靶向整合素α_vβ_3受体的二硫键成环的RGD肽的设计、^(131)I标记及在荷瘤鼠中的生物分布与显像

Design of ^(131)I labeling of a Disulfide Bridged RGD-peptide Targeted to Integrin α_vβ_3 Receptor and its Biodistribution and Imaging in Tumor Bearing Mice

[目的]设计与制备131I标记的针对αvβ3受体的通过二硫键成环的RGD肽,研究其在肿瘤中的摄取情况。[方法]根据文献报道的构效关系研究结果设计RGD肽,基于αvβ3受体的胞外区及其配体复合物三维晶体结构,通过分子对接筛选出能量打分最低的多肽结构;采用ChT法进行131I标记,建立荷黑色素瘤动物模型,进行体内分布实验、非标记肽竞争抑制实验及肿瘤显像研究。[结果]c(CRGDYC)具有最低的对接能量,其131I的标记率为90%,放射化学纯度达99%;131I-c(CRGDYC)在肿瘤中有较高的摄取率,且清除缓慢,静脉注射后24h,肿瘤与肌肉(T/M)和肿瘤与血液(T/B)摄取比值分别为6.34与1.1。未标记肽可明显抑制肿瘤对131I-c(CRGDYC)的摄取。静脉注射后1h即可见肿瘤显影,随时间延长,影像逐渐清晰,148h仍可见肿瘤影像。[结论]c(CRGDYC)可被肿瘤组织特异性摄取并有较高的摄取率和较长的滞留时间,有可能应用于肿瘤血管生成显像与肿瘤治疗。

[Purpose] To design and prepare 131I labeled cyclo RGD peptide with disulfide bond targeted to αvβ3 receptor and investigate its uptakes in tumor. [Methods] cRGD peptide was designed according to the published results of structure-activity relationship study and selected by docking procedure based on the crystal structure of integrin αvβ3 extracellular segment in complex with an RGDfV ligand. The peptide was labeled with 131I by ChT method. The biodistribution, inhibition with unlabeled peptide and imaging were performed by injecting the labeled peptide into the mice bearing meloma B16. [Results] c（CRGDYC） showed the lowest docking energy. The 131I labeling efficiency and radiochemical purity were 90% and 99%, respectively. The labeled peptide had high uptake and low clearance in tumor. The T/M and T/B 24h postinjection were 6.34 and 1.1, respectively. The tumor uptake was significantly lower while it inhibited with unlabeled peptide. Tumor imaging was clear 1h postinjection and became more clear with time lasted, and the imaging was still observed in 148h postinjection. [Conclusion] c （CRGDYC） has high uptake and long time retain in tumor, which suggested it might be used for tumor imaging and therapy.