Tavitian Bertrand, Marzabal Stéphane, Boutet Valérie, Kühnast Bertrand, Terrazzino Salvatore, Moynier Marinette, Dollé Frédéric, Deverre Jean Robert, Thierry Alain R
INSERM M 0103, CEA-SHFJ, Orsay, France.
Pharm Res. 2002 Apr;19(4):367-76. doi: 10.1023/a:1015133205457.
To compare the pharmacokinetics and bioavailability of an oligonucleotide delivered in a free form or using cationic or anionic synthetic carrier systems.
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.
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 T 1/2beta and distribution volume increased by 4- and 7-fold, respectively. No evidence of toxicity was found after a single dose administration.
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.
比较以游离形式或使用阳离子或阴离子合成载体系统递送的寡核苷酸的药代动力学和生物利用度。
在狒狒中比较静脉内给予游离的或掺入合成载体中的HIV反义寡核苷酸的全身动态定量成像和代谢情况，分别使用非侵入性正电子发射断层扫描和基于酶的竞争性杂交测定法。
以游离形式存在时，寡核苷酸在肝脏和肾脏中的浓度较高，血浆中降解迅速且从体内消除。使用阳离子载体可略微保护寡核苷酸不被降解，并增强网状内皮系统的摄取。相反，阴离子载体显著增强了在包括肺、脾和脑在内的多个器官中的摄取，脑内放射性积累时间延长。使用该载体时，注射后长达两小时在血浆中可检测到完整的寡核苷酸，T1/2β和分布容积分别增加了4倍和7倍。单次给药后未发现毒性证据。
阴离子载体显著提高了寡核苷酸的生物利用度和药代动力学，是用于体内递送治疗性核酸的有前景给药系统。
