Feasibility of SPECT-CT imaging to study the pharmacokinetics of antisense oligonucleotides in a mouse model of Duchenne muscular dystrophy
| Jazyk: | angličtina |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Duchenne muscular dystrophy
Male Drug uptake Unclassified drug Mouse Skeletal muscle Drug half life RNA-based therapeutics Iodine 123 Animal tissue Mouse model In vivo study Life Tracer Drug distribution Animal model Animal experiment Life and Social Sciences Nutrition Antisense oligonucleotide i 123 SPECT imaging Antisense oligonucleotides Antisense oligonucleotide in 111 Target tissue Drug tissue level ELSS - Earth Nonhuman Indium 111 MSB - Microbiology and Systems Biology Single photon emission computed tomography-computed tomography Controlled study |
| 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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