Perspective Patel, Cole, Bradshaw et al.
attributed to a pharmacological rather than a toxico- logical response. Additionally, the study did not test the drug response at different concentrations, thus no information on the TD of the compound could be retrieved.
Future perspective MALDI-MSI is capable of providing extensive infor- mation of PD/TD responses way beyond the capa- bilities of histological staining, especially with techno- logical advancements towards single cell imaging. The application of MALDI-MSI in this area so far has been limited, and further uptake may depend on an accep- tance that pure MALDI-MSI studies are currently restricted to the study of major responses because of sensitivity issues. Therefore, more sensitive instrumen- tation needs to be developed along with robust quan- tification methods for drugs, their biotransformation products and endogenous compounds if the full poten- tial of this technique is to be fully exploited. We firmly
Executive summary
Background • Pharmacodynamics (PD) is the study of the biochemical and physiological effects of therapeutic agents and their mechanisms of action, and considers both drug action and drug effect. This also involves the intended effects of therapeutic agents and any unintended toxic side effects.
• Toxicodynamics (TD) considers toxicant action and effects caused by exposure/administration of chemical, biological or physical agents that are toxic at the exposure/administered dose.
MALDI-MS imaging • MS imaging (MSI) is a sensitive and selective analytical tool enabling the visualization of the distribution of specific compounds within tissue sections.
• MSI techniques do not require any specific antibodies or probes and can provide significant advantages over many traditional histological approaches.
• MALDI-MS is one of the most rapidly developing MSI techniques allowing for analyses over a broad mass range, high-resolution imaging (10–200 μm) and relative ease of spectral interpretation.
Advantages of MSI for PD/TD studies • Detection of multiple species (e.g., drug compounds and metabolites) can be achieved simultaneously in a label-free manner.
• There is an opportunity to correlate proteomic/lipidomic profiles to a drug treatment time course, aiding in the assessment of drug efficacy and dose/response relationships.
• Microdialysis analysis of plasma or LC–MS/MS analysis of homogenized tissue does not provide an accurate representation of compound levels in specific organs or organ regions.
• Autoradiography and positron emission tomography employ radiolabels that could affect the in vivo behavior and the pharmacokinetic/PD properties of compounds, and may also affect the ability to distinguish the parent from any deriving biotransformation products.
PD/TD responses in tumors studied by MALDI-MSI • Tumor tissue is notoriously sinusoidal, leaky and malformed; these unique characteristics need to be fully embraced before embarking upon drug distribution and PD/TD studies.
• Scrupulous sample preparation protocols are imperative in allowing for the most sensitive/reliable detection of the species of interest.
• Validation of the data obtained, high throughput, cost effectiveness and good communication between the mass spectrometrist, clinician and patient are all necessary criterion to enale MALDI-MSI to be integrated into routine oncological clinical diagnostics.
• Employing MALDI-MSI in combination with conventional MS techniques and in vivo imaging modalities (e.g., MRI) could provide a route for biomarker discovery and reveal molecular targets for future drug design.
believe that the reality here is that MALDI-MSI will be only one tool amongst many used for such stud- ies, and that actual identification of PD/TD responses will still be the task of conventional tissue-based pro- teomics/metabolomics with MALDI-MSI being used to map the distribution and level of the response in tissue sections. Thus, MALDI-MSI is an exciting and valuable addition to the analytical tools available in this area and we expect reports of its application to begin to appear imminently.
Financial & competing interests disclosure The authors have no relevant affiliations or financial involve- ment with any organization or entity with a financial inter- est in or financial conflict with the subject matter or mate- rials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this
manuscript.
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Bioanalysis (2015) 7(1)
future science group
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