Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo
Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo
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DOI：
10.1148/radiol.2483072231
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发表时间：
2008-09-01
期刊：
影响因子：
19.7
通讯作者：
Gambhir, Sanjiv S.
中科院分区：
文献类型：
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作者：
Willmann, Juergen K.;Lutz, Amelie M.;Gambhir, Sanjiv S.
目的：为了开发和验证具有微泡（MB）的双靶向超声（US）成像剂，所述微泡（MB）附着于血管内皮生长因子（VEGF）受体2（VEGFR 2）和α（v）β（3）整联蛋白，并且在肿瘤血管生成的小鼠模型中比较从双靶向MB（MBD）和从单靶向MB（MBS）获得的US成像信号。动物方案由实验室动物护理机构管理小组批准。通过将抗VEGFR 2、抗α（v）β（3）整联蛋白或这两种抗体连接到全氟化碳填充的MB的外壳上来制备单靶向和双靶向US成像剂。与同种型匹配的免疫球蛋白G标记的对照MB（MBC）和非靶向的非标记MB（MBN）相比，靶向MB的结合特异性用VEGFR 2阳性和α（v）β（3）整联蛋白阳性细胞（小鼠SVR细胞）和对照细胞（小鼠4 T1细胞）进行了测试。在49只携带SK-OV-3肿瘤（人卵巢癌）的小鼠中，通过使用抗VEGFR 2靶向MB（MBV）、抗α（v）β（3）整联蛋白靶向MB（MBI）、MBD和MBC对造影剂增强的US的体内成像信号进行定量。对肿瘤组织进行VEGFR 2、α（v）β（3）整合素和CD 31染色。MBD与SVR细胞的附着（平均值，每个细胞0.74 MB +/- 0.05 [标准差]）显着高于对4 T1细胞的附着（平均值为0.04 ± 0.03），MBD与SVR细胞的粘附高于MBV（平均值，0.58 ± 0.09），MBI（平均值，0.42 ± 0.21），MBC（平均值，0.11 ± 0.13），和MBN（平均值，0.01 ± 0.01）（P <0.05）。在鼠肿瘤血管生成模型中，MBD（平均值，16.7 +/- 7.2）的成像信号显著高于MBV（平均值，11.3 +/- 5.7）、MBI（平均值，7.8 +/- 5.3）、MBC（平均值，2.8 +/- 0.9）和MBN（平均值，1.1 +/- 0.4）（P <0.001）。免疫荧光证实了VEGFR 2和α（v）β（3）整合素在肿瘤vascularis.Conclusion上的表达：针对VEGFR 2和α（v）β（3）整合素的双靶向对比增强US改善了小鼠人卵巢癌异种移植肿瘤模型中肿瘤血管生成的体内可视化。(C)RSNA，2008年。
Purpose: To develop and validate a dual-targeted ultrasonographic (US) imaging agent with microbubbles (MBs) that attaches to both vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and alpha(v)beta(3) integrin and to compare the US imaging signal obtained from dual-targeted MBs (MBD) with that from single-targeted MBs (MBS) in a murine model of tumor angiogenesis.Materials and Methods: Animal protocols were approved by the institutional Administrative Panel on Laboratory Animal Care. Single-and dual-targeted US imaging agents were prepared by attaching anti-VEGFR2, anti-alpha(v)beta(3) integrin, or both antibodies to the shell of perfluorocarbon-filled MBs. Binding specificities of targeted MBs compared with isotype-matched immunoglobulin G-labeled control MBs (MBC) and nontargeted nonlabeled MBs (MBN) were tested with VEGFR2-positive and alpha(v)beta(3) integrin-positive cells (mouse SVR cells) and control cells (mouse 4T1 cells). In vivo imaging signals of contrast material-enhanced US by using anti-VEGFR2-targeted MBs (MBV), anti-alpha(v)beta(3) integrin-targeted MBs (MBI), MBD, and MBC were quantified in 49 mice bearing SK-OV-3 tumors (human ovarian cancer). Tumor tissue was stained for VEGFR2, alpha(v)beta(3) integrin, and CD31.Results: Attachment of MBD to SVR cells (mean, 0.74 MBs per cell +/- 0.05 [standard deviation]) was significantly higher than attachment to 4T1 cells (mean, 0.04 +/- 0.03), and attachment to SVR cells was higher for MBD than for MBV (mean, 0.58 +/- 0.09), MBI (mean, 0.42 +/- 0.21), MBC (mean, 0.11 +/- 0.13), and MBN (mean, 0.01 0.01) (P < .05). Imaging signal in the murine tumor angiogenesis model was significantly higher (P < .001) for MBD (mean, 16.7 +/- 7.2) than for MBV (mean, 11.3 +/- 5.7), MBI (mean, 7.8 +/- 5.3), MBC (mean, 2.8 +/- 0.9), and MBN (mean, 1.1 +/- 0.4). Immunofluorescence confirmed expression of VEGFR2 and alpha(v)beta(3) integrin on tumor vasculature.Conclusion: Dual-targeted contrast-enhanced US directed at both VEGFR2 and alpha(v)beta(3) integrin improves in vivo visualization of tumor angiogenesis in a human ovarian cancer xenograft tumor model in mice. (C) RSNA, 2008.