Perspective Patel, Cole, Bradshaw et al. Key terms
Pharmacodynamics: Study of the biochemical and physiological effects of therapeutic agents and their mechanisms of action, considering both drug action and drug effect. Intended beneficial effects and any unintended toxic side effects are considered.
Toxicodynamics: Study of toxicant action and toxic effects caused by exposure/administration of chemical, biological or physical agents that are toxic at the exposure/ administered dose.
MALDI: An ionization source that employs a ‘matrix’ to cocrystallize with analytes contained within a sample, aiding in the vaporization and ionization of molecules following irradiation using a pulsed laser beam.
MS: The use of advanced analytical instruments to produce ions and measure specific mass-to-charge ratios (m/z) and relative abundances in order to determine the chemical composition of a sample.
MS imaging: Mass spectra are recorded at predetermined points (x, y coordinates) of intact tissue samples, allowing for molecular images to be generated by plotting the spatial dimensions against the relative abundance of a selected ion.
Pharmacokinetics: The processes by which a therapeutic agent is absorbed, distributed, metabolized and excreted in living organisms.
coworkers [4] following the pioneering work of Bern- hard Spengler [5]. Its usefulness as an analytical tool has made it one of the most rapidly developing MSI techniques available today. The primary step of any MALDI-MSI experiment relies on the coating of tis- sue sections with a homogenous layer of the matrix (generally a small organic acid that absorbs energy at the wavelength of the laser [6]). The MALDI matrix cocrystallizes with analytes on the tissue surface and aids in the vaporization and ionization of molecules contained within the sample following irradiation using a pulsed laser beam (most commonly generated by a nitrogen [337 nm] or Nd:YAG [335 nm] laser). During the MALDI-MSI acquisition, the laser is fired at the sample at a series of predetermined points and for each x, y coordinate a mass spectrum is recorded. Images are then reconstructed by plotting the spatial dimensions against the relative abundance of a selected ion [7]. There are now a number of software packages for postimage processing, statistical analysis and iden- tifying tissue markers [8]. These packages can be used to overlay drug distribution patterns and to clearly identify the localization of a drug or metabolite within tissue sections. The basic principle of MALDI-MSI is depicted in Figure 1. As our understanding of biological processes
develops, so too does our desire to obtain maximum information from a single sample. It is commonplace
92 Bioanalysis (2015) 7(1)
for niche applications to require lateral resolutions of <20 μm when observing biological differences at the cellular level [9]. The typical lateral resolution of modern MALDI-MSI
instruments is between 10
and 200 μm [10]. It is superior to many other surface- based MS approaches (e.g., direct analysis in real time [∼300 μm]) and spray-based MS approaches (e.g., desorption electrospray
ionization [50–500 μm]),
rivalled only by secondary ion MS (50 nm-submicron) [11]. MALDI-MS also offers significant advantages over other MSI techniques by allowing for analyses over a broad mass range [7] and spectral interpretation is rela- tively easy through the generation of predominantly singly charged species [12]. The first demonstration of the use of MALDI to
directly study pharmaceutical compounds in animal tissue was published by Troendle et al. [13]. In this study, the anticancer drug paclitaxel was detected in an ovarian tumor xenograft and the antipsychotic spi- perone in spiked sections of liver. Matrix was applied to the surface of the tissue sections by either simple pipetting or electrospraying and the samples were ana- lyzed using MALDI quadrupole ion trap MS. Imaging experiments were not conducted in this initial study. The first true imaging experiments were reported by Reyzer et al. in a study of the distribution of antitumor drugs in mouse tumor tissue and rat brain [14], using SRM to specifically monitor the drug under study. This group has also described some of the practical aspects of obtaining MALDI-MSI data for drug and metabolite distributions in whole body sections and has reported some of the limitations of this technique [15]. The Caprioli group combined their own work on
protein imaging with developments in drug and metab- olite imaging to produce whole body images that show the location of drug, drug metabolites and endogenous markers for various organs of the body [16].
Advantages of MSI for PD/TD studies The major advantage of MALDI-MSI for the study of PD/TD responses in tissue is its capability to study multiple biomarkers simultaneously in a label-free manner. Advancement of drug design and develop- ment requires meticulous comprehension of the phar- macological mechanism, toxicological action and drug distribution within the target tissue. During the past decade there have been numerous studies where research groups have implemented MALDI-MSI into pharmacological themed proteomic, lipidomic and metabolomic workflows [17–21]. Proteomic/lipidomic correlation between a drug
treatment time course and the presence of the par- ent drug and metabolites can provide vital informa- tion needed to assess drug efficacy. MALDI-MSI
future science group
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