PEG修饰有效提高热休克蛋白gp96抑制性多肽抗乳腺癌的功能  

PEGylation effectively improves anti-breast cancer efficiency of heat shock protein gp96 inhibitory polypeptide

作　　者：刘璐璐 高建伟 李长菲[2] 武岳 孟颂东[2,3] LIU Lulu;GAO Jianwei;LI Changfei;WU Yue;MENG Songdong(Institutes of Physical Science and Information Technology,Anhui University,Hefei 230039,Anhui,China;CAS Key Laboratory of Pathogenic Microbiology and Immunology,Institute of Microbiology,Chinese Academy of Sciences,Beijing 100101,China;University of Chinese Academy of Sciences,Beijing 100049,China;Cominghealth Biotechnology Co.Ltd.,Beijing 100101,China;Foshan Heat Shock Biotech Co.Ltd.,Foshan 528000,Guangdong,China)

机构地区：[1]安徽大学物质科学与信息技术研究院,安徽合肥230039 [2]中国科学院微生物研究所中国科学院病原微生物与免疫学重点实验室,北京100101 [3]中国科学院大学,北京100049 [4]北京康明海慧生物科技有限公司,北京100101 [5]佛山热休生物技术有限公司,广东佛山528000

出　　处：《生物工程学报》2022年第9期3363-3378,共16页Chinese Journal of Biotechnology

基　　金：中国科学院佛山产业技术研究院产业创新团队资助(81761128002);中关村前沿技术成果转化和产业化项目。

摘　　要：乳腺癌是女性恶性肿瘤中发病率最高的肿瘤,严重威胁女性生命健康。其中三阴性乳腺癌因其特殊的生理学特点,成为乳腺癌中预后最差的亚型,因此急需寻找新的靶点进行治疗来提高患者预后及生存率。多项研究表明,热休克蛋白gp96在多种癌细胞的膜表面过表达,且胞膜gp96与乳腺癌的恶性程度与不良预后密切相关,因此其可能是乳腺癌治疗的新靶点。前期研究根据gp96的结构,开发一种靶向胞膜gp96 ATP结合区的α螺旋肽p37。虽然p37多肽作用位点专一,但其在体内容易被降解,因此本研究将多肽的N端或C端分别偶联PEG_(2000)或PEG_(5000),得到4个具有抑瘤功能的PEG多肽:mPEG_(2000)CY、mPEG_(5000)CY、mPEG_(2000)LC和mPEG_(5000)LC。它们可以抑制乳腺癌细胞SK-BR-3的增殖和侵袭,其中抑制效果最明显的是mPEG_(2000)CY。经测定,mPEG_(2000)CY在体内的半衰期较多肽p37明显延长,且有效抑制三阴性乳腺癌MDA-MB-231小鼠移植瘤的生长。这为研发新型抗乳腺癌尤其是三阴性乳腺癌的靶向药物提供了依据。Breast cancer is the most common tumor in female,which seriously threatens the health of women.Triple-negative breast cancer is a subtype with the worst prognosis because of its special physiological characteristics and lack of targeted drugs.Therefore,it is urgent to develop new targeted treatments to improve the prognosis and survival rate of the patients.Previous studies have shown that heat shock protein gp96 is expressed on the membrane of a variety of cancer cells but not on the normal cells.Cell membrane gp96 levels are closely related to the poor prognosis of breast cancer,which may serve as a new target for breast cancer treatment.Based on the structure of gp96,we designed anα-helical peptide p37 that specifically targeting the ATP binding region of gp96.To improve the stability and decrease the degradation of the peptide,the N-terminus or C-terminus of p37 was coupled to PEG_(2000) or PEG_(5000) respectively,and four PEGylated polypeptides were obtained:mPEG_(2000)CY,mPEG_(5000)CY,mPEG_(2000)LC,and mPEG_(5000)LC.The PEGylated polypeptides inhibited the proliferation and invasion of breast cancer cell SK-BR-3,among which mPEG_(2000)CY showed the most significant inhibitory effect.The half-life of mPEG_(2000)CY in vivo was significantly longer than p37,and it effectively inhibited the growth of xenografted tumors of triple-negative breast cancer MDA-MB-231.The results provide a basis for the development of new targeted drugs against breast cancer,especially the triple-negative breast cancer.

关 键 词：肿瘤 三阴性乳腺癌 胞膜gp96 抑制性多肽 PEG修饰多肽 

分 类 号：R737.9[医药卫生—肿瘤]