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Development of a detection method for antisense oligonucleotides in mouse kidneys by matrix‐assisted laser desorption/ionization imaging mass spectrometry
Author(s) -
Yokoi Hiroyuki,
Kasahara Yuya,
Obika Satoshi,
Doi Takefumi,
Kamada Haruhiko
Publication year - 2018
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.8274
Subject(s) - chemistry , oligonucleotide , locked nucleic acid , mass spectrometry imaging , matrix assisted laser desorption/ionization , mass spectrometry , matrix (chemical analysis) , nucleic acid , chromatography , desorption , dna , biochemistry , organic chemistry , adsorption
Rationale Oligonucleotide therapeutics have recently gained much attention, but its pharmacokinetic evaluation methods are still not sufficient, and, in particular, more tools are needed to evaluate their tissue distribution and metabolites. We developed a matrix‐assisted laser desorption/ionization imaging mass spectrometry (MALDI‐IMS)‐based method to evaluate the tissue distribution of oligonucleotide therapeutics. Methods We used an antisense oligonucleotide containing locked nucleic acids (LNA‐A). Various washing protocols were examined using mouse kidney homogenate sections. Next, we applied a two‐step matrix preparation strategy. As a first step, 3‐hydroxypicolinic acid (3‐HPA) matrix containing citrate and amines was sprayed using an airbrush and subsequently 3‐HPA matrix containing citrate only was sprayed using the ImagePrep. Finally, kidney sections prepared from LNA‐A‐dosed mice were treated with our optimized method and analyzed with MALDI‐IMS. Results The selected washing method made it possible to detect LNA‐A with MALDI‐IMS and, furthermore, our developed matrix pretreatment method enhanced signal intensity approximately two‐fold. MALDI‐IMS revealed that LNA‐A localized in a portion presumed to be the renal cortex. We also obtained information on LNA‐A metabolites, which showed the same distribution profile as LNA‐A in kidneys. Conclusions This study shows that MALDI‐IMS can be applied to evaluate the tissue distribution of oligonucleotide therapeutics. Our method can evaluate the tissue distribution along with metabolites and has the potential to help the development of novel oligonucleotide therapeutics.