In situ growth of a PEG-like polymer from the C terminus of an intein fusion protein improves pharmacokinetics and tumor accumulation

Weiping Gao; Wenge Liu; Trine Christensen; Michael R. Zalutsky; Ashutosh Chilkoti

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In situ growth of a PEG-like polymer from the C terminus of an intein fusion protein improves pharmacokinetics and tumor accumulation

机译：从内含肽融合蛋白C端原位生长PEG样聚合物可改善药代动力学和肿瘤积累

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This paper reports a general in situ method to grow a polymer conjugate solely from the C terminus of a recombinant protein. GFP was fused at its C terminus with an intein; cleavage of the intein provided a unique thioester moiety at the C terminus of GFP that was used to install an atom transfer radical polymerization (ATRP) initiator. Subsequent in situ ATRP of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) yielded a site-specific (C-terminal) and stoichiometric conjugate with high yield and good retention of protein activity. A GFP-C-poly(OEGMA) conjugate (hydrody-namic radius (R_h): 21 nm) showed a 15-fold increase in its blood exposure compared to the protein (R_h: 3.0 nm) after intravenous administration to mice. This conjugate also showed a 50-fold increase in tumor accumulation, 24 h after intravenous administration to tumor-bearing mice, compared to the unmodified protein. This approach for in situ C-terminal polymer modification of a recombinant protein is applicable to a large subset of recombinant protein and peptide drugs and provides a general methodology for improvement of their pharmacological profiles.

机译：本文报道了仅从重组蛋白的C末端生长聚合物共轭物的一般原位方法。 GFP在其C末端与内含肽融合。内含肽的切割在GFP的C末端提供了独特的硫酯部分，该硫酯部分用于安装原子转移自由基聚合（ATRP）引发剂。随后的低聚乙二醇乙二醇甲基丙烯酸甲酯（OEGMA）的原位ATRP产生具有高收率和良好的蛋白质活性保留能力的位点特异性（C末端）和化学计量的共轭物。 GFP-C-聚（OEGMA）缀合物（水动力学半径（R_h）：21 nm）与静脉内给予小鼠的蛋白质（R_h：3.0 nm）相比，血液暴露量增加了15倍。与未修饰的蛋白质相比，在对荷瘤小鼠静脉内给药后24小时，该缀合物还显示出肿瘤积累增加了50倍。用于重组蛋白的原位C端聚合物修饰的这种方法适用于重组蛋白和肽药物的大部分子集，并提供了改善其药理学特性的通用方法。

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来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2010年第38期|p.16432-16437|共6页
作者
Weiping Gao; Wenge Liu; Trine Christensen; Michael R. Zalutsky; Ashutosh Chilkoti;
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作者单位

Center for Biologically Inspired Materials and Material Systems, Duke University, Durham, NC 27708;

rnDepartment of Biomedical Engineering Center for Biologically Inspired Materials and Material Systems, Duke University, Durham, NC 27708;

rnDepartment of Biomedical Engineering;

rnDepartment of Radiology, Duke University Medical Center, Durham, NC 27710;

rnDepartment of Biomedical Engineering Center for Biologically Inspired Materials and Material Systems, Duke University, Durham, NC 27708;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类
关键词
drug delivery; polymer bioconjugate; protein engineering;

机译：药物输送;聚合物生物共轭物;蛋白质工程;

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专利

1. In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics [J] . Weiping Gao, Wenge Liu, J. Andrew Mackay, Proceedings of the National Academy of Sciences of the United States of America . 2009,第36期

机译：化学计量的PEG样共轭物在蛋白质N端的原位生长，药代动力学显着改善
2. Site-specific in situ growth of a cyclized protein-polymer conjugate with improved stability and tumor retention [J] . Hu Jin, Zhao Wenguo, Gao Yan, Biomaterials . 2015,第Null期

机译：特定位置的环化蛋白质-聚合物共轭物原位生长，具有改善的稳定性和肿瘤保留能力
3. Erratum: Ubiquitin-intein and SUMO2-intein fusion systems for enhanced protein production and purification (Protein Expression and Purification (2012) 82 (174-178)) (Erratum) [J] . Wang Z., Li N., Wang Y., Protein Expression and Purification . 2012,第1期

机译：勘误表：泛素-内含子和SUMO2-内含肽融合系统可增强蛋白质的产生和纯化（蛋白质表达和纯化（2012）82（174-178））（勘误）
4. In situ Polymerization of a PEG Monomer from the C-Terminus of an Intein Fusion Protein Significantly Improves Pharmacokinetics and Tumor Accumulation [C] . Weiping Gao, Ashutosh Chilkoti Annual meeting of the Society for Biomaterials . 2011

机译：从内含蛋白融合蛋白C端的PEG单体的原位聚合显着改善了药代动力学和肿瘤积累。
5. Role of the C Terminus of the Parainfluenza Virus 5 Fusion Protein in Membrane Fusion. [D] . Zokarkar, Aarohi. 2012

机译：副流感病毒5融合蛋白C末端在膜融合中的作用。
6. In situ growth of a PEG-like polymer from the C terminus of an intein fusion protein improves pharmacokinetics and tumor accumulation [O] . Weiping Gao, Wenge Liu, Trine Christensen, 2010

机译：从内含肽融合蛋白C端的PEG状聚合物的原位生长可改善药代动力学和肿瘤蓄积
7. In situ growth of a PEG-like polymer from the C terminus of an intein fusion protein improves pharmacokinetics and tumor accumulation [O] . Gao, Weiping, Liu, Wenge, Christensen, Trine, 2010

机译：从内含肽融合蛋白C端的PEG状聚合物的原位生长可改善药代动力学和肿瘤蓄积

In situ growth of a PEG-like polymer from the C terminus of an intein fusion protein improves pharmacokinetics and tumor accumulation

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