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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。
In order to improve the circulatory half-life of doxorubicin in blood, albumin-binding peptides derived from bacterial surface proteins were recombinantly expressed by E. coli system based on the abundant, stable and long-lived albumin in plasma. A purification process was established to obtain a recombinant albumin-binding polypeptide with a purity higher than 95%, and the recombinant polypeptide could be rapidly bound to human serum albumin in vitro. A recombinant albumin-binding peptide-doxorubicin conjugate was prepared by chemical coupling with the DOXO-EMCH molecule. A549 cytotoxicity test results showed that the IC50 concentration of the conjugate increased pharmacokinetic results showed that recombinant albumin binding peptide can significantly prolong the circulatory half-life of doxorubicin in the blood relative to doxorubicin or DOXO-EMCH Respectively, increased by 5.6 times and 3.8 times. Tumor-bearing mice tumor growth inhibition test results show that the antitumor efficacy of the conjugate is improved. It proves that the mechanism based on albumin binding can provide new ideas for the long-term design of small molecule drugs.