基于敲减三阴性乳腺癌趋化因子受体CCR4的自封孔纳米羟基磷灰石材料的靶向治疗研究

Triple negative breast cancer (TNBC) is very difficult to treat due to the lack of effective therapeutic targets. It is necessary to develop new targeted drug delivery systems to improve efficacy. Studies have shown that CCR4 plays an important role in the development and metastasis of TNBC, and is a promising new target for TNBC. Nano-hydroxyapatite（NHAP）can protect loaded drugs form premature release during the circulation and then release drugs in the tumor-specific acidic environment after capped by itself. Therefore, it can be used as a carrier to delivery drugs for on-demand release at tumor site and small interfering RNA (siRNA) of CCR4 expression to improve the efficacy and reduce toxicity. This project intends to build new NHAP drug carriers loaded CCR4 and doxorubicin to recognize c(RGDFK) and for targeting and CCR4 for therapy. Then investigate the delivery efficiency and controlled-release profiles of siRNA and doxorubicin in TNBC cell lines and xenografts in situ. Furthermore, combine with MRI and fluorescence imaging to real-time monitor distribution and treatment efficacy for TNBC. The project is expected to construct a new anticancer drug system for target therapy and efficacy monitor of TNBC.

缺乏明确有效的治疗靶点是三阴性乳腺癌（TNBC）治疗的瓶颈，探索靶向、高效、安全的药物是其难点。研究表明趋化因子受体CCR4在TNBC发生、发展和转移中均起重要作用，可能成为TNBC治疗的新靶点，RNA干扰抑制CCR4表达将会提高TNBC的治疗疗效。为了高效安全递送小干扰RNA（siRNA）抑制CCR4的表达，我们拟研制自封孔的纳米羟基磷灰石材料，实现pH刺激响应性递送siRNA。又因TNBC细胞表面高表达整合素αvβ3，环化肽c(RGDFK)可与其特异性结合，连接c(RGDFK)能靶向到肿瘤细胞。因此，本项目拟以CCR4为治疗靶点，环化肽c(RGDFK)为识别分子，自封孔纳米羟基磷灰石为载体，递送可敲减CCR4的siRNA和抗癌药物阿霉素靶向治疗TNBC，并结合磁共振/光学成像技术进行实时监测和评估治疗，预期提高TNBC的治疗疗效，为临床TNBC的治疗提供新的方法和疗效检测手段。

缺乏明确有效的治疗靶点是三阴性乳腺癌（TNBC）治疗的瓶颈，探索靶向、高效、安全的药物是其难点。研究表明XBP1在TNBC发生、发展和转移中均起重要作用，有可能成为TNBC的新靶点；纳米羟基磷灰石（NHAP）可在肿瘤特有的微酸环境下降解实现高效安全递药。本项目以XBP1为治疗靶点，环化肽c(RGDFK)为识别分子，利用装载抗癌药物阿霉素（DOX）和可敲减XBP1的siRNA的NHAP对TNBC治疗进行研究，通过RNA干扰抑制XBP1表达和可控释放DOX联合治疗TNBC, 并结合磁共振/光学成像技术进行监测和评估治疗，提高TNBC的治疗疗效，并抑制了转移，为临床TNBC的分子靶向治疗及磁共振成像提供手段和奠定基础。