Evaluation of 111In-labeled cyclic RGD peptides: tetrameric not tetravalent.
Evaluation of 111In-labeled cyclic RGD peptides: tetrameric not tetravalent.
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DOI：
10.1021/bc900555q
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发表时间：
2010-05-19
影响因子：
4.7
通讯作者：
Liu, Shuang
中科院分区：
文献类型：
--
作者：
Chakraborty, Sudipta;Shi, Jiyun;Kim, Young-Seung;Zhou, Yang;Jia, Bing;Wang, Fan;Liu, Shuang
本报告介绍了111 In的合成和评价（DOTA-6G-RGD4）（DOTA = 1，4，7，10-四氮杂环十二烷-1，4，7，10-四乙酸; 6G-RGD4 = E{G3-E[G3-c（RGDfK）]2}2和G3 = Gly-Gly-Gly），111 In（DOTA-RGD 4）（RGD 4 = E{E[c（RGDfK）]2}2）和111 In（DOTA-3G-RGD 2）（3G-RGD 2 = G3-E[G3-c（RGDfK）]2）作为整合素αvβ3阳性肿瘤显像的新放射性示踪剂。DOTA-6 G-RGD 4、DOTA-RGD 4和DOTA-3G-RGD 2对与整合素αvβ3阳性U87 MG人胶质瘤细胞结合的125 I-c（RGDyK）的IC 50值分别为0.4 ± 0.1、1.5 ± 0.2和1.3 ± 0.2 nM。111 In（DOTA-6 G-RGD 4）、111 In（DOTA-RGD 4）和111 In（DOTA-3G-RGD 2）通过使111 InCl 3与相应的DOTA缀合物在NH 40 Ac缓冲液（100 mM，pH = 5.5）中反应来制备。放射性标记可通过在100 °C下加热反应混合物15 - 20 min完成。111 In（DOTA-3G-RGD 2）的比活度约为1850 MBq/μmol，111 In（DOTA-6 G-RGD 4）的比活度约为1480 MBq/μmol。采用U87 MG人胶质瘤裸鼠移植瘤模型，研究111 In（DOTA-6 G-RGD 4）、111 In（DOTA-3G-RGD 4）和111 In（DOTA-3G-RGD 2）的摄取和排泄动力学。整联蛋白αvβ3结合试验和生物分布研究的结果均表明，四聚体环状RGD肽（如RGD 4和6 G-RGD 4）与整联蛋白αvβ3的结合最可能是二价的。由于RGD 4和6 G-RGD 4中额外的RGD基序，在注射后24 - 72 h，111 In（DOTA-6 G-RGD 4）和111 In（DOTA-RGD 4）的肿瘤摄取均显著高于111 In（DOTA-3G-RGD 2）。111 In（DOTA-3G-RGD 2）在2小时内通过肾脏和肝胆途径排泄期间代谢非常少，而111 In（DOTA-6 G-RGD 4）代谢显著，可能是由于其体积大得多。高肿瘤摄取与长肿瘤保留的组合表明它们相应的90 Y和177 Lu类似物M（DOTA-6 G-RGD 4）（M = 90 Y和177 Lu）可能用作治疗性放射性示踪剂用于治疗整合素αvβ3阳性实体瘤。
This report presents the synthesis and evaluation of 111In(DOTA-6G-RGD4) (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid; 6G-RGD4 = E{G3-E[G3-c(RGDfK)]2}2 and G3 = Gly-Gly-Gly), 111In(DOTA-RGD4) (RGD4 = E{E[c(RGDfK)]2}2) and 111In(DOTA-3G-RGD2) (3G-RGD2 = G3-E[G3-c(RGDfK)]2) as new radiotracers for imaging integrin αvβ3–positive tumors. The IC50 values of DOTA-6G-RGD4, DOTA-RGD4 and DOTA-3G-RGD2 were determined to be 0.4 ± 0.1, 1.5 ± 0.2 and 1.3 ± 0.2 nM against 125I-c(RGDyK) bound to integrin αvβ3–positive U87MG human glioma cells. 111In(DOTA-6G-RGD4), 111In(DOTA-RGD4) and 111In(DOTA-3G-RGD2) were prepared by reacting 111InCl3 with the respective DOTA conjugate in NH4OAc buffer (100 mM, pH = 5.5). Radiolabeling could be completed by heating the reaction mixture at 100 °C for 15 – 20 min. The specific activity was ~1850 MBq/μmol for 111In(DOTA-3G-RGD2) and ~1480 MBq/μmol for 111In(DOTA-6G-RGD4). The athymic nude mice bearing U87MG human glioma xenografts were used to evaluate tumor uptake and excretion kinetics of 111In(DOTA-6G-RGD4), 111In(DOTA-RGD4) and 111In(DOTA-3G-RGD2). The results from both the integrin αvβ3 binding assay and biodistribution studies suggest that the tetrameric cyclic RGD peptides, such as RGD4 and 6G-RGD4, are most likely bivalent in binding to the integrin αvβ3. Both 111In(DOTA-6G-RGD4) and 111In(DOTA-RGD4) had significantly higher tumor uptake than 111In(DOTA-3G-RGD2) at 24 – 72 h post-injection due to the extra RGD motifs in RGD4 and 6G-RGD4. 111In(DOTA-3G-RGD2) had very little metabolism while 111In(DOTA-6G-RGD4) had a significant metabolism during its excretion via both renal and hepatobiliary routes over the 2 h period, probably due to its much larger size. The combination of high tumor uptake with long tumor retention suggests that their corresponding 90Y and 177Lu analogs M(DOTA-6G-RGD4) (M = 90Y and 177Lu) might be useful as therapeutic radiotracers for treatment of integrin αvβ3-positive solid tumors.
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