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Design, synthesis, and evaluation of VEGFR-targeted macromolecular MRI contrast agent based on biotin–avidin-specific binding

Authors Liu YJ, Wu XY, Sun XH, Wang D, Zhong Y, Jiang DD, Wang TQ, Yu DX, Zhang N

Received 7 January 2017

Accepted for publication 3 April 2017

Published 14 July 2017 Volume 2017:12 Pages 5039—5052


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Linlin Sun

Yongjun Liu,1 Xiaoyun Wu,1 Xiaohe Sun,1 Dan Wang,1 Ying Zhong,1 Dandan Jiang,1 Tianqi Wang,1 Dexin Yu,2 Na Zhang1

1School of Pharmaceutical Science, Shandong University, 2Department of Radiology Medicine, Qilu Hospital, Jinan, People’s Republic of China

Abstract: Developing magnetic resonance imaging (MRI) contrast agents with high relaxivity and specificity was essential to increase MRI diagnostic sensitivity and accuracy. In this study, the MRI contrast agent, vascular endothelial growth factor receptor (VEGFR)-targeted poly (l-lysine) (PLL)-diethylene triamine pentacetate acid (DTPA)-gadolinium (Gd) (VEGFR-targeted PLL-DTPA-Gd, VPDG), was designed and prepared to enhance the MRI diagnosis capacity of tumor. Biotin-PLL-DTPA-Gd was synthesized first, then, VEGFR antibody was linked to biotin-PLL-DTPA-Gd using biotin–avidin reaction. In vitro cytotoxicity study results showed that VPDG had low toxicity to MCF-7 cells and HepG2 cells at experimental concentrations. In cell uptake experiments, VPDG could significantly increase the internalization rates (61.75%±5.22%) in VEGFR-positive HepG2 cells compared to PLL-DTPA-Gd (PDG) (25.16%±4.71%, P<0.05). In MRI studies in vitro, significantly higher T1 relaxivity (14.184 mM-1 s-1) was observed compared to Magnevist® (4.9 mM-1 s-1; P<0.01). Furthermore, in vivo MRI study results showed that VPDG could significantly enhance the tumor signal intensity and prolong the diagnostic time (from <1 h to 2.5 h). These results indicated that macromolecular VPDG was a promising MRI contrast agent and held great potential for molecular diagnosis of tumor.

Keywords: MRI, contrast agent, VEGFR, biotin–avidin reaction, relaxivity

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