Palmowski Moritz, Huppert Jochen, Ladewig Gesa, Hauff Peter, Reinhardt Michael, Mueller Margareta M, Woenne Eva C, Jenne Juergen W, Maurer Mathias, Kauffmann Guenter W, Semmler Wolfhard, Kiessling Fabian
Department of Diagnostic Radiology, Ruprecht-Karls University, Heidelberg, Germany.
Mol Cancer Ther. 2008 Jan;7(1):101-9. doi: 10.1158/1535-7163.MCT-07-0409.
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 alphavbeta3 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 alphavbeta3 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 alphavbeta3 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 alphavbeta3 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.
分子超声能够在体内阐明血管生成标志物的表达。然而，该方法在体积“多靶点定量”以及评估抗血管生成治疗反应方面的能力尚未得到充分研究。因此，我们制备了与血管内皮生长因子受体2（VEGFR2）和αvβ3整合素结合配体相连的氰基丙烯酸酯微泡，并采用定量体积超声扫描技术（灵敏颗粒声学定量法）对其在小鼠鳞状细胞癌异种移植瘤（HaCaT-ras-A-5RT3）中的蓄积进行定量。研究了VEGFR2和αvβ3整合素结合微泡的特异性，并观察了基质金属蛋白酶抑制剂治疗过程中标志物表达的变化。在肿瘤中，靶向微泡的蓄积明显高于非特异性微泡，并且过量加入游离配体可竞争性抑制其蓄积。此外，在同一次成像过程中可以成功地进行多标志物成像。分子超声进一步表明，肿瘤生长过程中VEGFR2和αvβ3整合素表达显著增加，而基质金属蛋白酶抑制剂治疗后两种标志物密度均显著降低。组织学数据表明，肿瘤生长过程中VEGFR2和αvβ3整合素浓度的增加与内皮细胞对其表达的上调有关，而治疗后其浓度的降低更多地与相对血管密度的降低有关。总之，靶向超声在体内对肿瘤血管生成进行纵向分子分析以及灵敏评估治疗效果方面似乎是可行的。
