热引导纳米化环巴胺靶向杀伤耐药性乳腺癌及作用机制

With respect to the rapidly increasing incidence and biochemical complexity, the cancer treatment and regulation emphasizes multimodality therapy. In recent years we have focused on cancer therapy by high-frequency hyperthermia in combination with radio-chemotherapy. Inspired by above clinical experience as well as basic research on nanomedicine, in this project we propose a hyperthermia guided targeting strategy to improve multidrug-resistant breast cancer treatment. The new strategy enables the selective accumulation of therapeutic “nanodrugs” within tumor area regulated by hyperthermia. These nanodrugs will be formulated by carrying cyclopamine into thermo-senstive elastin like polypeptides(ELPs), which is prone to aggregation subject to a specific temperature leading to subsequent accumulation in tumor site given a higher tumor temperature than normal tissue.Then the TAT, one kind of cell penetrating peptides，is added te the surface of cyclopamine-ELPs nano particles and at last congstrcut the cyclopamine-ELPs -TAT nano system.the By using multidrug-resistant breast cancer as the model, the in vivo targeting capability by this new strategy will be confirmed and be correlated with thermosensitive property of the nanodrug system. The therapeutic efficacy towards cyclopamine resistant breast cancer will be evaluated. The mechanism on biochemical levels will be explored to show how it reverse the drug resistance property and inhibit the tumor growth. The implement of this project is not only provides an effective approach for cancer treatment, buts also addresses the critical challenges faced in tumor targeting.

恶性肿瘤发病率逐年升高,治疗以多学科综合治疗为原则。申请人近年用高频热疗联合放化疗综合治疗肿瘤，获得了创新启发。拟在前期构建的温敏纳米靶向载体（ELPs）以及潜在抗肿瘤新药环巴胺的研究基础上，探索热引导温敏性环巴胺-类弹性蛋白（ELPs）-细胞穿膜肽TAT高效靶向新思路，研究“热引导靶向”显著提高耐药性乳腺癌的杀伤作用及逆转耐药机制。以耐药性乳腺癌细胞和动物为平台，环巴胺为化疗药物，类弹性蛋白ELPs和穿膜肽TAT为载体，利用环巴胺-ELPs-TAT纳米系统的“热富集”作用，在热疗介导下，富集于肿瘤部位。研究体内靶向性和温度响应性相互关系，验证对乳腺癌耐药的高效逆转性杀伤性，对MDR的相关通路作用方面初步探讨其逆转肿瘤耐药的机制。开发热引导靶向结合温敏纳米载体材料作为一种高效可行的临床肿瘤物理靶向新模式，为潜在抗肿瘤应用前景的新药环巴胺安全应用临床提供新思路，为耐药性乳腺癌治疗提供新手段。

恶性肿瘤发病率逐年升高,治疗以多学科综合治疗为原则。申请人近年用高频热疗联合放化疗综合治疗肿瘤，获得了创新启发。拟在前期构建的温敏纳米靶向载体（ELPs）以及潜在抗肿瘤新药环巴胺的研究基础上，探索热引导温敏性环巴胺-类弹性蛋白（ELPs）-细胞穿膜肽TAT高效靶向新思路，研究“热引导靶向”显著提高耐药性乳腺癌的杀伤作用及逆转耐药机制。以耐药性乳腺癌细胞和动物为平台，环巴胺为化疗药物，类弹性蛋白ELPs和穿膜肽TAT为载体，利用环巴胺-ELPs-TAT纳米系统的“热富集”作用，在热疗介导下，富集于肿瘤部位。研究体内靶向性和温度响应性相互关系，验证对乳腺癌耐药的高效逆转性杀伤性，对MDR的相关通路作用方面初步探讨其逆转肿瘤耐药的机制。开发热引导靶向结合温敏纳米载体材料作为一种高效可行的临床肿瘤物理靶向新模式，为潜在抗肿瘤应用前景的新药环巴胺安全应用临床提供新思路，为耐药性乳腺癌治疗提供新手段。