Department of Ultrasonography, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, PR China.
Department of Ultrasonography, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, PR China.
Cancer Lett. 2014 May 28;347(1):105-13. doi: 10.1016/j.canlet.2014.01.022. Epub 2014 Feb 11.
This study investigated the efficacy of concurrent delivery of an anti-angiogenic drug and ultrasonic cavitation therapy in a mouse model of human colon cancer. A biotinylated form of the anti-angiogenic drug Endostar was conjugated to a streptavidin-coated microbubble (MB). Mice bearing subcutaneous tumors (HT29) were divided into 4 groups. Group 1 served as an untreated control. Group 2 served as a cavitation control and received naked microbubbles and sham ultrasonic cavitation (MB+sham cavitation). Group 3 received naked microbubbles and ultrasonic cavitation (MB+cavitation). Group 4 received Endostar loaded microbubbles and ultrasonic cavitation (Endostar-MB+cavitation). Ultrasonic cavitation was performed using a high-power custom built sonicator. Contrast-enhanced ultrasound imaging (CEUS) was used to measure tumor blood flow before and after ultrasonic cavitation. In vivo fluorescence imaging was performed to monitor changes in tumor volume. Immunohistochemistry was performed to assess CD31, VEGFR-2 and alpha-v beta-3 integrin expression within the tumor. Apoptosis of the tumor cells was determined by TUNEL assay, and ultrastructural changes within the tumor were examined by electron microcopy. Ultrasonic cavitation with Endostar-MB demonstrated a significantly greater inhibition of tumor blood flow on day 7 and tumor growth on day 16 compared with naked MB and control groups. The Endostar-MB treated mice showed significantly decreased expression VEGFR-2 and alpha-v beta-3 integrin, and increased apoptosis of tumor cells and degradation of the tumor ultrastructure. Our findings indicated that the anti-vascular and anti-tumor effects of ultrasonic cavitation could be potentiated by simultaneously delivering an anti-angiogenic drug in colon cancer.
本研究探讨了在人结肠癌小鼠模型中联合应用抗血管生成药物和超声空化治疗的疗效。将抗血管生成药物恩度的生物素化形式与链霉亲和素包被的微泡（MB）连接。将荷有人结肠癌皮下肿瘤（HT29）的小鼠分为 4 组。第 1 组为未处理对照组。第 2 组为单纯空化对照组，接受裸微泡和假超声空化（MB+假空化）。第 3 组接受裸微泡和超声空化（MB+空化）。第 4 组接受负载恩度的微泡和超声空化（Endostar-MB+空化）。超声空化使用大功率定制超声仪进行。在超声空化前后使用对比增强超声成像（CEUS）测量肿瘤血流。进行体内荧光成像以监测肿瘤体积的变化。免疫组织化学检测肿瘤内 CD31、VEGFR-2 和 alpha-v beta-3 整合素的表达。通过 TUNEL 测定评估肿瘤细胞的凋亡，通过电子显微镜检查肿瘤内的超微结构变化。与裸 MB 和对照组相比，Endostar-MB 联合超声空化在第 7 天显著抑制肿瘤血流，在第 16 天显著抑制肿瘤生长。Endostar-MB 治疗组小鼠的 VEGFR-2 和 alpha-v beta-3 整合素表达显著降低，肿瘤细胞凋亡增加，肿瘤超微结构降解。我们的研究结果表明，同时给予抗血管生成药物可增强超声空化的抗血管和抗肿瘤作用。
