HCC往往到了中晚期才确诊，给化疗和手术造成困难。纳米级分子探针在肿瘤早期影像诊断与靶向治疗中有着广阔的应用前景。但是目前合成的分子探针或多或少存在安全性差、特异性弱和灵敏度低的缺陷，无法满足临床应用的要求。为了解决这些问题，本项目将在前期研究工作的基础上，以开发特异性的MRI对比剂为切入点，开展新型分子探针的设计、合成、性能研究与药理学评估。项目拟选用磁性纳米颗粒和高度生物相容性聚合物为功能及基质材料，将层层组装与溶胶凝胶、共价键合、乳化作用和静电吸引等技术相结合，针对肿瘤微环境和肿瘤细胞膜受体的HCC特点，合成高度特异性的分子探针，并通过成像和抑瘤分子机理相结合进行HCC早期诊治的药理学研究，为进一步探索特异性好、信号灵敏的HCC分子探针的合成规律提供思路。这无论对于推动分子影像技术和靶向治疗的理论研究，还是促进分子探针的临床应用都具有重要的意义。

Hepatocellular carcinoma (HCC) is mostly diagnosed at the middle or advanced stage, which causes difficulties to chemotherapy and surgery. Nanoscale molecular probe is promising in comprehensive application of early imaging diagnosis and targeting therapy in tumor. Nowaday, the molecular probes synthesized, however, possess the defects such as poor safety, weak specificity and low sensitivity to some extent, which are unable to meet the requirements of clinical applications. To address this concern, based on our previous research, we conduct design, synthesis, performance research and pharmacological evaluation of novel molecular probes regarding developing specific MRI contrast agents as the starting point. In the present project, super paramagnetic nanoparticles and highly biocompatible polymers are selected as functional and matrix material, respectively. We manage to synthesize highly specific molecular probes by combination of layer-by-layer assembly with sol-gel processes, covalent conjugation, emulsification, and electrostatic attraction. These probes aim at different target sites of HCC, respectively, including tumor microenvironment and tumor cell membrane receptors. The performance of early diagnosis and therapy of HCC is evaluated through investigating imaging and molecular mechanism of tumor inhibition. This will provide new ideas for further exploring the synthetic rules for HCC molecular probes with the good specificity and high sensitivity. In view of this, the study is important for both promoting theoretical research of molecular imaging technology and tumor-targeted therapy, and enhancing clinical application of molecular probe.

为了降低抗癌药物阿霉素对正常组织器官的毒副作用，提高靶向特异性和肿瘤早期成像诊断的检测灵敏度，本项目设计合成了一种新型的纳米级分子探针。这种探针将RGD-GX1异质二聚肽键合于多聚赖氨酸和磁性纳米颗粒形成的复合物上，以发挥αvβ3-整合素/血管内皮受体协同介导的靶向内吞作用。经过一系列形貌和化学组成表征（透射电镜、红外光谱、X-线衍射、动态光散射、振动样品磁力）发现，合成的纳米探针完全符合设计要求，粒径为150-160 nm的球形颗粒。阿霉素在该载体的上载率为414.4 mg/g。细胞毒性、诱导细胞凋亡和细胞摄入成像等体外实验结果一致表明该纳米探针能够特异性靶向HepG2肝癌细胞。根据体外分子机制研究揭示，该纳米探针诱导细胞凋亡的机制与细胞凋亡的膜表面分子Fas蛋白的过分表达，以及与半胱天冬酶-3（caspase-3）的显著激活有关。对荷瘤小鼠体内磁共振成像（MRI）和生物分布研究显示，该纳米探针对肿瘤组织具有高度的亲和性，能在肿瘤病灶区大量聚集，并且具有显著的抗肿瘤活性，其抑瘤率达到78.5%。这些结果表明，合成的特异性纳米探针将在肝细胞癌的早期诊治中具有良好的应用前景。