Mapping drug distribution in brain tissue using liquid extraction surface analysis mass spectrometry imaging.
Liquid extraction surface analysis mass spectrometry (LESA-MS) is a surface sampling technique that incorporates liquid extraction from the surface of tissue sections with nanoelectrospray mass spectrometry. Traditional tissue analysis techniques usually require homogenization of the sample prior to analysis via high-performance liquid chromatography mass spectrometry (HPLC-MS), but an intrinsic weakness of this is a loss of all spatial information and the inability of the technique to distinguish between actual tissue penetration and response caused by residual blood contamination. LESA-MS, in contrast, has the ability to spatially resolve drug distributions and has historically been used to profile discrete spots on the surface of tissue sections. Here, we use the technique as a mass spectrometry imaging (MSI) tool, extracting points at 1 mm spatial resolution across tissue sections to build an image of xenobiotic and endogenous compound distribution to assess drug blood-brain barrier penetration into brain tissue. A selection of penetrant and "nonpenetrant" drugs were dosed to rats via oral and intravenous administration. Whole brains were snap-frozen at necropsy and were subsequently sectioned prior to analysis by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and LESA-MSI. MALDI-MSI, as expected, was shown to effectively map the distribution of brain penetrative compounds but lacked sufficient sensitivity when compounds were marginally penetrative. LESA-MSI was used to effectively map the distribution of these poorly penetrative compounds, highlighting its value as a complementary technique to MALDI-MSI. The technique also showed benefits when compared to traditional homogenization, particularly for drugs that were considered nonpenetrant by homogenization but were shown to have a measurable penetration using LESA-MSI.
Drug Safety and Metabolism, AstraZeneca R&D , Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.|Biomedical Research Centre, Sheffield Hallam University , Howard Street, Sheffield, South Yorkshire S1 1WB, U.K.
John G
JG
Swales
Drug Safety and Metabolism, AstraZeneca R&D , Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
James W
JW
Tucker
Drug Safety and Metabolism, AstraZeneca R&D , Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
Michael J
MJ
Spreadborough
Drug Safety and Metabolism, AstraZeneca R&D , Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
Suzanne L
SL
Iverson
Biomedical Research Centre, Sheffield Hallam University , Howard Street, Sheffield, South Yorkshire S1 1WB, U.K.
Malcolm R
MR
Clench
Drug Safety and Metabolism, AstraZeneca R&D , Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
Peter J H
PJ
Webborn
Drug Safety and Metabolism, AstraZeneca R&D , Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
Richard J A
RJ
Goodwin
D000818:Animals; D001921:Brain / Q000378:metabolism*; D008297:Male; D004364:Pharmaceutical Preparations / Q000032:analysis*; D010599:Pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*; D014018:Tissue Distribution
D004364:Pharmaceutical Preparations