Stability of siRNA polyplexes from poly(ethylenimine) and poly(ethylenimine)-g-poly(ethylene glycol) under in vivo conditions: Effects on pharmacokinetics and biodistribution measured by Fluorescence Fluctuation Spectroscopy and Single Photon Emission Computed Tomography (SPECT) imaging
Stability of siRNA polyplexes from poly(ethylenimine) and poly(ethylenimine)-g-poly(ethylene glycol) under in vivo conditions: Effects on pharmacokinetics and biodistribution measured by Fluorescence Fluctuation Spectroscopy and Single Photon Emission Computed Tomography (SPECT) imaging
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DOI：
10.1016/j.jconrel.2009.05.016
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发表时间：
2009-09-01
影响因子：
10.8
通讯作者：
Kissel, Thomas
中科院分区：
文献类型：
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作者：
Merkel, Olivia M.;Librizzi, Damiano;Kissel, Thomas
在寻求优化 siRNA 递送系统以用于全身应用时，一个关键参数仍然是其在血液循环中的稳定性。在这项研究中，我们通过体内实时伽马相机记录、SPECT 成像以及血液样本和解剖器官的闪烁计数，追踪了由聚乙烯亚胺 25 kDa (PEI) 或聚乙二醇化 PEI 形成的 siRNA 复合物的每种成分的药代动力学和生物分布。在通过荧光波动光谱（FFS）测量的聚合复合物的体内稳定性的背景下，比较和解释了siRNA和聚合物的体内行为。聚合物复合siRNA的药代动力学和生物分布均由聚合物主导。与 PEI 25 kDa 相比（肝脏沉积：36.2% ID 的聚合物和 14.6% ID 的 siRNA），PEG 化聚合物及其 siRNA 复合物显示出肝脏（13.6-19.7% ID 的 PEG 化聚合物和 9.5-10.2% ID 的 siRNA）和脾脏的摄取显着减少。通过非侵入性成像方法，我们能够预测活体动物的动力学和沉积，从而能够实时研究不同时间点的器官分布。 FFS 测量证明了所应用的聚合复合物在体内条件下的稳定性，这解释了复合物与游离 siRNA 的不同行为。尽管它们在循环中稳定，但我们观察到复合物在肝脏通过时解离。因此，siRNA/(PEG-)PEI递送系统不适合全身给药，但当首过效应被规避时可能有用，这就是局部应用的情况。 (C) 2009 Elsevier B.V. 保留所有权利。
in search of optimizing siRNA delivery systems for systemic application, one critical parameter remains their stability in blood circulation. In this study, we have traced pharmacokinetics and biodistribution of each component of siRNA polyplexes formed with polyethylenimine 25 kDa (PEI) or PEGylated PEIs by in vivo real-time gamma camera recording, SPECT imaging, and scintillation counting of blood samples and dissected organs. In vivo behavior of siRNA and polymers were compared and interpreted in the context of in vivo stability of the polyplexes which had been measured by fluorescence fluctuation spectroscopy (FFS). Both pharmacokinetics and biodistribution of polymer-complexed siRNA were dominated by the polymer. PEGylated polymers and their siRNA polyplexes showed significantly less uptake into liver (13.6-19.7% ID of PEGylated polymer and 9.5-10.2% ID of siRNA) and spleen compared to PEI 25 kDa (liver deposition: 36.2% ID of polymer and 14.6% ID of siRNA). With non-invasive imaging methods we were able to predict both kinetics and deposition in living animals allowing the investigation of organ distribution in real time and at different time points. FFS measurements proved stability of the applied polyplexes under in vivo conditions which explained the different behavior of complexed from free siRNA. Despite their stability in circulation, we observed that polyplexes dissociated upon liver passage. Therefore, siRNA/(PEG-)PEI delivery systems are not suitable for systemic administration, but instead may be useful when the first-pass effect is circumvented, which is the case in local application. (C) 2009 Elsevier B.V. All rights reserved.