Linker Effects on Biological Properties of 111In-Labeled DTPA Conjugates of a Cyclic RGDfK Dimer

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• 作者：Bing Jia ; Zhaofei Liu ; Jiyun Shi ; Zilin Yu ; Zhi Yang ; Huiyun Zhao ; Zhengjie He ; Shuang Liu ; Fan Wang
• 刊名：Bioconjugate Chemistry
• 出版年：2008
• 出版时间：January 2008
• 年：2008
• 卷：19
• 期：1
• 页码：201 - 210
• 全文大小：271K
• 年卷期：v.19,no.1(January 2008)
• ISSN：1520-4812

文摘

In this report, we present in vitro and in vivo evaluation of three ¹¹¹In-labeled DTPA conjugates of a cyclic RGDfK dimer: DTPA-Bn-SU016 (SU016 = E[c(RGDfK)]₂; DTPA-Bn = 2-(p-isothioureidobenzyl)diethylenetriaminepentaacetic acid), DTPA-Bn-E-SU016 (E = glutamic acid) and DTPA-Bn-Cys-SU016 (Cys = cysteic acid). The integrin α_vβ₃ binding affinities of SU016, DTPA-Bn-SU016, DTPA-Bn-E-SU016, and DTPA-Bn-Cys-SU016 were determined to be 5.0 ± 0.7 nM, 7.9 ± 0.6 nM, 5.8 ± 0.6 nM, and 6.9 ± 0.9 nM, respectively, against ¹²⁵I-c(RGDyK) in binding to integrin α_vβ₃, suggesting that E or Cys residue has little effect on the integrin α_vβ₃ affinity of E[c(RGDfK)]₂. It was also found that the ¹¹¹In-labeling efficiency of DTPA-Bn-SU016 and DTPA-Bn-E-SU016 is 3–5 times better than that of DOTA analogues due to fast chelation kinetics and high-yield ¹¹¹In-labeling under mild conditions (e.g., room temperature). Biodistribution studies were performed using BALB/c nude mice bearing U87MG human glioma xenografts. ¹¹¹In-DTPA-Bn-SU016, ¹¹¹In-DTPA-Bn-E-SU016, and ¹¹¹In-DTPA-Bn-Cys-SU016 all displayed rapid blood clearance. Their tumor uptake was comparable between 0.5 and 4 h postinjection (p.i.) within experimental error. ¹¹¹In-DTPA-Bn-E-SU016 had a significantly lower (p < 0.01) kidney uptake than ¹¹¹In-DTPA-Bn-SU016 and ¹¹¹In-DTPA-Bn-Cys-SU016. The liver uptake of ¹¹¹In-DTPA-Bn-SU016 was 1.69 ± 0.18% ID/g at 24 h p.i., while the liver uptake values of ¹¹¹In-DTPA-Bn-E-SU016 and ¹¹¹In-DTPA-Bn-Cys-SU016 were 0.55 ± 0.11% ID/g and 0.79 ± 0.15% ID/g at 24 h p.i., respectively. Among the three ¹¹¹In radiotracers evaluated in this study, ¹¹¹In-DTPA-Bn-E-SU016 has the lowest liver and kidney uptake and the best tumor/liver and tumor/kidney ratios. Results from metabolism studies indicated that there is little metabolism (<10%) for three ¹¹¹In radiotracers at 1 h p.i. Imaging data showed that tumors can be clearly visualized at 4 h p.i. with good contrast in the tumor-bearing mice administered with ¹¹¹In-DTPA-Bn-E-SU016. It is concluded that using a glutamic acid linker can significantly improve excretion kinetics of the ¹¹¹In-labeled E[c(RGDfK)]₂ from liver and kidneys.