MALDI-MS imaging for the study of tissue pharmacodynamics & toxicodynamics Perspective Executive summary (cont.)
PD/TD responses in lung studied by MALDI-MSI • MALDI-MSI has been successfully employed for distribution studies of drugs targeting the lungs and has been shown to provide high-quality distribution and quantitative data.
• The effect compounds have on endogenous molecules in the lung is yet to be explored indepth within PD/TD studies.
• Traditional techniques such as immunohistochemistry and quantitative whole-body autoradiography are still necessary for validation purposes.
PD/TD responses in skin studied by MALDI-MSI • The skin is a major site for the delivery of pharmaceuticals and cosmetics, both in situations where the skin is the desired target and where topically administered pharmaceuticals are intended to reach systemic circulation.
• For the last decade, MALDI-MSI in skin research has been primarily concerned with interrogating exogenous and endogenous species at site-specific regions across the breadth/thickness of the tissue.
• Although groups have embarked on the MALDI-MSI analysis of skin, its application to TD/PD studies has been relatively seldom explored.
Discussion of prior work • Although the possibility of obtaining PD/TD information by MALDI-MSI was first highlighted in 2006, this opportunity has not been fully embraced.
• The majority of the published studies in pharmaceutical analysis by MALDI-MSI concerns the localization and attempts quantification of the drugs.
• These studies lack information on the underlying biomolecular changes induced by the drug and do not provide a link to the associated toxicological damage or pharmacological activity.
• Inaccurate wording in the abstract and introduction to some papers accidentally misleads the reader to believe that PD/TD responses have been investigated.
Conclusion • MALDI-MSI is capable of providing extensive information on PD/TD responses, beyond the capabilities of histological staining, especially with technological advancements towards single cell imaging.
• To date, the application of MALDI-MSI in this area has been limited, and further uptake may depend on an acceptance that currently, pure MALDI-MSI studies are restricted to the study of major responses owing to sensitivity issues. Therefore, the development of more sensitive instrumentation along with robust quantification methods for drugs, their biotransformation products and endogenous compounds are essential for the future potential of the technique to be fully exploited.
• MALDI-MSI will likely be only one amongst many tools used for such studies, and that actual identification of PD/TD responses will still be the task of conventional tissue-based proteomics/metabolomics with MALDI-MSI being used to map the distribution and level of the response in tissue sections.
• This still makes MALDI-MSI 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.
References Papers of special note have been highlighted as: • of interest; •• of considerable interest
1
FDA. Guidance for Industry: Exposure-response Relationships – Study Design, Data Analysis and Regulatory Applications (2003).
www.fda.gov/downloads/Drugs/ GuidanceCompianceRegulatoryInformation/Guidances/ ucm072109.pdf
2 Mainini V, Bovo G, Chinello C et al. Detection of high molecular weight proteins by MALDI imaging mass spectrometry. Mol. Biosyst. 9(6), 1101–1107 (2013).
3
Pol J, Strohalm M, Havlicek V, Volny M. Molecular mass spectrometry imaging in biomedical and life science research. Histochem. Cell Biol. 134(5), 423–443 (2010).
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4 Caprioli RM, Farmer TB, Gile J. Molecular imaging of biological samples: localization of peptides and proteins using MALDI-TOF MS. Anal. Chem. 69(23), 4751–4760 (1997).
5
Spengler B, Hubert M, Kaufmann R. MALDI ion imaging and biological ion imaging with a new scanning UV-laser microprobe. Proceedings of the 42nd
Annual Conference of
Mass Spectrometry and Allied Topics. Chicago, IL, USA, 29 May–3 June 1994.
6
Schwartz SA, Reyzer ML, Caprioli RM. Direct tissue analysis using matrix-assisted laser desorption/ionization mass spectrometry: practical aspects of sample preparation. J. Mass Spectrom. 38(7), 699–708 (2003).
Francese S, Dani FR, Traldi P, Mastrobuoni G, Pieraccini G, Moneti G. MALDI mass spectrometry imaging, from its origins up to today: the state of the art. Comb. Chem. High Throughput Screen. 12(2), 156–174 (2009).
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