具有癌症早期精确诊断及治疗功能的纳米金系统研究

The development of high-sensitivity CT contrast agents is imperative for the early diagnosis and treatment of cancer. The researches show that, the image quality is positive correlation to the density of AuNPs in the image sites, but the significant toxicity of AuNPs with high dose could not be neglected. Moreover, the nanoparticles (AuNPs) with smaller size have better tissue penetration ability. So, the achievement of higher AuNPs density in target site with less injection dose and better tissue penetration ability, is the key point in the design of AuNPs CT contrast agent..In this study, the AuNPs (10 nm) will be modified with targeting ligand, appropriate acid-sensitive group and hydrophobic group. By regulating the structure of these group, the small AuNPs can assemble into large diameter (100-200 nm) in physiological condition (pH=≥7.2), resulting in the shielding of GA in circulation and enrichment of contrast agents in the tumor sites by EPR effect. Then the assembled AuNPs will disassemble in tumor site (pH≤6.8), which will endow the AuNPs with stronger tissue penetration ability and better imaging sensitivity. In conclusion, this AuNPs contrast agent with pH responsibility will offer the high sensitivity and low toxicity for CT image. More importantly, it is necessary to establish a platform to realize the aggregation and dispersion of AuNPs with different ligands at pH7.2 and 6.8.

发展高灵敏度的CT造影剂有助于癌症的早期精确诊断与治疗。研究表明，纳米金在造影部位的浓度越高，CT成像效果越好，但大剂量注射存在安全隐患。同时，颗粒越小组织渗透能力越强；因此，如何以较小的注射量实现在靶部位的高浓度富集，同时又具有较强的癌组织渗透能力，是设计高灵敏度纳米金CT造影剂的关键所在。.本申请拟在小粒径(10 nm 左右)纳米金表面连接靶向配体及酸敏感基团和疏水基团，使纳米金的聚集与分散呈现pH响应性。使其在血液循环中（pH=≥7.2）聚集成100-200 nm的“大粒径”纳米金形式，屏蔽靶向配体的同时使EPR效应最大化，实现在靶部位高浓度富集以降低注射剂量；到达靶部位（pH≤6.8）后分散成小粒径的纳米金形式以利于渗透进入癌组织，获得高灵敏性CT成像效果，经载化疗药物后具有治疗功能。更关键的是建立一个平台，使含不同靶向配体的纳米金都能准确实现pH7.2和6.8的聚集与分散。

本研究主要以纳米金为载体，构建了用于肿瘤诊断和治疗的纳米体系。通过对纳米金表面进行修饰，构建了肿瘤酸性微环境响应的自组装/解组装体系。聚集态纳米金具有更高的表面等离子共振效应，因此相对分散态纳米金，其对拉曼信号的放大约10.3倍，肿瘤区域的CT成像精度提高了约1.5倍，而且光热转化能力也大为提高，抑瘤率达86.40％。这些研究结果为其在肿瘤的早期诊断及治疗上的应用提供了依据。.金、铂作为高原子序数的元素，具有放疗增敏的作用。在此基础上，构建了使肿瘤区域血管正常化的纳米金放疗增敏剂，来增加肿瘤区域的血流灌注，平均灌注单位（PU）显著增加了52%，放疗的疗效提高了38%。纳米铂增敏体系提高了肿瘤组织的ROS的水平，缓解了辐射抗性。在低剂量X射线照射下（4 Gy），抑瘤率高达到91.2%，明显减小了放疗的副作用，说明该体系具有明显的放疗增敏作用。.此外，构建了单光激活的多功能硒化铋纳米体系，实现了CT成像介导的级联光热&无氧光动力&免疫三重协同治疗，该纳米粒子的X射线衰减系数高达37.77 Hu·mL/mg，是临床用碘海醇造影剂的2.65倍，能够显著提高CT成像效果有利于肿瘤的早期诊断，肿瘤抑制率高达99.6%。并基于硒化铋，构建了血红素辅助的“三合一”级联催化纳米体系，实现了化学动力&光动力&光热三重联合治疗，肿瘤抑制率高达92.3%。这些以纳米金、铂为基础构建的纳米体系为其用于肿瘤的早期诊断和治疗奠定了基础。