Recombinant human serum albumin dimer has high blood circulation activity and low vascular permeability in comparison with native human serum albumin
Recombinant human serum albumin dimer has high blood circulation activity and low vascular permeability in comparison with native human serum albumin
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DOI：
10.1007/s11095-006-9933-1
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发表时间：
2006-05-01
影响因子：
3.7
通讯作者：
Otagiri, Masaki
中科院分区：
文献类型：
--
作者：
Matsushita, Sadaharu;Chuang, Victor Tuan Giam;Otagiri, Masaki
人血清白蛋白（HSA）是临床上使用的一种重要的血浆扩张剂。不建议对低血容量、烧伤或低白蛋白血症的危重患者输注白蛋白，因为白蛋白渗漏到血管外空间的增加，从而加重水肿。在本研究中，我们试图克服这个问题，通过生产重组人血清白蛋白（rHSA）二聚体具有降低血管通透性和增加半衰期。在正常大鼠和角叉菜胶诱导的足肿胀小鼠模型中评价了重组蛋白的药代动力学和生物分布。Western blot和光谱研究表明，该重组蛋白的构象性质与天然HSA（HSA单体）的构象性质相似。rHSA二聚体的生物半衰期和血浆浓度-时间曲线下面积约为单体的1.5倍。二聚化还导致天然HSA稳态时的总体清除率和分布体积显著降低。与天然HSA相比，rHSA二聚体在肝脏、皮肤、肌肉和脂肪中的累积程度较低。在足水肿小鼠模型中，rHSA二聚体的血管渗透性小于天然HSA的血管渗透性，直至96 h。rHSA二聚体在水肿模型大鼠中的血浆半衰期延长，在循环血中的留存率高，血管通透性较天然HSA低。
Human serum albumin (HSA) is used clinically as an important plasma expander. Albumin infusion is not recommended for critically ill patients with hypovolemia, burns, or hypoalbuminemia because of the increased leakage of albumin into the extravascular spaces, thereby worsening edema. In the present study, we attempted to overcome this problem by producing a recombinant HSA (rHSA) dimer with decreased vascular permeability and an increased half-life.Two molecules of rHSA were genetically fused to produce a recombinant albumin dimer molecule. The pharmacokinetics and biodistribution of the recombinant proteins were evaluated in normal rats and carrageenin-induced paw edema mouse model.The conformational properties of this rHSA dimer were similar to those for the native HSA (the HSA monomer), as evidenced by the Western blot and spectroscopic studies. The biological half-life and area under the plasma concentration-time curve of the rHSA dimer were approximately 1.5 times greater than those of the monomer. Dimerization has also caused a significant decrease in the total body clearance and distribution volume at the steady state of the native HSA. rHSA dimer accumulated to a lesser extent in the liver, skin, muscle, and fat, as compared with the native HSA. Up to 96 h, the vascular permeability of the rHSA dimer was less than that of the native HSA in paw edema mouse models. A prolonged plasma half-life of the rHSA dimer was also observed in the edema model rats.rHSA dimer has a high retention rate in circulating blood and a lower vascular permeability than that of the native HSA.