Division of Pharmaceutics, College of Pharmacy, and Institute of Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
Mol Pharm. 2011 Feb 7;8(1):78-92. doi: 10.1021/mp100216h. Epub 2010 Sep 23.
Clinically relevant doses of helper-dependent adenoviruses (HDAds) provoke the host response against capsid proteins in primates and rodents. To determine if PEGylation truly affects this, baboons and mice were given either HDAd or PEG-HDAd expressing beta-galactosidase at 5 × 10¹¹ or 3 × 10¹² virus particles per kilogram (vp/kg) by iv infusion. Serum cytokines and blood chemistries were assessed for 96 h. PEG-HDAd reduced IL-6 6-fold in mice and 3-fold in the primate. This vector reduced IL-12 by 50% in both animal models. PEGylation reduced serum transaminases by approximately 50% at each dose in the primate and the mouse. PEGylation did not alter hepatic transduction efficiency in the mouse but did reduce transduction efficiency in the liver and the spleen of primates. Unmodified and PEGylated virus suppressed hepatic CYP3A activity in both animal models. PEGylation doubled the half-life (t(½)) of the virus in the mouse and cut plasma clearance (CL) in half without affecting the half-life in primates. These results suggest that there are notable species-specific differences in the biodistribution of and response to PEG-modified vectors which may be linked to differences in binding properties to coagulation factors, receptor density and tissue architecture in the liver.
临床相关剂量的辅助依赖性腺病毒（HDAd）会引发灵长类动物和啮齿动物针对衣壳蛋白的宿主反应。为了确定聚乙二醇化是否真的会影响这种情况，给狨猴和小鼠静脉输注 5×10¹¹ 或 3×10¹² 病毒颗粒/千克（vp/kg）的 HDAd 或聚乙二醇化 HDAd，表达β-半乳糖苷酶。在 96 小时内评估血清细胞因子和血液化学。PEG-HDAd 将小鼠中的 IL-6 减少了 6 倍，将灵长类动物中的 IL-6 减少了 3 倍。该载体使两种动物模型中的 IL-12 减少了 50%。PEG 化使灵长类动物和小鼠的每种剂量的血清转氨酶降低约 50%。PEG 化不会改变小鼠肝内转导效率，但会降低灵长类动物肝和脾内的转导效率。未修饰和聚乙二醇化的病毒均可抑制两种动物模型中的肝 CYP3A 活性。PEG 化使病毒在小鼠中的半衰期（t(½)）增加了一倍，使血浆清除率（CL）减半，而对灵长类动物的半衰期没有影响。这些结果表明，聚乙二醇化载体的生物分布和对其的反应在物种间存在显著差异，这可能与凝血因子、受体密度和肝组织结构的结合特性差异有关。
