Ultrasound-targeted microbubble destruction (UTMD) has been proven as an effective technique to assist drugs to cross the vascular wall and cell membrane. This study was aimed at evaluating the synergistic antiangiogenic and growth-inhibiting effects of apatinib (APA) and UTMD on the triple negative breast cancer (TNBC). The TNBC xenograft model was established in nude mice () which were then randomly divided into the APA plus UTMD (APA-U) group, UTMD group, APA group, and model control (M) group ( per group). Corresponding treatment was done once daily for 14 consecutive days. The general condition and body weight of tumor-bearing nude mice were monitored. Routine blood test and detection of liver and kidney function were done after treatments. The tumor size and microcirculation were examined by two-dimensional ultrasonography (2DUS) and contrast-enhanced ultrasonography (CEUS), respectively. Then, the tumor tissues were harvested for the detection of vascular endothelial growth factor (VEGF) by immunohistochemistry and for CD31-PAS double staining to assess microvessel density (MVD) and heterogeneous vascular positivity rate. After treatments, the tumor growth and angiogenesis were significantly inhibited in the APA group and the APA-U group, and these effects were more obvious in the APA-U group. The tumor volume, CEUS parameters, VEGF expression, and MVD in the APA-U group were significantly lower than those in the APA group (), while there were no marked differences in the heterogeneous vascular positivity rate, body weight, and blood parameters between the two groups (). In the UTMD group, the tumor growth and angiogenesis were not significantly inhibited, and all the parameters were similar to those in the M group (). During the experiment, all mice survived and generally had good condition. In conclusion, APA combined with UTMD may exert synergistic antiangiogenic and growth-inhibiting effects on the TNBC and not increase the heterogeneous vasculature and the severity of APA-related systemic side effects.

中文翻译：

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超声靶向微泡破坏增强阿帕替尼对三阴性乳腺癌异种移植物血管生成的抑制作用


超声靶向微泡破坏（UTMD）已被证明是辅助药物穿过血管壁和细胞膜的有效技术。本研究旨在评估阿帕替尼（APA）和UTMD对三阴性乳腺癌（TNBC）的协同抗血管生成和生长抑制作用。建立裸鼠TNBC异种移植模型（ ）然后随机分为APA加UTMD（APA-U）组、UTMD组、APA组和模型对照（M）组（每组）。相应治疗每日1次，连续14天。监测荷瘤裸鼠一般状况和体重。治疗后进行血常规检查及肝肾功能检测。分别通过二维超声检查（2DUS）和超声造影（CEUS）检查肿瘤大小和微循环。然后，收获肿瘤组织，采用免疫组织化学法检测血管内皮生长因子（VEGF），并进行CD31-PAS双染色评估微血管密度（MVD）和异质性血管阳性率。治疗后，APA组和APA-U组的肿瘤生长和血管生成均受到明显抑制，且APA-U组的效果更为明显。 APA-U组的肿瘤体积、CEUS参数、VEGF表达和MVD均显着低于APA组（），而两组间的异质性血管阳性率、体重和血液参数无显着差异（ ）。 UTMD组肿瘤生长和血管生成未受到明显抑制，各项参数与M组相似（ ）。实验过程中，所有小鼠均存活，总体状况良好。总之，APA联合UTMD可能对TNBC发挥协同抗血管生成和生长抑制作用，并且不会增加血管的异质性和APA相关全身副作用的严重程度。