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Improving Tumor-Targeting Capability and Pharmacokinetics of Tc-99m-Labeled Cyclic RGD Dimers with PEG(4) Linkers
Wang, Lijun1; Shi, Jiyun1; Kim, Young-Seung1; Zhai, Shizhen1; Jia, Bing2; Zhao, Huiyun2; Liu, Zhaofei3; Wang, Fan2; Chen, Xiaoyuan3; Liu, Shuang1
关键词Integrin alpha(v)beta(3) Tc-99m-labeled peptides cyclic RGD dimers tumor imaging
刊名MOLECULAR PHARMACEUTICS
2009
DOI10.1021/mp800150r
6期:1页:231-245
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Medicine, Research & Experimental ; Pharmacology & Pharmacy
资助者Purdue University ; National Cancer Institute ; National Institute of Biomedical Imaging and Bioengineering ; National Heart, Lung, and Blood Institute ; Department of Energy ; NCI ; Purdue University ; National Cancer Institute ; National Institute of Biomedical Imaging and Bioengineering ; National Heart, Lung, and Blood Institute ; Department of Energy ; NCI
研究领域[WOS]Research & Experimental Medicine ; Pharmacology & Pharmacy
关键词[WOS]GLIOMA INTEGRIN-ALPHA(V)BETA(3) EXPRESSION ; INTEGRIN ALPHA(V)BETA(3) EXPRESSION ; CANCER ALPHA(V)-INTEGRIN EXPRESSION ; RECEPTOR ANTAGONIST USEFUL ; TERNARY LIGAND SYSTEM ; BREAST-CANCER ; BIODISTRIBUTION CHARACTERISTICS ; BIOLOGICAL EVALUATION ; INITIAL EVALUATION ; F-18-LABELED RGD
英文摘要

This report describes the synthesis of two cyclic RGD (Arg-Gly-Asp) conjugates, HYNIC-2PEG(4)-dimer (HYNIC = 6-hydrazinonicotinyl; 2PEG(4)-dimer = E[PEG(4)-c(RGDfK)](2); and PEG(4) = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and HYNIC-3PEG(4)-dimer (3PEG(4)-dimer = PEG(4)-E[PEG(4)-c(RGDfK)](2)), and evaluation of their Tc-99m complexes [Tc-99m(HYNIC-2PEG(4)-dimer)(tricine)(TPPTS)] (Tc-99m-2PEG(4)-dimer: TPPTS = trisodium triphenylphosphine-3,3′,3 ′′-trisulfonate) and [Tc-99m(HYNIC-3PEG(4)-dimer)(tricine)(TPPTS)] (Tc-99m-3PEG(4)-dimer) as novel radiotracers for imaging integrin alpha(v)beta(3) expression in athymic rude mice bearing U87MG glioma and MDA-MB-435 breast cancer xenografts. The integrin alpha(v)beta(3) binding affinities of RGD peptides were determined by competitive displacement of I-125-c(RGDyK) on U87MG glioma cells. It was found that the two PEG4 linkers between RGD motifs in HYNIC-2PEG(4)-dimer (IC50 = 2.8 +/- 0.5 nM) and HYNIC-3PEG(4)-dimer (IC50 = 2.4 +/- 0.7 nM) are responsible for their higher integrin alpha(v)beta(3) binding affinity than that of HYNIC-PEG(4)-dimer (PEG(4)-dimer = PEG(4)-E[c(RGDfK)](2); IC50 = 7.5 +/- 2.3 nM). Addition of extra PEG(4) linker in HYNIC-3PEG(4)-dimer has. little impact on integrin alpha(v)beta(3) binding affinity. Tc-99m-2PEG(4)-dimer and Tc-99m-3PEG(4)-dimer were prepared in high yield with >95% radiochemical purity and the specific activity of > 10 CI/mu mol. Biodistribution :studies clearly demonstrated that PEG(4) linkers are particularly useful for improving the tumor uptake and clearance kinetics of 99mTc-2PEG4-dimer and Tc-99m-3PEG(4)-dimer from noncancerous organs. It was also found that there was a linear relationship between the tumor size and radiotracer tumor uptake expressed as %ID (percentage of the injected dose) in U87MG glioma and MDA-MB-435 breast tumor models. The blocking experiment showed that the tumor uptake of Tc-99m-2PEG(4)-dimer is integrin alpha(v)beta(3)-mediated. In the metabolism study, Tc-99m-2PEG(4)-dimer had high metabolic stability during its excretion from renal and hepatobiliary routes. Tc-99m-3PEG(4)-dimer also remained intact during thee excretion from the renal route, but, had similar to 30% metabolism during the excretion from the hepatobiliary route. Planar imaging studies in U87MG glioma and MDA-MB-435 breast tumor models showed that the tumors of similar to 5 mm in diameter could be readily visualized with excellent contrast. Thus, Tc-99m-3PEG(4)-dimer is a very promising radiotracer for the early detection of integrin alpha(v)beta(3)-positive tumors, and may have the potential for noninvasive monitoring of tumor growth or treatment efficacy.

语种英语
所属项目编号R01 CA115883 A2 ; R21 EB003419-02 ; R21 HL083961-01 ; DE-FG02-08ER64684 ; R01 CA119053
资助者Purdue University ; National Cancer Institute ; National Institute of Biomedical Imaging and Bioengineering ; National Heart, Lung, and Blood Institute ; Department of Energy ; NCI ; Purdue University ; National Cancer Institute ; National Institute of Biomedical Imaging and Bioengineering ; National Heart, Lung, and Blood Institute ; Department of Energy ; NCI
WOS记录号WOS:000263035000024
引用统计
被引频次:95[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/60875
专题北京大学医药卫生分析中心
作者单位1.Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA
2.Peking Univ, Med Isotopes Res Ctr, Beijing 100083, Peoples R China
3.Stanford Univ, Mol Imaging Program Stanford, Dept Radiol & BioX, Stanford, CA USA
推荐引用方式
GB/T 7714
Wang, Lijun,Shi, Jiyun,Kim, Young-Seung,et al. Improving Tumor-Targeting Capability and Pharmacokinetics of Tc-99m-Labeled Cyclic RGD Dimers with PEG(4) Linkers[J]. MOLECULAR PHARMACEUTICS,2009,6(1):231-245.
APA Wang, Lijun.,Shi, Jiyun.,Kim, Young-Seung.,Zhai, Shizhen.,Jia, Bing.,...&Liu, Shuang.(2009).Improving Tumor-Targeting Capability and Pharmacokinetics of Tc-99m-Labeled Cyclic RGD Dimers with PEG(4) Linkers.MOLECULAR PHARMACEUTICS,6(1),231-245.
MLA Wang, Lijun,et al."Improving Tumor-Targeting Capability and Pharmacokinetics of Tc-99m-Labeled Cyclic RGD Dimers with PEG(4) Linkers".MOLECULAR PHARMACEUTICS 6.1(2009):231-245.
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