manually spotted onto control tissue producing a linear calibration curve, which enabled the quantitative estimation of drug compound in dosed tissue [23,40]. Conversely, spotting the drug compound on tissue can potentially result in lateral diffusion, thus decreasing the concentration and ion signal [41]. In order to determine the suppression effects, the
homogenous application of a structurally and chemi- cally similar reference compound within the matrix facilitated the normalization of the heterogeneous lung and granuloma tissue [38]. Multiple reaction monitor- ing imaging showed that more moxifloxacin accumu- lated in the granulomatous lesions compared with the surrounding normal lung tissue. A limitation to this
96 Bioanalysis (2015) 7(1)
method of applying the reference is the assumption that the standard applied on top of the tissue will extract and cocrystallize in the same way as an endogenous compound from within the tissue. To expand on the numerous animal model studies
published, Fehniger et al. [36] conducted the first ‘proof- of-principle’ study of ipratropium localization dosed at therapeutic levels within human bronchial biopsies of chronic obstructive pulmonary disease patients. Find- ings showed that ipratropiumrapidly absorbed into the airway wall; and additionally a biopsy of an airway region that failed to uptake the drug indicated that this was due to the presence of a tumour within the airway wall. This reconfirms that drug dispersion to a tumor remains a challenge owing to ineffective perfusion and vascularization providing local blood flow. Whilst
technological improvements have enabled
MALDI-MSI to be successfully applied to pharmaceu- tical and drug discovery studies, traditional techniques such as immunohistochemistry and quantitative whole body autoradiography may still be necessary for vali- dation purposes. In the context of pulmonary studies, MALDI-MSI has been shown to provide high-quality distribution and quantitative data of a known target compound; however, the effect compounds have on endogenous molecules in the lung is yet to be explored indepth.
PD/TD responses in skin studied by MALDI-MSI The skin is an organ that is rich in lipids, low-molec- ular-weight species and protein content, and is con- stantly exposed to xenobiotics. It is a major site for the delivery of pharmaceuticals and cosmetics, both in situations in which the skin is the desired target or in which topically administered pharmaceuticals are intended to reach systemic circulation. MALDI-MSI was first used a decade ago to study
the disposition of a topical compound absorbed in skin [42]. In this study, the spatial distribution of keto- conazole, a component of a medicated shampoo, was imaged in porcine skin following topical administra- tion. Recently, Hart et al. [43] reported the mapping of lipids in ex vivo human skin, and Enthaler et al. [44] demonstrated that small endogenous species such as cholesterol sulfate could be mapped in the stratum corneum. Other authors have shown the potential of MALDI-MSI for observing changes in skin associ- ated with desquamation (the biological process of skin renewal) [45,46]. The distribution of skin proteins has been investi-
gated by MALDI-MSI. In a report by Francese et al. [47], rat leg and porcine skin were exposed to bee venom and changes in both protein expression and markers of
future science group
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