Matrix-assisted laser desorption/ionization imaging mass spectrometry of intraperitoneally injected danegaptide (ZP1609) for treatment of stroke-reperfusion injury in mice

Rationale: This work focuses on direct matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) detection of intraperitoneally (IP)-injected dipeptide ZP1609 in mouse brain tissue. Direct analysis of drug detection in intact tissue sections provides distribution information that can impact drug development. MALDI-IMS capabilities of uncovering drug transport across the blood-brain barrier are demonstrated. Methods: Successful peptide detection using MALDI-IMS was achieved using a MALDI TOF/TOF system. Upon optimization of sample preparation procedures for dipeptide ZP1609, an additional tissue acidification procedure was found to greatly enhance signal detection. The imaging data acquired was able to determine successful transport of ZP1609 across the blood-brain barrier. Data obtained from MALDI-IMS can help shape our understanding of biological functions, disease progression, and effects of drug delivery. Results: Direct detection of ZP1609 throughout the brain tissue sections was observed from MALDI-MS images. However, in cases where there was induction of stroke, a peak of lower signal intensity was also detected in the target m/z region. Although distinct differences in signal intensity can be seen between control and experimental groups, fragments and adducts of ZP1609 were investigated using MALDI-IMS to verify detection of the target analyte. Conclusions: Overall, the data reveals successful penetration of ZP1609 across the blood-brain barrier. The benefits of tissue acidification in the enhancement of detection sensitivity for low-abundance peptides were demonstrated. MALDI-IMS has been shown to be a useful technique in the direct detection of drugs within intact brain tissue sections.