Ultrasound-targeted microbubble destruction improved the antiangiogenic effect of Endostar in triple-negative breast carcinoma xenografts

  • Yang Jing
  • Zhang Xiu-Juan
  • Cai Hong-Jiao
  • Chen Zhi-KuiEmail author
  • Qian Qing-Fu
  • Xue En-Sheng
  • Lin Li-Wu
Original Article – Cancer Research



Ultrasound-targeted microbubble destruction (UTMD) has been reported to be a meritorious technique for drug targeting delivery. In this study, we aimed to evaluate the synergistic antiangiogenic effect of UTMD combined with Endostar on triple-negative breast carcinoma tumors.

Materials and methods

The lipid-shelled microbubbles (MBs) conjugated with Endostar were constructed using a biotin–avidin bridging chemistry method, and the morphological characteristics and drug-conjugating content were determined. MBs were administered intravenously to nude mice bearing MDA-MB-231 breast carcinoma xenografts and ultrasound exposure followed. The tumor microcirculation was observed by contrast-enhanced ultrasonography (CEUS) and the Endostar biodistribution was detected by enzyme-linked immunosorbent assay. Twenty-four breast carcinoma-bearing nude mice were divided into four groups. After treatment, every 3 days for 15 days the in vivo antitumor effects were assessed by calculating the tumor growth inhibition rate (TGIR). The tumor microcirculation was observed by CEUS, the tumor microvessel density (MVD) was calculated by immunohistochemistry under a microscope, and the vascular endothelial growth factor (VEGF) gene expression was detected by real-time quantitative polymerase chain reaction.


The prepared Endostar-conjugated MBs were round and well-dispersed with a mean size of 2.8 ± 0.7 µm and a drug conjugating content of 800.72 ± 70.53 µg/108 MBs. UTMD blocked the tumor microcirculation, and improved Endostar release in the targeted tumor tissue with a drug content of 1.12 ± 0.43 µg/gram protein, which was about three times higher than that in Endostar group or Endostar conjugated MBs group. Endostar-conjugated MBs combined with UTMD treatment achieved the optimal antitumor effects in vivo with a TGIR of 46.29%, and apparent antiangiogenic effects with minimal tumor blood perfusion, MVD and VEGF gene expression level.


UTMD can improve Endostar delivery in the targeting tumor tissue and mediate synergistic antiangiogenetic and antitumor effects, which may be a potential therapeutic strategy for refractory breast cancer.


Ultrasound-targeted microbubble destruction Endostar Antiangiogenesis Triple-negative breast carcinoma Vascular endothelial growth factor 



This work was supported by the Key Project for Youth Academic Talents (2015-ZQN-ZD-13), Medical Innovation Project (2015-CXB-17) from Health and Family Planning Commission of Fujian Province and the General Program (2016J01710) of Science and Technology Department of Fujian Province of China.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PharmacyAffiliated Union Hospital of Fujian Medical UniversityFuzhouChina
  2. 2.Department of UltrasoundAffiliated Union Hospital of Fujian Medical UniversityFuzhouChina
  3. 3.Fisheries College of Jimei UniversityXiamenChina

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