Fully degradable hydrophilic polyals for protein modification.
Fully degradable hydrophilic polyals for protein modification.
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DOI：
10.1021/bm049210k
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发表时间：
2005-08
影响因子：
6.2
通讯作者：
A. Yurkovetskiy;Sungwoong Choi;A. Hiller;M. Yin;Catherine D. McCusker;S. Syed;A. Fischman;M. Papisov
中科院分区：
文献类型：
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作者：
A. Yurkovetskiy;Sungwoong Choi;A. Hiller;M. Yin;Catherine D. McCusker;S. Syed;A. Fischman;M. Papisov
用亲水性聚合物修饰蛋白质是调节蛋白质药代动力学的有效策略。然而，已知缓慢或不可生物降解材料的缀合物，例如聚（乙二醇），会引起持久的细胞空泡化，特别是在肾上皮中。更可降解的聚合物的缀合物，例如，多糖具有显著的免疫毒性风险。结合了完全可降解性、体内长循环和低免疫和化学毒性的联合收割机的聚合物作为蛋白质缀合物组分将是最有益的。本研究探讨了新的完全生物降解的亲水性聚合物，亲水性聚缩醛。它们是无毒的，在生理条件下稳定的，并在溶酶体pH值下进行质子催化水解。模型酶-polyal缀合物的制备具有61-98%的产率，使用常规和新颖的缀合技术，并保留90-95%的比活性。模型缀合物显示啮齿动物中蛋白质循环的显著延长，肾蓄积减少5倍。这些数据表明，亲水性聚缩醛可用于设计具有改进性质的蛋白质缀合物。
Modification of proteins with hydrophilic polymers is an effective strategy for regulation of protein pharmacokinetics. However, conjugates of slowly or non-biodegradable materials, such as poly(ethylene glycol), are known to cause long-lasting cell vacuolization, in particular in renal epithelium. Conjugates of more degradable polymers, e.g., polysaccharides, have a significant risk of immunotoxicity. Polymers that combine complete degradability, long circulation in vivo, and low immuno and chemical toxicity would be most beneficial as protein conjugate components. This study explores new fully biodegradable hydrophilic polymers, hydrophilic polyals. They are nontoxic, stable at physiological conditions, and undergo proton-catalyzed hydrolysis at lysosomal pH. The model enzyme-polyal conjugates were prepared with 61-98% yield using conventional and novel conjugation techniques and retained 90-95% of specific activity. The model conjugates showed a significant prolongation of protein circulation in rodents, with a 5-fold reduction in the renal accumulation. The data suggests that hydrophilic polyals may be useful in designing protein conjugates with improved properties.