Ultrasound Molecular Imaging of Angiogenesis Using Vascular Endothelial Growth Factor-Conjugated Microbubbles.
Ultrasound Molecular Imaging of Angiogenesis Using Vascular Endothelial Growth Factor-Conjugated Microbubbles.
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DOI：
10.1021/acs.molpharmaceut.6b01033
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发表时间：
2017-03-06
影响因子：
4.9
通讯作者：
Villanueva FS
中科院分区：
文献类型：
--
作者：
Wang J;Qin B;Chen X;Wagner WR;Villanueva FS
血管生成受体的成像可以提供一种灵敏的和临床上有用的方法，用于检测新血管形成，如发生在恶性肿瘤中，和对这种肿瘤的抗血管生成治疗的反应。我们测试了这样的假设，即标记有人VEGF 121（MBVEGF）的微泡（MB）在体外与激酶插入结构域受体（KDR）结合，在体内与血管生成内皮细胞结合，并且这种特异性结合可以在临床超声系统上成像。在这项工作中，MBVEGF的靶向粘附进行了评估，在体外使用平行板流动系统含有吸附重组人KDR。当每个MB上的VEGF 121的量或板上的KDR密度增加时，MBVEGF与KDR包被的板的粘附更多。MBVEGF与KDR涂层板的粘附随着壁剪切速率的增加而降低。在活体显微成像bFGF刺激的大鼠提睾肌，有更大的微血管粘附MBVEGF相比，同种型IgG结合的控制MB（MBCTL）。为了确定MBVEGF是否可用于超声成像血管生成，在静脉内注射MBVEGF后在携带鳞状细胞癌的小鼠中进行超声成像。MBVEGF组肿瘤的超声增强强度（17.3± 9.7dB）明显高于MBCTL组（3.8± 4.4dB，n=6，p<0.05）。这项工作证明了使用MBVEGF对血管生成标记物进行靶向超声成像的可行性。这种方法提供了一种用于检测肿瘤血管生成的非侵入性床边方法，并且可以扩展到其他应用，例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。
Imaging of angiogenesis receptors could provide a sensitive and clinically useful method for detecting neovascularization such as occurs in malignant tumors, and responses to anti-angiogenic therapies for such tumors. We tested the hypothesis that microbubbles (MB) tagged with human VEGF121 (MBVEGF) 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 MBVEGF was evaluated in vitro using a parallel plate flow system containing adsorbed recombinant human KDR. There was more adhesion of MBVEGF to KDR-coated plates when the amount of VEGF121 on each MB or KDR density on the plate was increased. MBVEGF 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 MBVEGF compared to that of isotype IgG-conjugated control MB (MBCTL). To determine if MBVEGF could be used to ultrasonically image angiogenesis, ultrasound imaging was performed in mice bearing squamous cell carcinoma after intravenous injection of MBVEGF. Ultrasound videointensity enhancement in tumor was significantly higher for MBVEGF (17.3±9.7 dB) compared to MBCTL (3.8±4.4 dB, n=6, p<0.05). This work demonstrates the feasibility of targeted ultrasound imaging of an angiogenic marker using MBVEGF. This approach offers a non-invasive bedside method for detecting tumor angiogenesis and could be extended to other applications such as molecular monitoring of therapeutic angiogenesis or anti-angiogenic therapies in cardiovascular disease or cancer.