分子靶向与电荷屏蔽协同修饰的新型低毒抗菌肽及其抗肿瘤应用

项目名称： 分子靶向与电荷屏蔽协同修饰的新型低毒抗菌肽及其抗肿瘤应用

项目编号： No.81202400

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 张邦治

作者单位： 兰州大学

项目金额： 23万元

中文摘要： 如何发展高效低毒的抗肿瘤药物仍然面临着巨大的挑战。抗菌肽因其独特的作用机制而受到广泛关注，但毒副作用却限制了它的临床抗肿瘤应用。本项目通过发展一类简单、新型的分子靶向和电荷屏蔽协同的修饰策略，以提高抗菌肽的临床应用能力。这种策略将叶酸分子通过可释放的连接子与抗菌肽Melittin的赖氨酸侧链氨基相连，既可以通过叶酸分子增加Melittin的选择性，又可以通过屏蔽赖氨酸侧链所带正电荷而降低Melittin的毒性。另外通过对连接子的筛选和研究，使药物进入肿瘤细胞后更容易将Melittin等抗菌肽释放出来，恢复其破膜活性，进而作用于线粒体诱导细胞凋亡，或者负载基因治疗药物等大分子使其更容易作用于靶位点。这种修饰策略简单易行，因此也可扩展到其它高活性抗菌肽的修饰与应用上，用于发展高效的抗肿瘤药物或肿瘤基因治疗的药物载体，为抗菌肽在抗肿瘤领域的应用进行有益的探索。

中文关键词： 抗菌肽；靶向屏蔽；抗肿瘤；选择性；抗菌

英文摘要： Development of anticancer drugs with efficiency and low toxicity remains a considerable challenge. Based on the unique mechanism of membrane damage, antimicrobial peptides are gaining more attention. However, the toxic and side effect hinders the clinical application of antimicrobial peptides. To improve the antitumor application of antimicrobial peptides, in this project, we designed a novel molecular targeting and charge shielding strategy that the lysines side chain aminos of antimicrobial peptide Melittin were conjugated with folate via cleavable linker. The decreased toxicity and increased selectivity are by masking the Lys positive charges with folate. After the folate targeted Melittin conjugate entering tumor cells, Melittin is released from the conjugate and then recover its membrane disruption activity. The released Melittin can induces cell apoptosis by disrupting mitochondria or facilitate the endosomal escape of macromolecules by ruptureing the endosomal membrane. This strategy is simple and feasible, therefore it also can be used to modify other antimicrobial peptides to develop efficient antitumor drugs or gene vectors. Additionly, this strategy is contributed to the useful exploration of clinical applications of antimicrobial peptide in the antitumor field.

英文关键词： Antimicrobial peptide；Targeting and shielding strategy；Antitumor activity；Tumor selectivity；Antimicrobial activity