抑制肿瘤生长和转移的新型喜树碱类抗癌药物的研究

The treatment and prognosis of tumor have been facing huge challenge in clinic，especially the toxicity of clinical anti-cancer drugs on normal cells, drug resistance, tumor metastasis, recurrence etc, have always been the key problems need to be resolved. It has been reported that E-selectin specifically expressed in activated endothelial cells related to occurrence, development and migration of tumor, for example, E-selectin was specifically experessed in tumor site, meanwhile, E-selectin could mediate the adhesion of tumor cells with endothelial cells which is one of the important initial steps in tumor migration. In order to realize tumor targeting and inhibit tumor metastasis at the same time, careful design and synthesis of anti-cancer drugs coupled with E-selectin antagonist could be a useful strategy. More specifically, camptothecin and 10-Hydroxycamptothecin, the well-known drugs with excellent anti-cancer activities but poor water solubilities, were choosen as starting materials. Introduction of E-selectin antagonist to camptothecin or 10-Hydroxycamptothecin may lead to overcome exsiting problems, for example, the water solubilities could be improved since most E-selectin ligands contains sugar-like or peptide structure, it has been showed that E-selectin was found in tumor besides activated endothelial cells, so the coupling compounds have potential to become targeting drugs. More importantly, anti-cancer drugs coupling E-selectin antagonist are especially valuable against metastasis and recurrence of tumor.

肿瘤的治疗和预后一直面临重大挑战，其中抗癌药物的毒副作用、肿瘤的转移和复发等是最突出的问题。研究显示E-选择素与肿瘤的发生发展及转移均有密切联系，例如其在多种肿瘤部位有特异性高表达，同时还介导肿瘤细胞与内皮细胞间的黏附，此黏附过程是肿瘤迁移的关键起始步骤。本课题拟精心设计和合成连有E-选择素拮抗剂的抗癌药物，目的是寻找同时具有靶部位富集和抑制肿瘤迁移的新型抗癌药物。具体讲，我们以经典的抗癌活性好但水溶性差的喜树碱和羟基喜树碱为起始物，通过STD等技术优化E-选择素拮抗剂并在合适位点与抗癌药物相连，该研究的优势有：（1）E-选择素配体多为寡糖、类糖或肽类分子，将其引入药物分子后预期可显著改善原药物的水溶性；（2）该偶联物可作为潜在的抗癌靶向药物使抗癌分子特异性富集于肿瘤部位；（3）通过阻断E-选择素介导的肿瘤细胞与血管内皮细胞的黏附，有望在抑制肿瘤生长的同时预防和治疗肿瘤的转移及复发。

肿瘤的治疗和预后一直面临重大挑战，其中抗癌药物的毒副作用、肿瘤的转移和复发等是最突出的问题。E-选择素与肿瘤的发生发展及转移均有密切联系，例如其在多种肿瘤部位有特异性高表达，同时还介导肿瘤细胞与内皮细胞间的黏附，此黏附过程是肿瘤迁移的关键起始步骤。本课题成功构建了E-选择素表达体系，亲和评价体系，细胞黏附体系以及抗肿瘤活性评价体系，合成了E-选择素肽类配体，并将E-选择素肽类配体通过含二硫键的连接桥与抗癌药物偶联，获得的偶联物可被肿瘤细胞内高浓度的谷胱甘肽切断释放出原药羟基喜树碱，同时研究结果表明其体外活性与原药羟基喜树碱相当，并且可通过与E选择素的结合有效抑制THP1细胞与HUVEC细胞的黏附，因此有望发挥抑制肿瘤生长和抗肿瘤转移的双重目的。上述偶联物虽具有很好的体外活性结果，但其溶解性差，因此在此基础上，我们进一步对偶联物的理化性质进行了改善，在其结构中以恰当方式引入聚乙二醇链，改善其生物利用度，获得了理化性质改善、活性提高的新型三元偶联物，具有进一步开发成抗肿瘤新药的潜力。