纳米自噬抑制剂联合三氧化二砷抗三阴性乳腺癌的同步辐射研究

化疗耐药是当前三阴性乳腺癌治疗中亟待解决的难题，癌细胞自噬是肿瘤对化疗耐药的主要原因，通过调控自噬实现对三阴性乳腺癌的高效治疗已成为当前生物医学领域的前沿热点。本项目拟通过严格的尺寸控制筛选纳米自噬抑制剂，在其表面修饰iRGD肿瘤靶向肽，再联用化疗药三氧化二砷，开发一种兼具肿瘤靶向与自噬抑制功能的纳米自噬抑制剂@iRGD+三氧化二砷联合给药策略。选用人三阴性乳腺癌细胞模型和原位异种移植裸鼠模型，利用同步辐射扫描透射X射线显微成像技术、硬X射线荧光显微成像技术和X射线相衬显微CT成像技术，研究纳米自噬抑制剂和三氧化二砷在细胞及肿瘤内的定位、分布及含量信息；同时结合常规药理药效评价技术探究联合给药策略在细胞和动物水平的抗癌效应及抗癌机制。研究结果将为三阴性乳腺癌等恶性肿瘤的治疗提供新思路，并为拓宽同步辐射技术在生物医药领域的应用提供理论支撑。

Chemotherapeutic resistance is a problem to be solved in the current treatment of triple-negative breast cancer. The cancer cell autophagy becomes the main reason of tumor resistance to chemotherapy. Regulating autophagy to achieve efficient treatment of triple-negative breast cancer has become a hot topic in the current biomedical field. This project aims to screen nanoparticle autophagy inhibitors (NAI) by strict size control, modify tumor targeting circle peptide iRGD on its surface, and then combine with the chemotherapeutic arsenic trioxide (ATO), to develop a kind of NAI@iRGD+ATO combination administration strategy with the function of tumor targeting and autophagy inhibition. Human triple-negative breast cancer cell line and orthotopic xenograft nude mice model are chosen as experimental models. Synchrotron radiation Scanning transmission X-ray microscopy imaging technology, hard X-ray fluorescence micro-imaging technique and X-ray phase-contrast micro-CT imaging technique were used to study the localization, distribution and concentration of nanoparticle autophagy inhibitor and arsenic trioxide in cells and tumors; at the same time, these three X-ray imaging techniques combined with conventional pharmacological efficacy evaluation techniques to explore the anticancer effects and possible anticancer mechanisms of combination administration strategy at the cellular and animal levels. The results will provide new ideas for the treatment of triple-negative breast cancer and other malignant tumors, and provide theoretical support for expanding the application of synchrotron radiation technology in the field of biomedicine.