发展高效低毒的抗肿瘤药物十分具有挑战性。将传统抗肿瘤药物与靶向载体偶联构建前药是一种提高药物治疗指数的有效策略。来源于细菌氧化还原蛋白azurin的p28是一种具有肿瘤细胞选择性和抗肿瘤活性的阴离子穿膜肽，治疗效果好且无毒副作用。尽管p28已完成I期临床，但是还没有其作为药物载体的报道。基于多肽类药物载体的优点和项目组前期关于穿膜肽-药物偶联以及p28的工作，本项目拟发展一类新型多肽-药物偶联物构建策略：通过引入十六烷酸提高p28与白蛋白的结合能力，从而提高p28-药物偶联物的体内半衰期和肿瘤组织蓄积能力；通过小分子抗肿瘤药物喜树碱、阿霉素、紫杉醇等的合理引入提高p28-药物偶联物的穿膜活性和抗肿瘤活性；通过将以上基团组合引入p28中构建一类长效、安全以及高效的抗肿瘤靶向前药。我们希望通过对这类构建策略的研究，为靶向抗肿瘤药物的设计提供新的思路和探索，并获得有临床应用价值的抗肿瘤候选药物。

Development of antitumor drugs with high selectivity and low toxicity remains a considerable challenge. Prodrug strategy by attachment of traditional drugs with targeted vectors is effective for improving the therapeutic index of antitumor drugs. p28, derived from azurin (a cupredoxin), is a type of anionic cell penetrating peptide with tumor selectivity and antitumor activity. Although p28 has completed the phase I trial, there is no study about taking p28 as a drug vector. In this project, we develop a novel strategy of construction of peptide-drug conjugates: increasing the albumin binding activity of p28 by introduction of palmitic acid is to enhance the half-life in vivo and tumor accumulation of p28; reasonable introduction of camptothecin, doxorubicin or paclitaxel is to enhance the cell penetrating activity and antitumor activity of p28-drug conjugates. Based on the design strategy, long-term, safe and efficient prodrugs are constructed by introduction of the combination of the above groups into the p28. In short, we hope that the studies on the construction strategy of peptide-drug conjugates can contribute to providing new ideas and useful exploration for the development of targeted antitumor drugs. Simultaneously, we hope to obtain the antitumor drug candidates with potent clinical application.