Improving tumor-targeting capability and pharmacokinetics of (99m)Tc-labeled cyclic RGD dimers with PEG(4) linkers.
Improving tumor-targeting capability and pharmacokinetics of (99m)Tc-labeled cyclic RGD dimers with PEG(4) linkers.
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DOI：
10.1021/mp800150r
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发表时间：
2009-01
影响因子：
4.9
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Wang L;Shi J;Kim YS;Zhai S;Jia B;Zhao H;Liu Z;Wang F;Chen X;Liu S
This report describes the synthesis of two cyclic RGD (Arg-Gly-Asp) conjugates, HYNIC-2PEG4-dimer (HYNIC = 6-hydrazinonicotinyl; 2PEG4-dimer = E[PEG4-c(RGDfK)]2; and PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and HYNIC-3PEG4-dimer (3PEG4-dimer = PEG4-E[PEG4-c(RGDfK)]2), and evaluation of their 99mTc complexes [99mTc(HYNIC-2PEG4-dimer)(tricine)(TPPTS)] (99mTc-2PEG4-dimer: TPPTS = trisodium triphenylphosphine-3,3′,3″-trisulfonate) and [99mTc(HYNIC-3PEG4-dimer)(tricine)(TPPTS)] (99mTc-3PEG4-dimer) as novel radiotracers for imaging integrin αvβ3 expression in athymic nude mice bearing U87MG glioma and MDA-MB-435 breast cancer xenografts. The integrin αvβ3 binding affinities of RGD peptides were determined by competitive displacement of 125I-c(RGDyK) on U87MG glioma cells. It was found that the two PEG4 linkers between RGD motifs in HYNIC-2PEG4-dimer (IC50 = 2.8 ± 0.5 nM) and HYNIC-3PEG4-dimer (IC50 = 2.4 ± 0.7 nM) are responsible for their higher integrin αvβ3 binding affinity than that of HYNIC-PEG4-dimer (PEG4-dimer = PEG4-E[c(RGDfK)]2; IC50 = 7.5 ± 2.3 nM). Addition of extra PEG4 linker in HYNIC-3PEG4-dimer has little impact on integrin αvβ3 binding affinity. 99mTc-2PEG4-dimer and 99mTc-3PEG4-dimer were prepared in high yield with >95% radiochemical purity and the specific activity of > 10 Ci/μmol. Biodistribution studies clearly demonstrated that PEG4 linkers are particularly useful for improving the tumor uptake and clearance kinetics of 99mTc-2PEG4-dimer and 99mTc-3PEG4-dimer from non-cancerous 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 99mTc-2PEG4-dimer is integrin αvβ3-mediated. In the metabolism study, 99mTc-2PEG4-dimer had high metabolic stability during its excretion from renal and hepatobiliary routes. 99mTc-3PEG4-dimer also remained intact during thee excretion from the renal route, but, had ~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 ~5 mm in diameter could be readily visualized with excellent contrast. Thus, 99mTc-3PEG4-dimer is a very promising radiotracer for the early detection of integrin αvβ3–positive tumors, and may have the potential for non-invasive monitoring of tumor growth or treatment efficacy.
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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：
64.5
作者：
BROOKS, PC;MONTGOMERY, AMP;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
46.9
作者：
Brower, V
通讯作者：
Brower, V