Blatherwick, Eleanor Q. (2013) Imaging mass spectrometry approaches for the detection and localisation of drug compounds and small molecules in tissue. PhD thesis, University of Warwick.

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Abstract

A crucial and challenging aspect of the drug development process is the requirement
to measure the distribution of a pharmaceutical compound and its metabolites in
tissue. Industry-standard methods used to look at total localisation of drug-related
material are limited due to their dependence on labels. These labelled techniques can
have difficulty in distinguishing between the drug of interest and its metabolites.
Imaging mass spectrometry is a technique that has the potential to spatially
distinguish between drug and metabolites, due to its high chemical specificity and
sensitivity. A number of imaging mass spectrometry approaches have been described
for localisation of drug compounds in tissue, most notably matrix-assisted laser
desorption/ionisation (MALDI) imaging, which can provide data complementary to
existing imaging techniques.
Two imaging mass spectrometry approaches have been evaluated and compared for
use in the localisation of a range of drug compounds in target tissues. The techniques
used were MALDI imaging and a recently described electrospray ionisation-based
technique, liquid extraction surface analysis (LESA).
Both techniques have been successfully used for the detection of drug compounds in
dosed tissue sections. A major challenge associated with imaging techniques is the
required selectivity of the experiment for the compound of interest, due to the
complex nature of tissue sections. Combining the shape-selective method of ion
mobility separation with MS/MS fragmentation has been shown to improve the
selectivity of both imaging approaches for the compound of interest.
Results obtained using LESA-MS have demonstrated the suitability of this technique
as a rapid and sensitive profiling technique for the detection of drugs and metabolites
in tissue, but with a lower achievable spatial resolution than MALDI imaging.
Higher spatial resolution was achieved with MALDI imaging; however data
acquisition times were longer and required higher dosing levels for successful
detection of drug compounds in tissue.
A biological application of MALDI imaging was also evaluated. Mobility-enabled
MALDI imaging was used to assess differences in the localisation of important
adenine nucleotides between control and metabolically stressed mouse brain sections.
Tissue fixation methods were evaluated to overcome rapid post-mortem degradation
of adenine nucleotides such that biologically relevant localisation images can be
obtained. These studies highlight the crucial importance of appropriate biological
sample preparation in MALDI imaging experiments.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology
Library of Congress Subject Headings (LCSH):	Drug development, Matrix-assisted laser desorption-ionization, Mass spectrometry
Official Date:	January 2013
Dates:	Date Event January 2013 Submitted
Institution:	University of Warwick
Theses Department:	School of Life Sciences
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Scrivens, James H.; Weston, D. (Dan)
Sponsors:	AstraZeneca (Firm); Medical Research Council (Great Britain) (MRC)
Extent:	1 volume (various pagings) : illustrations, charts.
Language:	eng

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