放射性药物FAK抑制剂靶向肿瘤侵袭力的作用研究

The Study of Radiolabeled Focal Adhesion Kinase Inhibitors on Biological Evaluation and Tumor Invasion Molecular Imaging

[目的]化学合成、放射性核素标记局部黏着斑激酶(FAK)抑制剂,评价新型放射性药物FAK抑制剂对恶性肿瘤组织侵袭力靶向示踪及治疗的潜在应用价值。[方法]以恶性肿瘤组织高表达FAK为靶点,利用计算机辅助药物设计方法的优势,经计算机模拟设计、化学合成新型FAK小分子抑制剂化合物,通过药物有效性筛选后,选择与FAK受体特异性结合,明显抑制肿瘤细胞增殖、侵袭能力的FAK抑制剂化合物,研究放射性核素碘标记方法,评价核素标记FAK小分子抑制剂的理化性质及体内外稳定性。[结果]对97个FAK抑制剂分子进行了3D-QSAR计算,得到FAK抑制剂的有效骨架结构,在此基础上进行不同结构修饰,设计并合成17个新型FAK小分子化合物。细胞活力实验检测发现FAK小分子抑制剂及其稳定碘标志物对恶性肿瘤细胞的毒性作用存在明显的差异。其中,对与恶性肿瘤细胞特异性结合的化合物3进行放射性核素125I标记,标记率达49%以上。应用HPLC对放射性核素标记化合物进行放化纯分析及稳定性研究发现125I标记化合物3在体外能够稳定存在。[结论 ]新型放射性药物FAK抑制剂靶向结合FAK位点,对多种恶性度较高,侵袭、转移能力较强的肿瘤靶向示踪和放射性核素靶向治疗具有潜在应用价值。

[Purpose] Focal adhesion kinase（FAK） inhibitors were synthesized and radiolabeled to evaluate the targeting imaging and therapeutical effects. [Methods] Design,synthesis and radionuclide-labeling of FAK small molecule inhibitors using of the advantage of computer aided drug design system. Then the ones with high affinity were labeled with radioiodine and as molecular targeted probes to trace tumor invasive and metastasis characteristics. The in vivo and in vitro experiments including physicochemical property assay and cell viability measurement were carried out at the same time. [Results] Seventeen compounds were synthesized and had different affinity to tumor cells. Compound 3 was radiolabeld by 125 I. The radiolabeling of 125 I-compound 3 had reached 49% and it was stable in vitro. [Conclusion] The new probe FAK inhibitor is useful to image malignant tumor with high invasive and metastasis characteristics and could monitor the effects of targeted FAK therapy.