抗明胶酶scFv-LDM双价融合蛋白的分子设计及其抗胰腺癌实验研究

项目名称： 抗明胶酶scFv-LDM双价融合蛋白的分子设计及其抗胰腺癌实验研究

项目编号： No.81201765

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 钟根深

作者单位： 新乡医学院

项目金额： 25万元

中文摘要： 胰腺癌是一种严重威胁人类健康的恶性肿瘤，非手术治疗除吉西他滨外还缺乏更有效的治疗药物，开发新型的胰腺癌治疗药物迫在眉睫。明胶酶在胰腺癌及其间质中高表达，在正常组织呈极低表达并受到严格调控，因此是一个潜在的治疗靶点；力达霉素LDM是一个高效的抗肿瘤抗生素，其与抗体分子的偶联物在动物体内展现了良好的抗肿瘤效果。本项目在前期抗明胶酶scFv-LDM双价融合蛋白的基础上，针对其不易被细胞内化的问题，拟采用可剪切的细胞穿透肽ACPPs技术，将明胶酶可切割的E9-GPLGMLSQ-R9多肽序列引入scFv和LDM之间，提高LDM在肿瘤局部释放和进入胞内的效率，以期获得一种新型、高效的抗胰腺癌抗体靶向药物。同时，本项目体内药效评价拟采用提前给予小剂量抗明胶酶scFv的策略，以规避ACPPs非特异剪切释放的问题，为后续基于MMP-2/9 ACPPs的融合蛋白体内给药策略提供新的思路和借鉴作用。

中文关键词： 胰腺癌；明胶酶；力达霉素；ACPP；活体成像

英文摘要： Pancreatic cancer is one of maligancies that is seriously threat to human health, there is no effictive drug other than Gemcitabine in non-surgical treatment of pancreatic cancer, the development of more potent drugs against pancreatic cancer is imperative. It was known that gelatinases was overexpressed on pancreatic cancer and its stromal cells, and was low-expressed on normal tissue which was strictly regulated, therefore, gelatinases was a potential target for cancer theapy of pancreatic cancer.Lidamycin (LDM) was a potent antitumor agent and demonstrated well antitumor efficiency against pancreatic cancer, its conjugates with antibody molecule could signficantly inhibited the tumor growth in vitro and in vivo. This project was designed based on the previous results of a tandem anti-gelatinases scFv-LDM fusion protein, which demonstrated that the fusion protein could not enter the cancer cells efficient. In order to improve the internalization efficacy of bivalent fusion protein scFv-LDM, the activatable cell-penetrating peptide (ACPP) of E9-GPLGMLSQ-R9 was introduced between the tandem scFv and LDM, and thus enhanced the antitumor efficacy of dFv-LDM fusion protein. In this project, a new approach of preinjecting the anti-gelatinases scFv was adopted,with an aim to avoid the non-specific activatble possibi

英文关键词： pancreatic cancer；gelatinase；lidamycin；ACPP；animal imaging