智能化双靶向肿瘤光学/核素/MRI多模态分子探针的合成及其性能研究

Early diagnosis is one of the most effective methods for improving cancer cure rates, and multimodality molecular imaging is the most effective tool for cancer early and accurate diagnosis. Multi-modal nano-probes can solve the problem of the different ratio of different probes, but how to improve the cancer targeting and to enhance cancer penetration of nano probes are still need to solve. In this project polyamidoamine (PAMAM) dendrimer which has a large number of amine groups on the surface will be conjugated to superparamagnetic iron oxide nanoparticles (SPIOs) coated by silica to prepare PAMAM-Fe3O4@SiO2 superparamagnetic nano-system. A novel peptide LCTP which has been screened by phage display in vivo in our early experiments as cancer targeting agent, and tumor-penetrating peptide iRGD and poly(β-amino ester)(PAE) which can reverse its charge with the change of pH will be conjugated to the nano system to form intelligent dual-targeting and high penetrating nano-carrier. The nano-carrier will be labeled with fluorescent molecule Cy7 and radionuclide 131I to synthesize cancer multimodality nano diagnostic probes which can be used for Optical Imaging (OI), Radionuclide Imaging and Magnetic Resonance Imaging (MRI). The ratio of different probes will be adjusted by in vitro and in vivo experiments, the function of cancer imaging and cancer penetration of nano-probe will also be studied. By completion of this project we hope the cancer early diagnosis and cancer cure rates can be improved.

肿瘤的早期准确诊断是目前提高肿瘤治愈率最为有效的手段之一，而多模态分子影像是肿瘤早期准确诊断的有效工具。多模态纳米分子探针能够很好的解决多模态影像中不同探针之间比例不同的问题，但存在着如何更好提高肿瘤靶向性及增强肿瘤内渗透性的问题。本项目拟将具有大量表面活性基团的聚酰胺-胺型（PAMAM）树枝状高分子材料连接至二氧化硅包覆超顺磁四氧化三铁的纳米粒上，制备具有超顺磁性的PAMAM-Fe3O4@SiO2纳米材料，以前期课题组自主筛选获得的肿瘤靶向多肽为靶向剂，进一步连接肿瘤穿透肽iRGD及能够进行电荷转变的聚β氨酯来制备对肿瘤微环境具有智能响应性的双靶向及高肿瘤渗透性的纳米载体。通过在纳米载体上标记荧光分子Cy7和碘[131I]来合成可以对肿瘤同时进行光学/放射性核素/MRI成像的肿瘤多模态纳米诊断探针，通过体内外实验来调整不同诊断探针的比例，验证纳米探针的成像功能，以期实现对肿瘤进行早期诊断

肿瘤的早期诊断及靶向治疗对提高肿瘤治愈率和延长生存期具有重要意义。我们通过自组装技术制备了一系列具有良好生物相容性、肿瘤微环境响应性的纳米载体，通过在纳米载体表面修饰RGD、叶酸等靶向基团实现了体内长循环及良好的肿瘤靶向性。对纳米载体进行放射性碘标记及荧光标记后实现了对肿瘤的SPECT/荧光/光声的多模态成像。同时我们对项目内容进行了延伸，利用纳米载体载药，实现了肿瘤化疗药物的靶向递送，到达肿瘤部位后，纳米载体能够识别肿瘤微环境的低pH、高浓度GSH、高浓度ROS等特性，实现化疗药物的快速释放，从而提高了肿瘤治疗疗效，降低了毒副作用，对肿瘤开展诊疗一体化的研究。此外，我们将对肿瘤的多模态诊断应用到耐药细菌的多模态诊断中，设计了能够在耐药细菌表面特异自组装，具有荧光和放射性成像的分子探针，实现了对耐药细菌的在体实时检测。在Angew Chem Int Ed Engl、Theranostics、ACS Appl Mater Interfaces、Chem Commun、Nanoscale等期刊发表SCI论文15篇，申请专利2项。