肿瘤靶向穿膜肽的设计、合成及影响肿瘤靶向性相关因素分析

穿膜肽广泛用于小分子药物、蛋白以及核酸的细胞运输，发展具有肿瘤靶向的穿膜肽，对于提高其在肿瘤治疗领域的应用具有重要意义。针对肿瘤靶向穿膜肽的潜在应用前景以及相关设计研究相对较少，本项目以具有高穿膜效率的双亲性穿膜肽TK和penetratin为模板，通过改变电荷、疏水性以及结构而合成一系列的类似物，研究解这些因素的变化与肿瘤选择性之间的关系，同时筛选获得具有高肿瘤选择性、高穿膜效率以及高酶解稳定性的类似物。在此基础上，以筛选出的类似物作为分子探针，通过作用机制研究评价肿瘤细胞膜表面高表达的阴离子物质对提高穿膜肽肿瘤细胞选择性的作用。总之，我们希望通过系统的构效关系和作用机制研究为肿瘤靶向穿膜肽的设计及应用提供更为翔实的理论支持。

Cell-penetrating peptides are always used to efficiently deliver many small molecule drugs, protein drugs and nuclear acid drugs into cells. Therefore, the development of tumor targeted cell-penetraing peptides is very significant for their use in tumor therapy field. For the potential application of cell-penetrating peptides and little study on the design of tumor targeted cell-penetrating peptides, the amphiphilic cell-penetrating peptides TK and penetratin with high cell penetrating activity are used as templates. We will design and synthesize a series of analogues of TK and penetratin by changing the charge, hydrophobicity and structure, and study the effects of these factors on the tumor selectivity of cell-penetrating peptides. Furthermore, we hope to obtain novel cell-penetrating peptides with high tumor selectivity, high permeable activity and high enzymatic stability by screening. Subsequently, we used these novel analogues as molecule probe to study the effects of the highly expressed anionic substances of tumor cell membranes on the tumor selectivity of cell-penetrating peptides. In short, we hope to the study of structure and activity relationship and action mechanism will give more theoretical support for designing tumor targeted cell-penetrating peptides.