title: A Lipopeptide-Based αvβ₃ Integrin-Targeted Ultrasound Contrast Agent for Molecular Imaging of Tumor Angiogenesis.
abstract: 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 αvβ3 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 distearoylphosphatidylethanolamine-polyethylene glycol 2000-maleimide. The resulting iRGD-lipopeptides were used for fabrication of the iRGD-carrying αvβ3 integrin-targeted MBs (iRGD-MBs). The binding specificity of iRGD-MBs 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-αv or anti-β3 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 αvβ3 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.
authors.affiliation: Department of Ultrasonography, Third Affiliated Hospital of Southern Medical University, Guangzhou, China; Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yan
authors.affiliation: School of Life Science and Engineering, Southwest University of Science and Technology, Sichuan, Mianyang, China.
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Ultrasonography, Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
authors.forename: Zhiting
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Ultrasonography, Third Affiliated Hospital of Southern Medical University, Guangzhou, China. Electronic address: lmeihong@fimmu.com.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Life Science and Engineering, Southwest University of Science and Technology, Sichuan, Mianyang, China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Echocardiography, Clinical Center of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, China.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Tan
authors.affiliation: Department of Physics, University of Vermont, Burlington, Vermont, USA.
authors.forename: Junru
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Ultrasonography, Third Affiliated Hospital of Southern Medical University, Guangzhou, China; Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. Electronic address: hr.zheng@siat.ac.cn.
authors.forename: Hairong
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism*; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000493:pharmacokinetics; D039302:Integrin alphaVbeta3 / Q000737:chemistry / Q000378:metabolism*; D055666:Lipopeptides / Q000737:chemistry*; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014463:Ultrasonography / Q000379:methods*
chemical_list: D003287:Contrast Media; D039302:Integrin alphaVbeta3; D055666:Lipopeptides
keywords: Microbubbles; Tumor angiogenesis; Ultrasound molecular imaging; iRGD; αvβ(3) integrin