智能型Purpurin-脂质体的构筑及应用于三阴性乳腺癌靶向性声化疗研究

Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer with low survival rate and high recurrence. Developing novel strategies with multimodal combination regiment may provide new hope to TNBC patients. Based on the previous work, this project aims to explore the mechanically informed combination therapy of triple-negative breast cancer using an ultrasound-controllable self-assembly of purpurin-liposome. Firstly, the phospholipid coupled with purpurin will be prepared to synthesize the multifunctional porphyrin-liposomes, which simultaneously carry the anti-tumor drug Doxorubicin and CHK1 inhibitor SRA737, thus establishing a stable ultrasound-responsive nano-delivery platform. Secondly, from the in vitro and in vivo experiments, we attempt to analyze the features of the smart liposomes, such as porphyrin multimodal imaging, image-guided ultrasound focusing, ultrasound-assist drug release, and to optimize the biophysical-chemical parameters of the synergy of sonodynamic therapy and chemotherapeutics. Lastly, this project will elucidate the spatiotemporally synergistic advantages of ultrasound combined with drug-loaded porphyrin-liposomes via many molecular, cellular and organic studies. Such system is expected to facilitate future TNBC clinical applications with image-guided local drug release, complementary function of drug targets, mechanically based signal-crosstalk, reduced systemic toxicity, etc. Success of the proposal will provide some valuable information and lay a scientific foundation for high-precision and accurate treatment of TNBC.

三阴性乳腺癌（TNBC）是威胁病患恶性程度较高的乳腺癌变，探索多模式联合治疗新策略可为TNBC患者带来生存机遇。项目拟在前期工作基础上，通过新型多功能Purpurin-脂质体可控自组装的构筑，探索靶向TNBC声化疗协同机制研究。首先是构建偶联Purpurin的磷脂作为载体材料，合成携载抗肿瘤药物Doxorubicin和CHK1抑制剂SRA737的卟啉脂质体，获得稳定的超声响应型纳米递药体系；其次从离体和在体实验分别探讨智能型Purpurin-脂质体的卟啉多模成像、影像引导超声聚焦、声控释药规律等性能，优化声化疗联合治疗TNBC的生物、理化参数组合；最后从分子、细胞、组织到机体各层次阐明超声联合载药卟啉脂质体时空同步协同治疗TNBC的作用优势和机制，从而为TNBC临床应用提供既可影像引导局部释药、合理利用药物靶点功能互补、多分子路径有机协同，同时又能有效降低系统毒副作用的高效精准治疗新策略。

三阴性乳腺癌（TNBC）是威胁病患恶性程度较高的乳腺癌变，探索多模式联合治疗新策略可为TNBC患者带来生存机遇。项目通过构筑新型多功能Purpurin-脂质体，研究了靶向TNBC声化疗协同作用的生物学机制。首先以偶联Purpurin的磷脂作为载体材料，设计合成了携载抗肿瘤药物Doxorubicin和CHK1抑制剂SRA737的卟啉脂质体，获得了稳定性良好的超声响应型纳米递药体系；其次从离体和在体方面分别探讨了Purpurin-脂质体的卟啉多模成像、影像引导超声聚焦、声控释药规律等性能，优化了声化疗联合治疗TNBC的生物、理化参数组合；最后从分子、细胞、组织到个体水平阐明了超声联合载药卟啉脂质体时空同步协同治疗TNBC的作用优势和生物学机制，为TNBC的临床应用提供了一种精准治疗新策略。