白蛋白结合肽-多柔比星耦合物的设计、制备、表征及初步评价

发布时间：2019-06-05 09:41

【摘要】：为了改善多柔比星在血液中的循环半衰期,基于白蛋白在血浆中含量丰富、性质稳定、半衰期持久的特点,通过大肠杆菌体系重组表达了源于细菌表面蛋白中白蛋白结合肽段,并建立了纯化工艺,获得了纯度高于95%的重组白蛋白结合多肽,并证明重组多肽在体外能够迅速地与人血清白蛋白结合。通过与DOXO-EMCH分子化学耦联,制备获得重组白蛋白结合肽-多柔比星耦合物。A549细胞毒力实验结果显示耦合物的IC50浓度升高,药代动力学结果显示重组白蛋白结合肽能够显著延长多柔比星在血液中的循环半衰期,相对于多柔比星或DOXO-EMCH分别提高了5.6倍和3.8倍。荷瘤小鼠肿瘤生长抑制实验结果显示耦合物的抗肿瘤效力得到提升。证明了基于白蛋白结合机制可为小分子药物长效设计提供新的思路。
[Abstract]:In order to improve the circulating half-life of doxorubicin in blood, albumin was rich in plasma, stable in nature and lasting in half-life. The albumin binding peptide segment originated from bacterial surface protein was expressed by E. coli system recombination. The recombinant albumin binding polypeptide with purity of more than 95% was obtained, and it was proved that the recombinant polypeptide could bind to human serum albumin rapidly in vitro. The recombinant albumin binding peptide-doxorubicin coupling complex was prepared by chemical coupling with DOXO-EMCH molecule. The virulence test results of A549 cells showed that the IC50 concentration of the coupling complex increased. The pharmacokinetics results showed that the recombinant albumin-binding peptide could significantly prolong the circulation half-life of doxorubicin in blood, which was 5.6 times and 3.8 times higher than that of doxorubicin or DOXO-EMCH, respectively. The results of tumor growth inhibition test in tumor-bearing mice showed that the antitumor effect of the coupling compound was improved. It is proved that the albumin binding mechanism can provide a new idea for the long-term design of small molecular drugs.
【作者单位】：四川大学华西药学院靶向药物及释药系统教育部重点实验室;中国科学院过程工程研究所生化工程国家重点实验室;
【基金】：国家自然科学基金(21576267) 教育部博士点基金(120120181110036) 生化工程国家重点实验室开放基金(2014KF-05) 北京市自然科学基金(2162041)资助项目
【分类号】：R943

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