HuCC49DeltaCH2-beta-半乳糖苷酶在结直肠癌异种移植模型中的生物分布。
Biodistribution of HuCC49DeltaCH2-beta-galactosidase in colorectal cancer xenograft model.
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, Ann Arbor, MI 48109, United States.
出版信息
Int J Pharm. 2010 Feb 15;386(1-2):208-15. doi: 10.1016/j.ijpharm.2009.11.020. Epub 2009 Nov 26.
Antibody-enzyme conjugate (AbE) has been widely studied for site-specific prodrug activation in tumors. The purpose of this study is to characterize the pharmacokinetics and tissue distribution of HuCC49DeltaCH2-beta-galactosidase conjugate. HuCC49DeltaCH2 and beta-galactosidase were chemically conjugated and injected into a LS 174T colon cancer xenograft model. A colorimetric assay was developed to quantify the HuCC49DeltaCH2-beta-galactosidase levels in plasma and tissues. The HuCC49DeltaCH2-beta-galactosidase conjugate distributed into tumor tissue as early as 6h with the tumor/blood ratio of 5. This favored distribution of conjugate activity in the tumor tissue which was maintained up to 4 days post conjugate injection, while the conjugate was cleared rapidly from blood and other normal tissues (heart, spleen, lung, liver, kidney and stomach). At a high dose of 3000 U/kg, HuCC49DeltaCH2-beta-galactosidase conjugate saturated the antigen binding sites and yielded decreased tumor/normal tissue ratios compared to 1500 U/kg. These data suggest that HuCC49DeltaCH2-beta-galactosidase specifically target to the tumors to increase tumor selectivity.
抗体-酶缀合物（AbE）已广泛用于肿瘤的特异性前药激活。本研究旨在描述 HuCC49DeltaCH2-β-半乳糖苷酶缀合物的药代动力学和组织分布。HuCC49DeltaCH2 和β-半乳糖苷酶通过化学方法连接，并注入 LS 174T 结肠癌异种移植模型。开发了比色测定法来定量血浆和组织中的 HuCC49DeltaCH2-β-半乳糖苷酶水平。HuCC49DeltaCH2-β-半乳糖苷酶缀合物早在 6 小时就分布到肿瘤组织中，肿瘤/血液比为 5。这种缀合物活性在肿瘤组织中的有利分布一直持续到缀合物注射后 4 天，而缀合物从血液和其他正常组织（心脏、脾脏、肺、肝脏、肾脏和胃）中迅速清除。在 3000 U/kg 的高剂量下，HuCC49DeltaCH2-β-半乳糖苷酶缀合物饱和了抗原结合位点，与 1500 U/kg 相比，肿瘤/正常组织的比值降低。这些数据表明 HuCC49DeltaCH2-β-半乳糖苷酶特异性靶向肿瘤以增加肿瘤选择性。
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