The use of MALDI-MS for imaging drug disposition in respiratory disease models

• Main Author: Flinders, Bryn
• Other Authors: Clench, Malcolm
• Published: Sheffield Hallam University 2013
• Subjects: 616.20046
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.606536

Matrix-assisted laser desorption/ionisation-mass spectrometry imaging (MALDI-MSI) has been extensively applied to monitoring the distribution of pharmaceutical compounds in tissues. The main aim of the work reported in this thesis is to monitor the distribution of respiratory compounds in the lungs following inhaled delivery. Glucocorticoids that contain multiple carbonyl functionalities are not easily protonated/de-protonated to form charged species due to the poor ionisation efficiencies of the carbonyl functionalities. Derivatisation with hydrazine based reagents has been proposed as a solution to this problem. These reagents have been employed for the in-solution and on-tissue derivatisation of a range of glucocorticoids to form their respective hydrazones improving their mass spectral ionisation efficiency and detection. MALDI-MSI has been used to screen a set of respiratory compounds in order to determine their on-tissue limit of detection. The distribution of a Tiotropium Bromide was monitored throughout the lungs following inhaled delivery. High spatial resolution imaging enabled a detailed view of the distribution of Tiotropium in the trachea and major airways. Quantitative mass spectrometry imaging is a new field that has recently gained a lot of attention especially in pharmaceutical research. The ability to obtain quantitative information as well as the distribution of pharmaceutical compounds and associated metabolites offers a distinct advantage over traditional quantitative methods such as LC-MS/MS and QWBA. The current methods of generating quantification information from MALDI-MS images has been evaluated, which let development of a method for the preparation of standards for use in the quantification of drugs in tissue sections. MALDI-MSI has been used to acquire data from serial sections obtained at equal intervals through control mouse lung tissue, homogenate registration markers were incorporated in order to aid the final 3D image construction. Using two 3D imaging software packages were used to reconstruct the images were stacked together to enable the 3D distribution of a particular endogenous species throughout the lungs to be displayed.