Distribution of Antisense Oligonucleotides in Rat Eyeballs Using MALDI Imaging Mass Spectrometry

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Abstract

Oligonucleotide-based therapeutics such as antisense oligonucleotides, small interfering RNAs (siRNAs), decoy and aptamer have been extensively developed. To investigate the pharmacokinetics of oligonucleotide therapeutics, it is common to label a radioisotope in a nucleic acid and visualize it. However, if the labeled terminal nucleotide is decomposed by a nuclease in vivo, only the labeled nucleotide is detected, and it is impossible to observe the nucleic acid exhibiting the drug effect. The distribution of biomolecules, such as phospholipids, proteins, and glycolipids, can be obtained and visualized without labeling using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). MALDI-IMS is also used in pharmacokinetic analysis to visualize a parent drug and its metabolites simultaneously. In this study, we reported a methodology for oligonucleotides analysis by MALDI-IMS. When phosphorothioate antisense oligonucleotide was administered into the eyeball of rats, it reached the retina after 30 min without undergoing decomposition by nucleases.

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Most cited references 23

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RNA-Targeted Therapeutics

Stanley Crooke, Brenda Baker, C Frank Bennett … (2018)

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Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial.

Frederick J. Raal, Raul Santos, Dirk Blom … (2010)

Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease. This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight ( /=50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373. 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11.4 mmol/L (SD 3.6) in the mipomersen group and 10.4 mmol/L (3.7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (-24.7%, 95% CI -31.6 to -17.7) than with placebo (-3.3%, -12.1 to 5.5; p=0.0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal. Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins. ISIS Pharmaceuticals and Genzyme Corporation. Copyright 2010 Elsevier Ltd. All rights reserved.

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MALDI-FTICR imaging mass spectrometry of drugs and metabolites in tissue.

L Frappier, Richard M. Caprioli, Dale S. Cornett (2008)

A new approach is described for imaging mass spectrometry analysis of drugs and metabolites in tissue using matrix-assisted laser desorption ionization-Fourier transform ion cyclotron resonance (MALDI-FTICR). The technique utilizes the high resolving power to produce images from thousands of ions measured during a single mass spectrometry (MS)-mode experiment. Accurate mass measurement provides molecular specificity for the ion images on the basis of elemental composition. Final structural confirmation of the targeted compound is made from accurate mass fragment ions generated in an external quadrupole-collision cell. The ability to image many small molecules in a single measurement with high specificity is a significant improvement over existing MS/MS based technologies. Example images are shown for olanzapine in kidney and liver and imatinib in glioma.

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Author and article information

Journal

Journal ID (nlm-ta): Mass Spectrom (Tokyo)

Journal ID (iso-abbrev): Mass Spectrom (Tokyo)

Journal ID (aggregator): massspectrometry

Title: Mass Spectrometry

Publisher: The Mass Spectrometry Society of Japan (c/o International Academic Publishing Co. Ltd., 4-4-19 Takadanobaba, Shinjuku-ku, Tokyo 169-0075, Japan )

ISSN (Print): 2187-137X

ISSN (Electronic): 2186-5116

Publication date (Print): 2018

Publication date (Electronic): 11 September 2018

Volume: 7

Issue: 1

Electronic Location Identifier: A0070

Affiliations

[1 ]International Mass Imaging Center and Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, Japan

[2 ]Preeminent Medical Photonics Education & Research Center, Japan

[3 ]Department of Anatomy, The University of Hong Kong, China

Author notes

[*]Correspondence to: Mitsutoshi Setou, International Mass Imaging Center and Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1–20–1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431–3192, Japan , setou@ 123456hama-med.ac.jp

Article

DOI: 10.5702/massspectrometry.A0070

PMC ID: 6131115

SO-VID: 2f0f21a3-21e2-4535-9ac2-5d5e39d12bc7

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This is an open access article distributed under the terms of Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Distribution of Antisense Oligonucleotides in Rat Eyeballs Using MALDI Imaging Mass Spectrometry

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Most cited references 23

RNA-Targeted Therapeutics

Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial.

MALDI-FTICR imaging mass spectrometry of drugs and metabolites in tissue.

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