抑制ABCG2增强肝癌组织集聚近红外荧光染料MHI-148的生物学意义及机制研究

Liver cancer operation has high risk and low safety, but intraoperative real-time imaging technology can greatly improve the operation quality. Near infrared fluorescence dyes make it possible to develop the real-time imaging technique of liver cancer. After the injection of ICG, the range and boundary of the tumor can be observed during the operation by the fluorescence system. However, the imaging time is short and the tumor specificity is poor. near infrared fluorescence heptamethine cyanine dye MHI-148 is a recently discovered novel fluorescent dyes, with longer imaging time and better tumor specificity. However, it still not be absorbed by part of the tumor , and the existing theory could not explain the reason. Therefore, this study intends to organize PDX model and verified MHI-148 dye imagine effect in HCC， determine the specific metabolic process of MHI-148 , make a comparison between MHI-148 and ICG, reveal the molecular mechanism that ACBG2 efflux of MHI-148 dye, filling the the blank of theory, build an innovative dye compound which is difficult to be discharged, break through the bottleneck of application of real-time imaging technology, and provide the basis for the application of HCC real-time imaging techniques in operation.

肝癌手术难度大风险高安全性差，术中实时显像技术可极大地提升手术质量。近红外荧光（ NIRF）染料使肝癌术中实时显像技术成为了可能，患者注射染料后，术中可通过荧光显像系统实时观察到肿瘤的范围与边界。但目前该技术显像持续时间短，肿瘤特异性较差。七甲川花菁NIRF染料MHI-148是新型荧光染料，课题组证实其显像时间更长肿瘤特异性更好，但不被部分肿瘤集聚，现有理论无法解释个中原因。因此本研究拟在前期基础之上构建裸鼠人肝癌组织原位移植模型验证MHI-148染料在肝癌组织中显像的生物学功能，确定MHI-148在肝癌组织中具体代谢过程与时间节点，比较MHI-148与传统NIRF染料ICG的优劣，揭示ACBG2外排MHI-148染料的分子机制，填补NIRF染料在部分肿瘤组织中不集聚的理论空白，创新性地构建难以被排出的染料复合物，突破实时显像技术的瓶颈，为肝癌切除术中实时显像技术的应用提供依据。

近红外荧光(NIRF)成像最近成为一种有前途的非侵入性癌症成像工具。然而，NIRF染料对肿瘤缺乏敏感性和特异性，限制了其在外科导航中的应用。在这里，我们证明了NIRF染料MHI-148具有吲哚菁绿(ICG)的生物相容性，但在肝细胞癌(HCC)细胞和组织中具有更高的成像强度和优先摄取和保留。此外，我们的数据表明，在β-catenin信号通路的调控下，膜转运蛋白OATP2B1和ABCG2介导了肝癌细胞中MHI -148的肿瘤特异性积累和保留。此外，β-catenin抑制剂的治疗显著增强了MHI-148在HCC组织中的积累，提高了MHI-148在体内的肿瘤显像效果。我们的研究揭示了膜转运蛋白OATP2B1和ABCG2的分布和表达与MHI-148的肿瘤特异性积累之间的联系机制，并为β-catenin信号通路在OATP2B1和ABCG2诱导的MHI-148在HCC组织中的滞留调节作用提供了证据。我们的研究结果表明，靶向MHI-148转运机制关键成分的策略可能是提高HCC成像的一种潜在方法。