Ultrasound-Targeted Microbubble Destruction EnhancesInhibitory Effect of Apatinib on Angiogenesis in Triple NegativeBreast Carcinoma Xenografts

Ultrasound-targeted microbubble destruction (UTMD) has been proven as an effective technique to assist drugs to cross thev ascular wall and cell membrane. This study was aimed at evaluating the synergistic antiangiogenic and growth-inhibitingeffects of apatinib (APA) and UTMD on the triple negative breast cancer (TNBC). The TNBC xenograft model was established in nude mice (n=40) which were then randomly divided into the APA plus UTMD (APA-U) group, UTMD group, APAgroup, and model control (M) group (n=10per 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 micro circulation were examined by two-dimensionalultrasonography (2DUS) and contrast-enhanced ultra sonography (CEUS), respectively. Then, the tumor tissues were harvestedfor the detection of vascular endothelial growth factor (VEGF) by immuno histochemistry 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 theAPA-U group. The tumor volume, CEUS parameters, VEGF expression, and MVD in the APA-U group were significant lylower than those in the APA group (P<0:05), while there were no marked differences in the heterogeneous vascular positivityrate, body weight, and blood parameters between the two groups (P>0:05). 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 (P>0:05). During the experiment, all mice survived and generally had good condition. In conclusion, APA combined with UTMD may exertsynergistic antiangiogenic and growth-inhibiting effects on the TNBC and not increase the heterogeneous vasculature and these verity of APA-related systemic side effects