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Development of a detection method for antisense oligonucleotides in mouse kidneys by MALDI imaging mass spectrometry.

RATIONALE: Oligonucleotide therapeutics have been recently gaining more 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 mouse 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 2-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.

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