Improving tumor uptake and pharmacokinetics of (64)Cu-labeled cyclic RGD peptide dimers with Gly(3) and PEG(4) linkers.
Improving tumor uptake and pharmacokinetics of (64)Cu-labeled cyclic RGD peptide dimers with Gly(3) and PEG(4) linkers.
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DOI：
10.1021/bc800455p
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发表时间：
2009-04
影响因子：
4.7
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Shi J;Kim YS;Zhai S;Liu Z;Chen X;Liu S
放射性标记的环状RGD(Arg-Gly-Asp)多肽代表了一类新的放射性示踪剂，具有早期发现肿瘤、无创监测肿瘤转移和癌症患者治疗反应的潜力。本文报道了两个环状RGD肽二聚物DOTA-PEG4-E[PEG4-c(RGDfK)]2(DOTA-3PEG4-二聚体：DOTA=1，4，7，10-tetraazacyclododecane-1，4，7，10-tetraacetic酸；PEG4=15-氨基-4，7，10，13-四氧十五烷酸)和DOTA-G3-E[G3-c(RGDfK)]2(DOTA-3G3-二聚体：G3=Gly-Gly-Gly)的合成。通过125I-α与人脑胶质瘤细胞的竞争性置换，确定了整合素RGD与β3的结合亲和力顺序为：DOTA-E[E[c(RGDfK)]2}2(DOTA-四聚体：IC_(50)=10±2 nm)>；DOTA-3G3-二聚体(IC_(50)=62±6 nm)~DOTA-3PEG4-二聚体(IC_(50)=74±3 nm)>；DOTA-E[c(RGDfK)]2(DOTA-二聚体：IC_(50)=102±5 nm)。在DOTA-3G3-二聚体和DOTA-3PEG4-二聚体的两个环状RGD基序之间加入PEG4和G3连接体，使它们能够以二价方式同时与整合素α和β3结合。高产率地制备了64铜(DOTA-3PEG4-二聚体)和64铜(DOTA-3G3-二聚体)，比活度为~50Ci/mmo1。对荷人胶质瘤U87 MG裸鼠移植瘤的生物分布和影像进行了研究。这些研究的结果表明，PEG4和G3连接体特别有助于改善肿瘤对非肿瘤器官(如肾脏、肝脏和肺)的~(64)Cu放射性示踪剂的摄取和清除动力学。肿瘤大小与肿瘤摄取率呈线性关系，提示64Cu(DOTA-3PEG4-二聚体)和64Cu(DOTA-3PEG4-二聚体)在抗血管生成治疗中可用于肿瘤生长或缩小的无创性监测。MicroPET成像数据清楚地证明了64Cu(DOTA-3G3-二聚体)作为一种新的PET放射性示踪剂用于对整合素αvβ3阳性肿瘤进行成像。
Radiolabeled cyclic RGD (Arg-Gly-Asp) peptides represent a new class of radiotracers with potential for the early tumor detection and non-invasive monitoring of tumor metastasis and therapeutic response in cancer patients. This report describes the synthesis of two cyclic RGD peptide dimer conjugates, DOTA-PEG4-E[PEG4-c(RGDfK)]2 (DOTA-3PEG4-dimer: DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and DOTA-G3-E[G3-c(RGDfK)]2 (DOTA-3G3-dimer: G3 = Gly-Gly-Gly). Integrin αvβ3 binding affinities of cyclic RGD peptides were determined by competitive displacement of 125I-echistatin bound to U87MG human glioma cells, and follow the order of DOTA-E{E[c(RGDfK)]2}2 (DOTA-tetramer: IC50 = 10 ± 2 nM) > DOTA-3G3-dimer (IC50 = 62 ± 6 nM) ~ DOTA-3PEG4-dimer (IC50 = 74 ± 3 nM) > DOTA-E[c(RGDfK)]2 (DOTA-dimer: IC50 = 102 ± 5 nM). The addition of PEG4 and G3 linkers between two cyclic RGD motifs in DOTA-3G3-dimer and DOTA-3PEG4-dimer makes it possible for them to achieve the simultaneous integrin αvβ3 binding in a bivalent fashion. Both 64Cu(DOTA-3PEG4-dimer) and 64Cu(DOTA-3G3-dimer) were prepared in high yield with specific activity being >50 Ci/mmol. Biodistribution and imaging studies were performed in athymic nude mice bearing U87MG human glioma xenografts. The results from those studies show that PEG4 and G3 linkers are particularly useful for improving tumor uptake and clearance kinetics of 64Cu radiotracers from the non-tumor organs, such as kidneys, liver and lungs. There is a linear relationship between the tumor size and %ID tumor uptake, suggesting that 64Cu(DOTA-3PEG4-dimer) and 64Cu(DOTA-3PEG4-dimer) might be useful for noninvasive monitoring of tumor growth or shrinkage during anti-angiogenic therapy. MicroPET imaging data clearly demonstrate the utility of 64Cu(DOTA-3G3-dimer) as a new PET radiotracer for imaging integrin αvβ3-positive tumors.
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影响因子：
3.1
作者：
Chen, XY;Liu, S;Conti, PS
通讯作者：
Conti, PS
影响因子：
2.8
作者：
Chen, Xiaoyuan;Tohme, Michel;Conti, Peter S.
通讯作者：
Conti, Peter S.
影响因子：
4
作者：
Costouros, NG;Diehn, FE;Libutti, SK
通讯作者：
Libutti, SK
影响因子：
56.9
作者：
BROOKS, PC;CLARK, RAF;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
4.7
作者：
Alves, Susana;Correia, Joao D. G.;Smith, Charles J.
通讯作者：
Smith, Charles J.