Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects
Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects
复制标题
DOI：
10.1158/1535-7163.mct-07-0409
复制
发表时间：
2008-01-01
影响因子：
5.7
通讯作者：
Kiesslin, Fabian
中科院分区：
文献类型：
--
作者：
Palmowski, Moritz;Huppert, Jochen;Kiesslin, Fabian
分子超声能够阐明体内血管生成标志物的表达。然而，容量的“多靶点定量”和抗血管生成治疗反应的评估方法的能力，而进行了研究。因此，我们产生了与血管内皮生长因子受体2（VEGFR 2）和α（v）β（3）整合素结合配体连接的氰基丙烯酸酯微泡，并使用定量体积超声扫描技术（灵敏的粒子声学定量）定量其在小鼠鳞状细胞癌异种移植物（HaCaT-ras-A-5 RT 3）中的蓄积。显示了VEGFR 2和α（v）β（3）整合素结合微泡的特异性，并研究了基质金属蛋白酶抑制剂治疗期间标志物表达的变化。在肿瘤中，靶向微泡的积累显着高于非特异性的，可以通过加入过量的游离配体竞争性抑制。此外，多标记成像可以在同一成像会话期间成功完成。分子超声进一步显示肿瘤生长过程中VEGFR 2和α（v）β（3）整合素表达显著增加，基质金属蛋白酶抑制剂治疗后两种标记物密度显著降低。组织学数据表明，肿瘤生长过程中VEGFR 2和α（v）β（3）整合素浓度的增加与内皮细胞对其表达的上调有关，而治疗下其降低与相对血管密度的降低更相关。总之，靶向超声似乎是可行的肿瘤血管生成的纵向分子谱和敏感的评估体内治疗效果。
Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric "multitarget quantification" and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and alpha(v)beta(3) integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and alpha(v)beta(3) integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and alpha(v)beta(3) integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and alpha(v)beta(3) integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo.