Modification with polysialic acid–PEG copolymer as a new method for improving the therapeutic efficacy of proteins
Modification with polysialic acid–PEG copolymer as a new method for improving the therapeutic efficacy of proteins
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DOI：
10.1080/10826068.2015.1135463
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发表时间：
2016-02
影响因子：
2.9
通讯作者：
Jianrong Wu;Shaozeng Lu;Z. Zheng;Li Zhu;X. Zhan
中科院分区：
文献类型：
--
作者：
Jianrong Wu;Shaozeng Lu;Z. Zheng;Li Zhu;X. Zhan
摘要：提出了一种利用嵌段共聚物进行蛋白质衍生化的新方法，以降低治疗蛋白的免疫原性。嵌段共聚物由聚乙二醇（PEG）和聚唾液酸（PSA）组成，这是一种非免疫原性和可生物降解的生物聚合物。以尿酸酶为模型蛋白。分子量分析结果表明，脲酶- peg - psa偶联物每个脲酶单元与2.5个共聚物相连。经PEG-PSA共聚物修饰后的尿酸酶残留酶活性为72.4%。与天然尿酸酶相比，该酶对热、酸、碱和胰蛋白酶的耐受性和稳定性显著提高。PEG-PSA共聚物修饰的尿酸酶免疫原性明显降低。尿素酶- peg - psa偶联物的透射电镜结果显示为球形水合壳，粒径较大。这些发现证明，psa - peg -蛋白缀合物是一种可以潜在地用于递送蛋白质和肽基药物的制剂。
ABSTRACT A new protein derivatization method was developed with a block copolymer to reduce the immunogenicity of therapeutic proteins. The block copolymer consisted of polyethylene glycol (PEG) and polysialic acid (PSA), a nonimmunogenic and biodegradable biopolymer. Uricase was used as a model protein. Molecular weight analysis results indicated that the uricase–PEG–PSA conjugate was linked with 2.5 copolymers for each uricase unit. The residual enzyme activity of the uricase with modification by the PEG–PSA copolymer was 72.4%. The tolerance and stability to heat, acid, alkaline, and trypsin treatments significantly improved compared with the native uricase. The immunogenicity of uricase modified with PEG–PSA copolymer was remarkably reduced. The transmission electron microscopy results of the uricase–PEG–PSA conjugate showed a spherical hydrated shell with a larger particle size. These findings proved that the PSA–PEG–protein conjugate is a formulation that can potentially be used to deliver the protein and peptide-based drugs.