Wang Jianjun, Qin Bin, Chen Xucai, Wagner William R, Villanueva Flordeliza S
Center of Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh Medical Center and the University of Pittsburgh , Pittsburgh, Pennsylvania 15213, United States.
McGowan Center for Regenerative Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
Mol Pharm. 2017 Mar 6;14(3):781-790. doi: 10.1021/acs.molpharmaceut.6b01033. Epub 2017 Feb 15.
Imaging of angiogenesis receptors could provide a sensitive and clinically useful method for detecting neovascularization such as occurs in malignant tumors, and responses to antiangiogenic therapies for such tumors. We tested the hypothesis that microbubbles (MB) tagged with human VEGF (MB) bind to the kinase insert domain receptor (KDR) in vitro and angiogenic endothelium in vivo, and that this specific binding can be imaged on a clinical ultrasound system. In this work, targeted adhesion of MB was evaluated in vitro using a parallel plate flow system containing adsorbed recombinant human KDR. There was more adhesion of MB to KDR-coated plates when the amount of VEGF on each MB or KDR density on the plate was increased. MB adhesion to KDR-coated plates decreased with increasing wall shear rate. On intravital microscopic imaging of bFGF-stimulated rat cremaster muscle, there was greater microvascular adhesion of MB compared to that of isotype IgG-conjugated control MB (MB). To determine if MB could be used to ultrasonically image angiogenesis, ultrasound imaging was performed in mice bearing squamous cell carcinoma after intravenous injection of MB. Ultrasound videointensity enhancement in tumor was significantly higher for MB (17.3 ± 9.7 dB) compared to MB (3.8 ± 4.4 dB, n = 6, p < 0.05). This work demonstrates the feasibility of targeted ultrasound imaging of an angiogenic marker using MB. This approach offers a noninvasive bedside method for detecting tumor angiogenesis and could be extended to other applications such as molecular monitoring of therapeutic angiogenesis or antiangiogenic therapies in cardiovascular disease or cancer.
血管生成受体成像可为检测恶性肿瘤中出现的新生血管形成以及此类肿瘤对抗血管生成疗法的反应提供一种敏感且具有临床实用性的方法。我们验证了以下假设：标记有人类血管内皮生长因子（VEGF）的微泡（MB）在体外可与激酶插入结构域受体（KDR）结合，在体内可与血管生成内皮结合，并且这种特异性结合可在临床超声系统上成像。在这项研究中，使用含有吸附的重组人KDR的平行板流动系统在体外评估了MB的靶向黏附。当每个MB上的VEGF量或平板上的KDR密度增加时，MB与KDR包被平板的黏附更多。随着壁面剪切率的增加，MB与KDR包被平板的黏附减少。在碱性成纤维细胞生长因子（bFGF）刺激的大鼠提睾肌活体显微镜成像中，与同型IgG缀合的对照微泡（MB）相比，MB的微血管黏附更多。为了确定MB是否可用于超声成像血管生成，在静脉注射MB后，对患有鳞状细胞癌的小鼠进行了超声成像。与MB（3.8±4.4 dB，n = 6，p < 0.05）相比，MB在肿瘤中的超声视频强度增强显著更高（17.3±9.7 dB）。这项工作证明了使用MB对血管生成标志物进行靶向超声成像的可行性。这种方法为检测肿瘤血管生成提供了一种非侵入性的床边方法，并且可以扩展到其他应用，如心血管疾病或癌症中治疗性血管生成或抗血管生成疗法的分子监测。
