靶向HER2的新型DNA纳米镊抗乳腺癌作用的研究

HER2-positive breast cancer is an aggressive disease with fast progress and poor prognosis. Thus, it is an urgent need to develop new targeted treatment technologies for HER2-positive breast cancer. Here, DNA nanomaterials own advantages of flexible design, excellent biocompatibility, which has great potential application in biomedicine. Our pre-work designed and constructed a novel DNA nanotweezer with strong target-induced regulatory capacity, which can be used for highly sensitive detection of binary targets..In this project, a novel technology will be developed by integrating the regulation of protein and gene regulation based on our previous work for the treatment of HER2-positive breast cancer. First, we will design and construct novel HER2-targeted DNA nanotweezer, and explore its new features and switching mechanism. Second, with multifunctional DNA nanotweezer, HER2-targeted regulation technology will be developed to effectively suppress the expression of HER2 at the cellular level. Apoptosis of HER2 - positive tumor cells will be induced by down-regulating HER2 protein and inhibiting HER2 mRNA translation, achieving targeted therapy of HER2-positive breast cancer. Finally, we will further validate the targeted therapeutic effect of the developed new methodology for HER2-positive breast cancer in vivo animal..The implementation of this project will provide new ideas for individualized precise treatment of HER2 - positive breast cancer.

HER2阳性型乳腺癌进展快、侵袭力强、预后差，亟待发展靶向治疗新技术。DNA纳米材料设计灵活、生物相容性好，在生物医学中极具应用潜力。我们前期构建的DNA纳米镊靶向诱导调控能力强，实现了对双靶物质的同时高灵敏检测。在此基础上，本项目拟发展一种基于DNA纳米镊的蛋白与基因靶向调控一体化新策略，用于HER2阳性型乳腺癌的靶向治疗。首先，我们将构建靶向HER2的新型多功能DNA纳米镊，研究其新特性及开关新机制；其次，我们将在细胞水平上，利用该新型DNA纳米镊建立靶向抑制HER2蛋白与mRNA表达的新方法，通过下调HER2蛋白表达与抑制HER2 mRNA转录后翻译双重机制诱导HER2阳性型肿瘤细胞凋亡，实现对乳腺癌的靶向治疗；最后，我们将在动物活体内进一步验证该新方法对HER2阳性型乳腺癌的靶向治疗作用；本项目的实施将为发展HER2阳性型乳腺癌的个体化精准治疗新策略提供新思路。

HER2+型乳腺癌是女性最常见的恶性肿瘤之一，进展快、侵袭力强、预后差，亟待发展新的靶向治疗方法。DNA纳米结构因具有设计灵活、生物兼容性好，在肿瘤的靶向治疗中具有广泛的应用前景。本项目在前期研究基础上，构建并发展了一种全新的HER2+型乳腺癌治疗策略：新型DNA纳米镊调控肿瘤细胞蛋白与基因一体化。.本项目首先建立了基于Mg2+依赖型DNA纳米蝎（AptDzy-DNS）的肿瘤细胞内基因沉默新方法。AptDzy-DNS上自主装的的特异性适体作为“蝎子刺”通过与肿瘤细胞表面的蛋白特异性结合而靶向肿瘤细胞，AptDzy-DNS上的DNAzyme作为“蝎子钳”通过将mRNA切割成片段用于靶向基因治疗。通过与AptDzy-DNS上的Mg2+依赖性DNAzyme反应，癌细胞中的mRNA因剪切断裂而降解，从而下调蛋白的表达，阻止癌细胞生长并实现高效靶向治疗。为了使DNA动态自组装在细胞内呈现最佳效果，本项目在靶向识别以及邻位诱导mRNA剪切作出了一定创新性的研究，并进一步探讨DNA纳米结构在DNA动态自组装方面的应用研究。最后，本项目发展了基于端粒酶诱导型DNA纳米镊的肿瘤细胞内基因沉默新方法，旨在通过内源性刺激驱动实现肿瘤细胞的靶向治疗：1）通过肿瘤细胞内过表达的端粒酶诱导DNA纳米镊闭合，介导纳米镊黏性末端与HER2 mRNA邻位识别；2）邻位识别激活纳米镊黏性末端的Mg2+依赖型剪切酶，通过组装与去组装的方式对HER2 mRNA的进行高效循环剪切，从而下调HER2蛋白的表达，实现肿瘤的靶向性治疗。.本项目的实施为HER2+型乳腺癌的靶向调控与个体化治疗提供了一个简单高效的平台。