A LIPOPEPTIDE-BASED αVβ3 INTEGRIN-TARGETED ULTRASOUND CONTRAST AGENT FOR MOLECULAR IMAGING OF TUMOR ANGIOGENESIS

作者：Yan, Fei; Xu, Xiuxia; Chen, Yihan; Deng, Zhiting; Liu, Hongmei; Xu, Jianrong; Zhou, Jie; Tan, Guanghong; Wu, Junru; Zheng, Hairong^*

来源：Ultrasound in Medicine and Biology, 2015, 41(10): 2765-2773.

DOI：10.1016/j.ultrasmedbio.2015.05.023

• Ultrasound molecular imaging
• Microbubbles
• alpha v beta(3) integrin
• iRGD
• Tumor angiogenesis

The design and fabrication of targeted ultrasound contrast agents are key factors in the success of ultrasound molecular imaging applications. Here, we introduce a transformable alpha v beta(3) integrin-targeted microbubble (MB) by incorporation of iRGD-lipopeptides into the MB membrane for non-invasive ultrasound imaging of tumor angiogenesis. First, the iRGD-lipopeptides were synthesized by conjugating iRGD peptides to distearoyl-phosphatidylethanolamine-polyethylene glycol 2000-maleimide. The resulting iRGD-lipopeptides were used for fabrication of the iRGD-carrying alpha v beta(3) integrin-targeted MBs (iRGD-MBs). The binding specificity of iRGDMBs for endothelial cells was found to be significantly stronger than that of control MBs (p < 0.01) under in vitro static and dynamic conditions. The binding of iRGD-MBs on the endothelial cells was competed off by pre-incubation with the anti-alpha v or anti-beta(3) antibody (p < 0.01). Ultrasound images taken of mice bearing 4T1 breast tumors after intravenous injections of iRGD-MBs or control MBs revealed strong contrast enhancement within the tumors from iRGD-MBs but not from the control MBs; the mean acoustic signal intensity was 10.71 +/- 2.75 intensity units for iRGD-MBs versus 1.13 +/- 0.18 intensity units for the control MBs (p, 0.01). The presence of alpha v beta(3) integrin was confirmed by immunofluorescence staining. These data indicate that iRGD-MBs can be used as an ultrasound imaging probe for the non-invasive molecular imaging of tumor angiogenesis, and may have further implications for ultrasound image-guided tumor targeting drug delivery. (E-mail: [e-mail] or [e-mail].

• 出版日期2015-10
• 单位中国科学院深圳先进技术研究院; 南方医科大学; 西南科技大学; 南京医科大学; 海南医学院