可敲减热休克蛋白表达的金纳米星对三阴性乳腺癌的疗效研究

Triple negative breast cancer (TNBC) comprises 10%-20% of female breast cancer, having the poorest outcome due to its high aggressiveness and poor response to chemical therapy, endocrine therapy and molecule targeting therapy, thus it’s important to develop new therapeutic method against TNBC. Photothermal therapy mediated by gold nanoparticles is promising for TNBC because photothermal therapy kills tumor cells by converting laser to heat and elevating local tumor temperature. Considering the high expression of heat shock protein-72 (HSP-72) that mitigates the damaging effects of heat may impair the therapeutic effect of photothermal therapy, we hypothesize that knocking down expression of HSP-72 may increase the therapeutic effect of photothermal therapy. We developed gold nanostars for photothermal therapy and loaded siRNA before. Here, we try to establish mice model of TNBC, to synthesize gold nanostars and to observe their photothermal therapeutic effect; Then we try to load siRNA against HSP-72 on the surface of gold nanostars and compare their therapeutic effect with gold nanostars; Finally we’ll using photoacoustic imaging to assess and monitor the photothermal therapeutic effect at early phase after treatment. We expect this new nanosystem will significantly improve the photothermal therapeutic effect, and pave the road for its use in clinical.

三阴性乳腺癌占女性乳腺癌的10～20％，侵袭性强，对常规治疗反应差，预后最差。因此开发三阴性乳腺癌治疗新策略是临床重大问题。光热治疗利用金纳米颗粒的光热转换能力杀灭肿瘤细胞，可为治疗三阴性乳腺癌提供新方案。由于三阴性乳腺癌本身高表达热休克蛋白-72（HSP-72），能帮助高温变性的蛋白恢复构型，对光热治疗产生耐受，所以我们假设金纳米颗粒装载敲减HSP-72表达的小干扰RNA，可克服肿瘤热耐受性，提高疗效。本项目组前期开发了介导光热治疗的金纳米星，并装载了小干扰RNA。在此基础上，本项目组拟构建三阴性乳腺癌小鼠模型，制备金纳米星，观察光热治疗效果；进而在表面装载敲减HSP-72表达的小干扰RNA，研究其对金纳米星的协同作用；并利用金纳米星本身的光声成像能力对疗效进行早期评估和动态监测。预期载可敲减HSP-72表达的金纳米星可显著提高三阴性乳腺癌光热治疗疗效，为构建诊疗新策略提供依据。

三阴性乳腺癌占女性乳腺癌的10~20%，侵袭性强，对常规治疗反应差，预后最差。因此开发三阴性乳腺癌治疗新策略是临床重大问题。光热治疗利用金纳米颗粒的光热转换能力杀灭 肿瘤细胞，可为治疗三阴性乳腺癌提供新方案。由于三阴性乳腺癌本身高表达热休克蛋白-72 (HSP-72)，能帮助高温变性的蛋白恢复构型，对光热治疗产生耐受，所以本课题提出了利用siRNA敲减HSP-72表达，提高光热治疗疗效的新思路。本课题首先设计了装载可敲减HSP-72表达的小干扰RNA的金纳米星，通过透射电镜和光散射方法对金纳米星的形貌尺寸进行表征，通过westen blot对纳米颗粒敲减HSP-72蛋白表达的能力进行表征，通过小鼠三阴性乳腺癌模型证明敲减HSP-72表达的金纳米星可以克服肿瘤热耐受性，显著提高克治疗效果。进一步的，本课题设计了多种金纳米颗粒，探索了其对多种肿瘤模型进行靶向、光声成像和光热治疗的效果。该课题为金纳米颗粒用于肿瘤诊疗一体化提供了新策略。