title: Selective depletion of tumor neovasculature by microbubble destruction with appropriate ultrasound pressure.
abstract: Low-intensity ultrasound-microbubble (LIUS-MB) treatment is a promising antivascular therapy for tumors. We sought to determine whether LIUS-MB treatment with an appropriate ultrasound pressure could achieve substantial and persistent cessation of tumor perfusion without having significant effects on normal tissue. Further, we investigated the mechanisms underlying this treatment. Murine S-180 sarcomas, thigh muscles, and skin tissue from 60 tumor-bearing mice were subjected to sham therapy, an ultrasound application combined with microbubbles in four different ultrasound pressures (0.5, 1.5, 3.0, 5.0 MPa), or ultrasound at 5.0 MPa alone. Subsequently, contrast-enhanced ultrasonic imaging and histological studies were performed. Tumor microvessels, tumor cell necrosis, apoptosis, tumor growth, and survival were evaluated in 85 mice after treatment with the selected ultrasound pressure. We found that twenty-four hours after LIUS-MB treatment at 3.0 MPa, blood perfusion and microvessel density of the tumor had substantially decreased by 84 ± 8% and 84%, respectively (p < 0.01). Similar reductions were not observed in the muscle or skin. Additionally, an extreme reduction in the number of immature vessels was observed in the tumor (reduced by 90%, p < 0.01), while the decrease in mature vessels was not significant. Further, LIUS-MB treatment at 3.0 MPa promoted tumor cell necrosis and apoptosis, delayed tumor growth, and increased the survival rate of tumor-bearing mice (p < 0.01). These findings indicate that LIUS-MB treatment with an appropriate ultrasound pressure could selectively and persistently reduce tumor perfusion by depleting the neovasculature. Therefore, LIUS-MB treatment offers great promise for clinical applications in antivascular therapy for solid tumors.
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Junfen
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.|Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, China.
authors.forename: Zonglei
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.|Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, China.
authors.forename: Shuxin
authors.initials: S
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Chuanxi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Shengcun
authors.initials: S
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yongkang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wangjun
authors.initials: W
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Bin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D008297:Male; D051379:Mice; D045423:Microbubbles / Q000627:therapeutic use*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000628:therapy*; D012510:Sarcoma 180 / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D012867:Skin / Q000473:pathology*; D013848:Thigh / Q000473:pathology*; D016896:Treatment Outcome; D014464:Ultrasonic Therapy / Q000379:methods*
keywords: antivascular therapy; low-intensity ultrasound; microbubbles; tumor neovasculature