超声靶向微泡破裂增强恩度凝胶抑制裸鼠乳腺癌移植瘤血管生成

Ultrasound-targeted microbubbles destruction for improving antiangiogenic effect of Endostar gel on human breast cancer xenograft nude mice models

目的探讨超声靶向微泡破裂对瘤体内注射恩度凝胶抑制裸鼠乳腺癌移植瘤血管生成作用的影响。方法制备载恩度的PLGA-PEG-PLGA温度敏感型凝胶,检测恩度凝胶体外释放及超声辐照对药物释放的影响;建立荷人乳腺癌裸鼠移植瘤模型,分为模型组、恩度凝胶瘤体内注射组、超声靶向微泡破裂组、恩度凝胶联合超声靶向微泡破裂组,每7天治疗1次,连续3次后行肿瘤CEUS,测定肿瘤组织微血管密度,评价各种处理对肿瘤血管生成的抑制作用。结果恩度凝胶在体外平稳释放约1周,超声辐照可提高恩度凝胶的释放速率;恩度凝胶瘤体内注射联合超声靶向微泡破裂处理具有明显的抑制肿瘤血管生成作用,肿瘤CEUS峰值强度及微血管密度均明显低于模型组及恩度凝胶治疗组(P<0.05)。结论超声靶向微泡破裂可阻断荷人乳腺癌裸鼠移植瘤微循环,并有效控制恩度凝胶的药物释放速率,使之释放更多药物作用于血管内皮细胞,具有明显的抑制肿瘤血管生成作用。

Objective To investigate the influence of ultrasound-targeted microbubbles destruction （UTMD） on Endostar gel inhibiting breast cancer xenograft angiogenesis. Methods Endostar-loaded PLGA-PEG-PLGA thermosensitive hydro- gel was prepared, and in vitro drug release with or without ultrasound exposure was performed. Human breast cancer-bear- ing nude mice were randomly divided into mode group, Endostar gel group, UTMD group and Endostar gel combined with UTMD group, and underwent treatment once a week for 3 times. After treatment, CEUS of tumor was performed, and microvascular density （MVD） of tumor was calculated. Results Endostar gel steadily released drug for 7 days, and ultra- sound exposure enhanced drug release velocity significantly. Compared with model group and Endostar gel group, the peak- intensity of CEUS and MVD in Endostar gel combined with UTMD group were lower. Conclusion Ultrasound-targeted microbubbles destruction could interrupt tumor blood circulation, control drug release from Endostar gel on human breast cancer-bearing nude mice, which may obviously improve antiangiogenic effect of Endostar.