Angiopep-2介导的共载siDNA-DBT/卡莫司汀的双靶向纳米复合物增强脑胶质瘤放化疗作用效果及其机制研究

项目名称： Angiopep-2介导的共载siDNA-DBT/卡莫司汀的双靶向纳米复合物增强脑胶质瘤放化疗作用效果及其机制研究

项目编号： No.81472349

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 丁雪鹰

作者单位： 上海交通大学

项目金额： 72万元

中文摘要： 放化疗敏感性低、特异性差是脑胶质瘤临床治疗中的两大难题，常导致病人无法耐受甚至放弃治疗。本课题前期验证：新一代生物放射增敏剂Dbait（siDNA-DBT）可有效增强恶性脑胶质瘤U251/R细胞的放射敏感性。因此，构建能突破血脑屏障BBB并靶向胶质瘤细胞的纳米基因载体，将siDNA-DBT和化疗药同步靶向递送、作用至肿瘤组织，有望减小照射和化疗药的毒性，提高脑胶质瘤的治疗效果。本课题在前期肿瘤靶向及脑靶向给药基础上，拟将siDNA-DBT与化疗药卡莫司汀（BCNU）以阳离子聚合物PAMAM共载，并以对BBB和胶质瘤细胞双重靶向的多肽Angiopep-2特异性修饰，构建新型靶向纳米复合物A-PAMAM(DBT/BCNU)，并对其脑部及肿瘤靶向性、细胞转染和基因沉默效率、体内分布、抗肿瘤活性、安全性、放射增敏机制和放化疗同步抗肿瘤机制进行研究，将为脑胶质瘤及其它肿瘤的综合治疗提供新途径。

中文关键词： C15_脑；中枢神经系统肿瘤；放化疗；放疗增敏剂；纳米复合物；靶向递送

英文摘要： Low sensitivity and poor specificity were recognized as two major problems in clinical radiochemotherapy of glioma, which always resulting in the patients's management failure and coursing the treatment abandonment. The preliminary experiment verified: Dbait (siDNA-DBT), a new generation of biological radiation sensitizer, could effectively enhance the radiosensitivity of malignant glioma U251/R cells. Therefore, a co-delivery of siDNA-DBT & chemotherapy drug nano-carrier, applying sequential blood-brain barrier(BBB) penetration and glioma targeting, may be expected to improve the effect of concomitant radiochemotherapy and solve the two major clinical problem in glioma treatment. Based on our early research in brain and tumor targeting drug delivery, this subject intends to build a new targeted nano-complex A-PAMAM(DBT/BCNU) mediated with BBB and glioma cells dual specific peptide Angiopep-2, which could co-deliver siDNA-DBT and anti-glioma drug carmustine (BCNU) with cationic polymer PAMAM. The targeted activity, transfection and gene silencing efficiency, the anti-tumor activity, drug distribution, safty, synergistic anti-tumor activity and mechanism of A-PAMAM(DBT/BCNU) in vitro and vivo would be studied. Research would provide a new way for combined treatment of glioma and other solid tumors.

英文关键词： glioma;radiochemotherapy;radiation sensitizer;nano-complex;targeted delivery