Feasibility of SPECT-CT imaging to study the pharmacokinetics of antisense oligonucleotides in a mouse model of Duchenne muscular dystrophy
| Autor: | Katia Donato, Peter C de Visser, Maria L. H. Vlaming, Rick Vermue, Begoña Aguilera, Raffaella Rossin, Evita van de Steeg, Daan Muilwijk, José W.A. van der Hoorn, Harm T. Jansen, Tilman Läppchen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Drug uptake Unclassified drug Mouse Duchenne muscular dystrophy Phosphorothioate Oligonucleotides Skeletal muscle Pharmacology Biochemistry Iodine 123 Animal tissue Iodine Radioisotopes In vivo study Life Drug Discovery Medicine Tissue Distribution Femur 610 Medicine & health media_common SPECT imaging Antisense oligonucleotides Target tissue Drug tissue level Indium 111 Drug development Molecular Medicine Drug Biodistribution media_common.quotation_subject Drug half life RNA-based therapeutics Mouse model 03 medical and health sciences Pharmacokinetics In vivo Tracer Drug distribution Spect imaging Iodine-123 Genetics Animals Animal model Animal experiment Muscle Skeletal Molecular Biology Nutrition Antisense oligonucleotide i 123 Tomography Emission-Computed Single-Photon Antisense oligonucleotide in 111 business.industry Oligonucleotides Antisense medicine.disease Nonhuman Mice Inbred C57BL Muscular Dystrophy Duchenne 030104 developmental biology MSB - Microbiology and Systems Biology Single photon emission computed tomography-computed tomography Mice Inbred mdx ELSS - Earth Life and Social Sciences business Controlled study |
| Zdroj: | Nucleic Acid Therapeutics, 4, 27, 221-231 |
| Popis: | Antisense oligonucleotides (AONs) are promising candidates for treatment of Duchenne muscular dystrophy (DMD), a severe and progressive disease resulting in premature death. However, more knowledge on the pharmacokinetics of new AON drug candidates is desired for effective application in the clinic. We assessed the feasibility of using noninvasive single-photon emission computed tomography-computed tomography (SPECT-CT) imaging to determine AON pharmacokinetics in vivo. To this end, a 2'-O-methyl phosphorothioate AON was radiolabeled with 123I or 111In, and administered to mdx mice, a rodent model of DMD. SPECT-CT imaging was performed to determine AON tissue levels, and the results were compared to data obtained with invasive analysis methods (scintillation counting and a ligation-hybridization assay). We found that SPECT-CT data obtained with 123I-AON and 111In-AON were qualitatively comparable to data derived from invasive analytical methods, confirming the feasibility of using SPECT-CT analysis to study AON pharmacokinetics. Notably, also AON uptake in skeletal muscle, the target tissue in DMD, could be readily quantified using SPECT-CT imaging, which was considered a particular challenge in mice, due to their small size. In conclusion, our results demonstrate that SPECT-CT imaging allows for noninvasive characterization of biodistribution and pharmacokinetics of AONs, thereby enabling quantitative comparisons between different radiolabeled AON drug candidates and qualitative conclusions about the corresponding unmodified parent AONs. This technology may contribute to improved (pre)clinical drug development, leading to drug candidates with optimized characteristics in vivo. |
| Databáze: | OpenAIRE |
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