Pharmacokinetics, biodistribution and metabolism of squalenoyl adenosine nanoparticles in mice using dual radio-labeling and radio-HPLC analysis.
Pharmacokinetics, biodistribution and metabolism of squalenoyl adenosine nanoparticles in mice using dual radio-labeling and radio-HPLC analysis.
复制标题
DOI：
10.1016/j.jconrel.2015.06.016
复制
发表时间：
2015-08-28
期刊：
影响因子：
--
通讯作者：
Couvreur P
中科院分区：
文献类型：
--
作者：
Gaudin A;Lepetre-Mouelhi S;Mougin J;Parrod M;Pieters G;Garcia-Argote S;Loreau O;Goncalves J;Chacun H;Courbebaisse Y;Clayette P;Desmaële D;Rousseau B;Andrieux K;Couvreur P
腺苷是一种多效性内源性核苷，具有潜在的神经保护药理活性。然而，腺苷的极快代谢阻碍了其临床应用。为了克服这一限制，我们最近开发了一种新的角鲨酰腺苷纳米药物[角鲨酰腺苷(SQAD)]，通过将这种核苷与角鲨烯(一种天然脂质)进行共价连接来实现。由此产生的纳米组件(NAS)在临床前的脑缺血和脊髓损伤模型中都显示出显著的药理活性。本研究的目的是用角鲨酰腺苷和[14C]角鲨酰腺苷作为SQAD生物结合物的腺苷和角鲨烯部分的示踪剂，研究SQAD NAS的血浆分布和组织分布。这项研究是通过放射-高效液相分析完成的，从而确定了SQAD的代谢谱。我们在这里报道，SQAD Nas允许腺苷在静脉给药后以其前药形式(SQAD)持续循环至少1小时，此时游离腺苷在注射后几秒钟内被代谢。此外，腺苷的角鲨烯基化及其作为Nas的配方也显著改善了生物分布，因为SQAD Nas主要被肝脏和脾捕获，允许腺苷在肝实质中显著释放。总之，这些结果表明，SQAD Nas为血流提供了一个腺苷储存库，这可能解释了以前观察到的SQAD Nas对脑缺血和脊髓损伤的神经保护作用。
Adenosine is a pleiotropic endogenous nucleoside with potential neuroprotective pharmacological activity. However, clinical use of adenosine is hampered by its extremely fast metabolization. To overcome this limitation, we recently developed a new squalenoyl nanomedicine of adenosine [Squalenoyl-Adenosine (SQAd)] by covalent linkage of this nucleoside to the squalene, a natural lipid. The resulting nanoassemblies (NAs) displayed a dramatic pharmacological activity both in cerebral ischemia and spinal cord injury pre-clinical models. The aim of the present study was to investigate the plasma profile and tissue distribution of SQAd NAs using both Squalenoyl-[3H]-Adenosine NAs and [14C]-Squalenoyl-Adenosine NAs as respective tracers of adenosine and squalene moieties of the SQAd bioconjugate. This study was completed by radio-HPLC analysis allowing to determine the metabolization profile of SQAd. We report here that SQAd NAs allowed a sustained circulation of adenosine under its prodrug form (SQAd) for at least 1 h after intravenous administration, when free adenosine was metabolized within seconds after injection. Moreover, the squalenoylation of adenosine and its formulation as NAs also significantly modified biodistribution, as SQAd NAs were mainly captured by the liver and spleen, allowing a significant release of adenosine in the liver parenchyma. Altogether, these results suggest that SQAd NAs provided a reservoir of adenosine into the bloodstream which may explain the previously observed neuroprotective efficacy of SQAd NAs against cerebral ischemia and spinal cord injury.