High Molecular Weight Polyethylene Glycol Cellular Distribution and PEG-associated Cytoplasmic Vacuolation Is Molecular Weight Dependent and Does Not Require Conjugation to Proteins
High Molecular Weight Polyethylene Glycol Cellular Distribution and PEG-associated Cytoplasmic Vacuolation Is Molecular Weight Dependent and Does Not Require Conjugation to Proteins
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DOI：
10.1177/0192623312474726
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发表时间：
2013-10-01
影响因子：
1.5
通讯作者：
Heidel, Shawn
中科院分区：
文献类型：
--
作者：
Rudmann, Daniel G.;Alston, James T.;Heidel, Shawn
治疗蛋白与高相对分子质量聚乙二醇(HMW-pegs)的结合可用于延长生物制剂的半衰期。为了评价HMW聚乙二醇酯在动物体内的作用，我们用免疫组织化学方法研究了大鼠静脉注射100 mg/kg(10K)、(20K)和(40K)聚乙二醇组分后未结合的HMW聚乙二醇组分的组织分布和毒性。聚乙二醇组间的细胞分布和组织学均不同。10K组和20K组在肾小管上皮细胞、肺泡巨噬细胞和肝枯否细胞中的表达最强，细胞空泡化消失。相比之下，给予(40K)聚乙二醇组大鼠脾被膜下红髓巨噬细胞、肾间质巨噬细胞和脉络丛上皮细胞有较强的聚乙二醇化免疫反应，这些细胞常与胞浆空泡化有关。虽然空泡化似乎是一种适应性反应，但在一只给予(40K)聚乙二醇组大鼠出现局灶性肾小管上皮细胞变性，并伴有强烈的聚乙二醇免疫反应。这些数据表明，用未结合的HMW PEGS观察到的组织分布和空泡化都受到聚乙二醇分子量的显着影响，当观察到空泡化时，这可能是一种与聚乙二醇胞浆免疫反应有关的适应性变化。
Conjugation of therapeutic proteins with high molecular weight polyethylene glycols (HMW PEGs) is used to extend the half-life of biologics. To evaluate the effects of HMW PEGs in animals, we used an immunohistochemical procedure to study the tissue distribution and toxicity of unconjugated HMW PEGs in rats given 100 mg/kg (10K)PEG, (20K)PEG, or (40K)PEG intravenously. Both the PEG cellular distribution and the histology were different between groups. In (10K)PEG and (20K)PEG groups, PEG immunoreactivity was most prominent in the renal tubule epithelium and in alveolar macrophages and hepatic Kupffer cells and cellular vacuolation was absent. In contrast, rats given (40K)PEG had strong PEG immunoreactivity in splenic subcapsular red pulp macrophages, renal interstitial macrophages, and choroid plexus epithelial cells that was frequently associated with cytoplasmic vacuolation. While the vacuolation appeared to be an adaptive response, there was focal renal tubular epithelial degeneration associated with strong PEG immunoreactivity in one rat given (40K)PEG. These data indicate that both the tissue distribution and the vacuolation observed with unconjugated HMW PEGs are markedly influenced by the molecular weight of the PEG and that when vacuolation is observed it is likely an adaptive change that is associated with PEG cytoplasmic immunoreactivity.