自降解焦糖化载Mn纳米体系在乳腺癌pH响应成像及药物控释诊疗一体化中的作用及机制研究

At present, breast cancer is faced with poor early and specific diagnosis and difficulties of multimode diagnosis and treatment and real-time monitoring, however, the emerging multifunctional theranostic nanosystem can be used to resolve this problem. Unfortunately, there are also many questions of the nanosystem including degradation and targeting of the carrier, imaging efficiency and drug control release, which may influence its clinical transformation. Based on this, we will develop a novel self-degradable caramelized nanosystem with pH sensitive MRI, photothermal therapy + thermal controlled release of DOX, real-time monitoring. Glucose monomer will be used to develop nanospheres (easy degradation), and its internal high-energy carbon-carbon double bonds promote photothermal conversion which will result in real-time NIR imaging, photothermal therapy and temperature controlled release of drugs. The surface glucose side chains can be recognized and uptaken by tumor cells to achieve the active targeting. The surface CNS is linked to MnCl2 and PEI chain to achieve pH sensitive MR imaging. The DOX in PEI chain will trigger DOX release in acidic environment, and photothermal + chemotherapy will achieve doubling effects. The vivo and in vitro experiments will be used to verify the effectiveness of breast cancer in diagnosis and treatment, and the metabolic mechanism will be explored. The Mn @ CNS @ DOX system aims to fundamentally solve the diagnosis and treatment problems of breast cancer, promote the development of individual and fine diagnosis and treatment, and the clinical transformation, which exhibits important significance and application potential.

目前乳腺癌面临早期及特异性诊断欠佳、多模式诊疗及实时监控困难等瓶颈，多功能诊治一体化纳米体系为此问题的解决提出了可能。但目前后者也因载体的降解及靶向性、成像效率、药物精准控释等问题而制约其临床转化。因此，本研究构建一种新型可自降解的焦糖化纳米体系，具有pH敏感MRI、光热治疗+热控释DOX治疗、实时疗效监控功能。葡萄糖单体制备纳米球，易于降解,其内部高能碳碳双键促进光热转换并实现NIR成像、光热治疗及温度控释，表面葡萄糖侧链可被瘤细胞识别、摄取以实现主动靶向；CNS表面络合MnCl2且PEI链化实现pH敏感MR成像；链状PEI负载DOX，酸性环境下光热触发DOX释放，而光热+化疗实现疗效倍增。体内及体外实验验证乳腺癌诊疗一体化的效果，并探讨其作用和代谢机制。该Mn@CNS@DOX体系旨在从根本上解决乳腺癌面临的诊治难题，促进个体化和精细化诊疗发展，促进临床转化，具有重要的意义及应用前景。

目前乳腺癌面临早期及特异性诊断欠佳、多模式诊疗及实时监控困难，多功能诊疗一体化纳米体系为以上问题的解决提出了可能。但纳米载体的降解、靶向性、成像效率、药物精准控释等问题制约其临床转化。因此，本研究用葡萄糖单体制备焦糖化纳米球（CNS），该载体具有易降解、高生物安全性及pH响应性的特征。在此基础上，制备具有靶向MR成像、精准光热治疗+热控释DOX治疗、实时疗效监控功能的多模态Mn@CNS@DOX体系。体内外实验表明该体系实现了乳腺癌的联合增益治疗：治疗组治疗前后肿瘤体积减少60%。该体系还实现了靶向MRI成像和实时疗效监控：静脉注射4h后肿瘤区域的T1信号强度增加至150%。ICP-MS及MR联合检测结果显示其具有pH响应性成像能力，可显著提高乳腺癌的诊断水平及疗效评估能力。因此，该复合纳米体系实现了乳腺癌准确诊断和精准治疗瓶颈问题的突破，为个体化和精细化诊疗发展提供了新的策略，同时高生物安全和降解性的CNS载体利于临床转化。此外，我们继续深化拓展该纳米体系的研究范围和功能。在肝癌方面：制备了氧化锰包被焦糖化纳米球(Mn@CNS)主动靶向肝脏肿瘤的新型探针，用RAW264.7、BRL-3A、HepG2细胞及大鼠肝胆动物模型证实了该体系具有细胞毒性小、可躲避巨噬细胞摄取的特点，其在体内延迟强化时间（24h）明显高于肝胆特异性对比剂优维显（2h），且r1及r2明显高于马根维显，具有良好的MR成像能力，且它可通过粪便排泄，是一种更理想的肝胆对比剂。在胰腺癌方面：制备了MnFe2O4焦糖化纳米球，细胞实验证实该体系具有良好的H2O2催化能力，促进了ROS产生，导致铁死亡发生，该纳米体系同步实现了胰腺癌化疗、铁死亡联合增益的胰腺癌治疗，为胰腺癌的治疗难题提出了新的解决方案。总之，该课题从多方面证实了CNS的生物学特征及其在乳腺癌、肝癌和胰腺癌精准诊疗中的价值，大大拓展深化了研究内容，为乳腺癌等类似恶性肿瘤精准个性化诊疗提供重要的方法，也为临床转化和多个肿瘤类似问题的解决奠定了基础，具有重要的临意义和潜在新药开发价值。