Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes
Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes
复制标题
DOI：
10.1016/j.jconrel.2006.08.001
复制
发表时间：
2006-10-27
影响因子：
10.8
通讯作者：
Kiwada, Hiroshi
中科院分区：
文献类型：
--
作者：
Ishida, Tatsuhiro;Ichihara, Masako;Kiwada, Hiroshi
众所周知，通过聚乙二醇（PEG）缀合的脂质对脂质体表面的空间稳定导致单核吞噬细胞系统的细胞对脂质体的识别减少，并因此延长脂质体的循环时间（t（1/2），在大鼠中为20 It）。最近，我们报道了“加速血液清除（ABC）现象”，导致PEG化脂质体在重复注射后从循环中非常迅速地清除。我们还报道了第一次给药后分泌到血流中的IgM与PEG化脂质体的大量结合在ABC现象的诱导中起着至关重要的作用。众所周知，脾脏在免疫反应中起核心作用，并在细菌感染后产生IgM。本研究的目的是确定脾脏是否有助于ABC现象的诱导，并阐明其在该现象中的作用。在首次注射脂质体（0.001 μ mol磷脂/kg）前进行脾切除（手术切除脾脏）的大鼠中，A13 C现象完全消失。在这些大鼠中，血清IgM浓度以及与聚乙二醇化脂质体结合的IgM量显著降低。脾切除术减弱ABC现象时，直到第一次注射后3天。首次注射后4天切除脾脏，ABC现象保持不变。这一发现表明，脾中针对PEG化脂质体的免疫反应在首次给药后至少2-3天内发生，然后产生与PEG化脂质体反应的IgM。本研究证明，脾脏在ABC现象的诱导阶段起着关键作用。为了有效的临床应用，许多脂质体药物制剂将需要多次注射。因此，在本论文和之前的几篇论文中描述的ABC现象对于需要多剂量给药的治疗有用的脂质体制剂的开发和评价具有重要意义。(c)2006 Elsevier B. V.保留所有权利。
It is well known that steric stabilization of the surface of liposomes by a polyethyleneglycol (PEG) conjugated lipid results in reduced recognition of the liposomes by the cells of the mononuclear phagocyte system and consequently extended circulation times of the liposomes (t(1/2), 20 It in rat). Recently, we reported on the "accelerated blood clearance (ABC) phenomenon", causing PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection. We also reported that abundant binding of IgM, secreted into the blood stream after the first dose and, to PEGylated liposomes, plays an essential role in the induction of the ABC phenomenon. Spleen is well known to play a central role in the immune reaction and to produce IgM following a bacterial infection. The aim of the present study was to determine whether spleen contributes to the induction of the ABC phenomenon and to unravel its role in the phenomenon. In rats that were splenectornized (surgical removal of spleen) prior to the first injection of liposomes (0.001 mu mol phospholipids/kg), the A13C phenomenon was totally abolished. In these rats serum IgM concentrations as well as the amounts of IgM bound to PEGylated liposomes were substantially reduced. Splenectomy attenuated the ABC phenomenon when performed until 3 days post-first injection. Removal of the spleen 4 days post-first injection left the ABC phenomenon unchanged. This finding indicates that the immune reaction in the spleen against the PEGylated liposomes occurs during at least 2-3 days following the first administration and then IgM reactive to PEGylated liposomes is produced. The present study proves that the spleen plays a critical role in the induction phase of the ABC phenomenon. For effective clinical application, many liposomal drug formulations will require multiple injections. The ABC phenomenon described in this and several preceding papers therefore has important implications for the development and evaluation of therapeutically useful liposomal formulations requiring multiple-dose administration. (c) 2006 Elsevier B.V. All rights reserved.