共载BCAR1/siRNA与顺铂的钙磷纳米载体治疗三阴性乳腺癌的研究

Triple negative breast cancer (TNBC),the most aggressive subtype of breast cancer, have high risk of death rates. According to the missing of surface receptor, the treatment of it was limited in standard conventional therapy, the prognosis and survival do not get a breakthrough till now. Recent studies found that BCAR1 mutations can increase the effect of platinum-based therapy in patients with TNBC. BCAR dysfunction would cause the unrepair of the DNA damage caused by Platinum. Other study found that the urokinase plasminogen activator receptor (uPAR) widely distributed on the surface of TNBC and tumor interstitial cell. This project combines the specific targeting ability of uPA to uPAR and the phenomenon of BCAR mutation associated with platinum-based drugs synergistic phenomenon, constructed a targeted sustained release delivery system. This system has a core which was combined with phospholipids -PEG polymer and Pt (II) and a shell which was combined with calcium phosphate and BCAR1/siRNA (BCAR1/siRNA-Pt (II) @ NPs-uPA). For the purpose of winning sufficient time for siRNA interference, thereby enhancing the Pt (II) therapeutic effect, the release properties were regulated by adjusting the size of the nanoparticles and the preparation process. This project intends to use TNBC breast cancer cell lines as a model to study the in vivo effects and anti-tumor effect of this nanoparticles, and in-depth research on cell cycle arrest, induction of apoptosis and autophagy induction regulatory mechanism.

三阴性乳腺癌（TNBC）作为乳腺癌最具侵袭性的亚型，死亡风险率极高，由于缺乏针对性治疗方案，亟待开发新的治疗模式。近来研究发现，BCAR1基因突变能够增加铂类药物对TNBC的治疗效果，为其治疗带来了新机遇。本项目结合uPA对尿激酶纤溶酶原激活物受体（uPAR）的特异性靶向作用，根据BCAR突变与铂类药物增效现象，构建磷酸钙和BCAR1/siRNA为壳（率先释放）、磷脂-PEG聚合物和Pt(II)为核（延迟释放）的具有协同作用的纳米靶向缓释系统。通过对纳米粒尺寸、壳核比例、制备工艺的调节，控制释放速率，达到序贯给药的目的，为BCAR1/siRNA基因干扰争取足够时间，从而增强Pt(II)的治疗作用。本项目拟以TNBC乳腺癌细胞株为模型，研究双靶向共载基因和药物的纳米粒的体内外作用特性和抗肿瘤效果，并深入研究其对细胞周期阻滞、凋亡诱导和自噬诱导的调控机制，期望为TNBC的治疗提供新的思路。

三阴性乳腺癌（TNBC）作为乳腺癌最具侵袭性的亚型，死亡风险率极高，由于缺乏针对性治疗方案，亟待开发新的治疗模式。本项目结合uPA对尿激酶纤溶酶原激活物受体（uPAR）的特异性靶向作用，根据BCAR突变与铂类药物增效现象，构建磷酸钙和BCAR1/siRNA为壳（率先释放）、磷脂-PEG聚合物和Pt(II)为核（延迟释放）的具有协同作用的纳米靶向缓释系统。通过对释放速率的控制，为BCAR1/siRNA基因干扰争取足够时间，从而增强Pt(II)的治疗作用，期望为TNBC的治疗提供新的思路，为向产业化转化的开发设计提供理论支持。通过本项目实施，在SCI期刊上发表10篇论文，其中Advanced Functional Materials (2篇)，Biomaterials (1篇)，ACS Applied Materials & Interfaces (1篇)，Theranostics (1篇)。参加多次国内和国际会议，并且在多次会议上做专题报告。获得2019年上海市“浦江人才计划”。