靶向整合素αvβ3受体的新型RGD肽二聚体的131I标记与生物活性的初步评价  

^(131)I labeling and bioactivity evaluation of a novel RGD dimer targeted to integrin α_vβ_3 receptor

作　　者：张春丽[1,2] 王荣福[2] 张丽[2] 郭凤琴[2] 李玲[2] 康磊[2] 闫平[2] 杨铭[1] 

机构地区：[1]北京大学药学院天然药物及仿生药物国家重点实验室,北京100191 [2]北京大学第一医院核医学科,北京100034

出　　处：《北京大学学报（医学版）》2011年第2期295-300,共6页Journal of Peking University:Health Sciences

基　　金：国家重点基础研究发展计划(973计划,2006GB705705);教育部教育振兴行动计划特殊专项(“九八五”工程Ⅱ期,985-2-056);放射性药物教育部重点实验室开放基金(0707)资助~~

摘　　要：目的:对所设计的新型精氨酰-甘氨酰-天冬氨酰(Arg-Gly-Asp,RGD)肽进行131I标记,研究其在肿瘤组织中的靶向性及其在荷瘤鼠体内的生物分布与显像,探讨将其应用于肿瘤血管生成显像的可能性。方法:参照文献报道的对环五肽c(RGDfV)构效关系的研究结果及多肽的化学修饰方法,设计了新型二硫键成环的并经亲水性修饰的cRGD肽二聚体[c(RGD)2],采用ChT法进行131I标记,测定c(RGD)2的亲和常数、标记物的稳定性与油水分配系数;建立荷黑色素瘤动物模型,研究131I-c(RGD)2的体内分布、非标记肽竞争抑制及肿瘤显像。结果:131I对c(RGD)2的标记率为(76.35±2.33)%,经Sephadex G10分离纯化后其放射化学纯度达(95.20±3.25)%。c(RGD)2对受体的亲和常数Ka为(0.137±0.057)×109/mol/L,油水分配系数lgP正辛醇/水为-1.628,131I-c(RGD)2在静脉注射后1 h、3 h、5 h与24 h在肿瘤中的摄取率分别为(0.67±0.13)%ID/g、(0.42±0.08)%ID/g、(0.51±0.11)%ID/g与(0.18±0.02)%ID/g,其在肿瘤中的清除相对缓慢,靶本比(T/NT)随时间延长而增高,静脉注射后24 h,肿瘤与肌肉(T/M)和肿瘤与血液(T/B)的摄取比值分别为4.42±1.70与2.27±0.45。131I-c(RGD)2的肝脏摄取低,静脉注射后1 h肿瘤与肝的摄取比可达2.10±0.60;未标记肽可明显抑制肿瘤对131I-c(RGD)2的摄取。荷瘤小鼠全身显像可见肾显影,在静脉注射后3 h胸部显像可见清晰的肿瘤影像。结论:所设计的通过二硫键成环的c(RGD)2可应用ChT法成功完成131I标记,其可被肿瘤组织特异性摄取,有可能应用于肿瘤血管的生成显像。131I-c(RGD)2的肝脏摄取低,在肿瘤显像中具有一定优势。Objective：To study the 131I labeling,tumor targeting property,biodistrubution and imaging of a novel disulfide bridged Arg-Gly-Asp（RGD） peptide dimer and investigate its possibility for tumor angiogenesis imaging.Methods： A disulfide bridged cRGD peptide dimer [c（RGD）2] was designed according to the published results of structure-activity relationship study of c（RGDfV） and modified with hydrophilic amino acid.The affinity of the peptide to αvβ3 receptor was determined by binding assay.The peptide was labeled with 131I by ChT method.The stability and lg n-octanol-water partition coefficient of the labeled peptide were tested.The biodistribution,inhibition with unlabeled peptide and imaging were performed by injecting the labeled peptide into the mice bearing meloma B16.Results： The 131I labeling efficiency and radiochemical purity were（76.35±2.33）% and（95.20±3.25）%,respectively.Ka was（0.137±0.057）×10 9 /mol/L,and lgPoctanol/water was-1.628.The tumor uptake of the labeled peptide at 1 h,3 h,5 h and 24 h were（0.67±0.13）%ID/g,（0.42±0.08）%ID/g,（0.51±0.11）%ID/g and（0.18±0.02）%ID/g,respectively.The tumor clearance was low,so the T/NT increased with time.The T/M and T/B were 4.42±1.70 and 2.27±0.45,respectively,24 h post-injection.The hepatic uptake of the labeled peptide was low.The tumor-to-liver ratio was 2.10±0.60 at 1 h post-injection,coinjection of c（RGD）2 with 131I-c（RGD）2 resulted in a significant decrease in tumor uptake.In total body images,only kidneys were distinctive whereas tumor was clear in chest images 3 h post-injection.Conclusion： c（RGD）2 can be successfully labeled with 131I by ChT method.The labeled peptide can be specifically combined with tumor,which suggests its possibility in tumor angiogenesis imaging.Its low liver uptake provides an advantage for tumor imaging.

关 键 词：寡肽类 二聚作用 碘放射性同位素 整合素ΑVΒ3 

分 类 号：R977.6[医药卫生—药品]