三阴性乳腺癌（TNBC）是恶性程度高、预后较差的乳腺癌变，常规治疗效果不佳，亟需探索新型联合治疗方案。本项目拟从肿瘤细胞及肿瘤相关巨噬细胞（TAMs）在肿瘤发生和进展过程中的重要作用出发，通过构筑超声响应型聚合物胶束共载SDT敏化剂Chlorin e6 (Ce6)和STAT3抑制剂Pyrimethamine (PYR)，探索靶向协同杀伤TNBC的治疗效应研究。首先将PYR和Ce6包载到Pluronic F127/P123胶束中，获得稳定的超声响应型载药胶束，并研究胶束的声控释药性能。其次从离体和在体实验探讨超声的联合作用下，Ce6-SDT协同PYR对肿瘤细胞的损伤机理；对TAMs的活化、极性重塑的影响，着重探讨联合作用下TAMs与肿瘤细胞的互作调节。从分子、细胞到机体各层次阐明超声辅助药物递送和控释、SDT协同PYR治疗TNBC的作用优势及机制，从而为TNBC的治疗研究提供新的思路和策略。

Triple-negative breast cancer (TNBC) is a malignant breast cancer with poor prognosis and low survival rate. The conventional treatment is not so effective, and it is urgent to explore novel strategies. Based on the important role of tumor cells and tumor-associated macrophages (TAMs) in tumorigenesis and progression, this project aims to explore the combinational therapy of TNBC using an ultrasound-controllable Chlorin e6 (Ce6, a sonosensitizer of SDT)/ Pyrimethamine (PYR, an inhibitor of STAT3) co-loaded polymeric micelles. Firstly, the Pluronic F127/P123 are used to synthesize the ultrasound-responsive drug delivery platform which simultaneously load Ce6 and PYR. Secondly, from the in vitro and in vivo experiments, we attempt to analyze the synergistic effects of Ce6-SDT combined with PYR on tumor cells and TAMs, including the mechanism of tumor cell death, and the regulation on activation and polar remodeling of TAMs, especially the cross-talking between the tumor cells and TAMs. This project will elucidate the spatiotemporally synergistic mechanisms of ultrasound combined with drug-loaded micelle via many molecular, cellular and animal studies. Such system is expected to facilitate future therapeutic study of TNBC with ultrasound- controlled drug delivery and release, and rational use of SDT and target molecular inhibitors, thus providing new ideas and strategies for the TNBC treatment.