自组装PET/MR/PA三模式纳米探针的构建及在转铁蛋白受体高表达肿瘤中的应用

Multimodality imaging is the current focus and future development in Molecular Imaging Field. For example, PET(Positron Emission Tomography) is high sensitive and MR(Magnetic Resonance) is anatomic with high spatial resolution. While PA (Photoacoustic) is frequently coregistered with ultrasonic imaging, can provide functional and cellular/molecular information about tissue. Combined with the above 3 techniques, anatomic, functional and molecular information can be collected for early and accurate diagnosis, therapy monitoring and adjustment. Multifunctional probes for PET/MR/PA are seldom reported. In this project, we want to develop a probe based on apoferritin, melanin, iron and 68Ga, set up transferrin receptor high/low expressed tumor models and try multimodel imaging. This is the first time to try to encapsulate large biopolymer into apoferritin in water solution with simple preparation method. All the materials are nature and endogenous, so the probe is safe, non-toxicity, biocompatible and cost-effective. The half life of 68Ga is short (about 60min), so the clearance of radiation is fast and no-worry to environment and operator. With PET, the target distribution, the metabolism and elimination route of the probe can be quickly and sensitively observed. MR and PA signal will be enhanced to supply more information about anatomic and molecular aspects. This probe can be a promising drug delivery platform too.

多模式成像是分子影像的热点和趋势，可提供解剖、功能及分子层面相结合的全方位信息。国内外对多模式分子显像及探针的研究还处于起步阶段，正电子发射计算机断层成像/磁共振成像/光声成像(PET/MRI/PA)三模式联合显像鲜有报道。本项目拟采用去铁铁蛋白，利用其pH依赖性加载黑色素和铁；利用其离子通道加载正电子金属核素68Ga；构建三功能探针，对铁蛋白受体阳性/阴性表达的肿瘤进行PET/MR/PA三模式显像。此新型探针尝试去铁铁蛋白包裹生物高分子，工艺简单，易于推广；选用天然材料，安全无毒，价廉节约；PET示踪灵敏度高，快速实现体内"暗箱"过程可视化；68Ga半衰期短，在体内清除快，对操作人员和环境均无影响；组合材料增强了MR和PA的信号，为PET显像补充提供解剖、功能、分子水平信息，体现了多模式显像的高灵敏度、高特异性和全面性；此探针还可作为有效的药物传输载体，为靶向分子显像和治疗翻开崭新的一页

多模式成像是分子影像的热点和趋势，可提供解剖、功能及分子层面相结合的全方位信息。国内外对多模式分子显像及探针的研究还处于起步阶段，正电子发射计算机断层成像/磁共振成像/光声成像(PET/MRI/PA)三模式联合显像鲜有报道。本项目通过酸碱调节，去铁铁蛋白（APF）开环、闭环，即可便捷组装黑色素纳米颗粒（MNP） 和多个金属离子（如Fe3+、64Cu2+、68Ga3+），APF、MNP、铁(Fe)的摩尔比为1/1/800。APF 和MNP双模板使Fe 的负载率大大提高，可达75%左右。64Cu 标记可在中性条件下、室温渗入，无需添加双功能螯合剂，无需APF开环，反应 30min 后，产率即可达80%。构建转铁蛋白受体TfR1高、低表达的结肠癌HT29、肝癌HepG2肿瘤模型，正电子发射计算机断层(PET)、磁共振成像(MRI)、光声成像(PAI)成像清晰，证明探针的靶向性好。PET最灵敏，HT29模型肿瘤高度摄取(5-8%ID/g)，滞留时间长，而阴性对照HepG2 肿瘤摄取相对较低(3-5%ID/g)，且清除较快。因APF 和Fe 的协同作用，MRI、PAI 成像效果均显著提高。此多功能探针工艺简单，易于推广；选用天然材料，安全无毒，价廉节约。此外，本项目还拓展了新型靶向肽的核素标记及临床转化、基于黑色素、铁蛋白为载体的新材料的探索及应用，并充分发挥核素示踪及分子影像的指导及验证作用。本项目提供了多种特异性探针，有助于实现肿瘤的精准诊疗。