Abstract
Purpose. To compare the pharmacokinetics and bioavailability of an oligonucleotide delivered in a free form or using cationic or anionic synthetic carrier systems.
Methods. Whole body dynamic quantitative imaging and metabolism of a HIV antisense oligonucleotide intravenously administered either free or incorporated into synthetic carriers were compared in baboons, using non invasive positron emission tomography and an enzyme-based competitive hybridization assay, respectively.
Results. In its free form, the oligonucleotide showed high liver and kidney concentration, rapid plasmatic degradation and elimination from the body. Use of a cationic vector slightly protected the oligonucleotide against degradation and enhanced uptake by the reticulo-endothelial system. In contrast, the anionic vector dramatically enhanced the uptake in several organs, including the lungs, spleen and brain, with a prolonged accumulation of radioactivity in the brain. Using this vector, intact oligonucleotide was detected in plasma for up to two hours after injection, and the T1/2β and distribution volume increased by 4- and 7-fold, respectively. No evidence of toxicity was found after a single dose administration.
Conclusions. The anionic vector improves significantly the bioavailability and the pharmacokinetics of the oligonucleotide, and is a promising delivery system for in vivo administration of therapeutic nucleic acids.
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Tavitian, B., Marzabal, S., Boutet, V. et al. Characterization of a Synthetic Anionic Vector for Oligonucleotide Delivery Using in Vivo Whole Body Dynamic Imaging. Pharm Res 19, 367–376 (2002). https://doi.org/10.1023/A:1015133205457
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DOI: https://doi.org/10.1023/A:1015133205457