title: Production and characterization of a novel long-acting Herceptin-targeted nanobubble contrast agent specific for Her-2-positive breast cancers.
abstract: BACKGROUND
  There is an unmet need for specific and sensitive imaging techniques to assess the efficacy of breast cancer therapy, particularly Her-2-expressing cancers. Ultrasonic microbubbles are being developed for use as diagnostic and therapeutic tools. However, nanobubbles circulate longer, are smaller, and diffuse into extravascular tissue to specifically bind target molecules. Here, we characterize a novel Herceptin-conjugated nanobubble for use against Her-2-expressing tumors.
  
  
  METHODS
  Phospholipid-shelled nanobubbles conjugated with Herceptin (NBs-Her) were fabricated using a thin-film hydration method and characterized in vitro in breast cancer cell lines and in vivo in a mouse model.
  
  
  RESULTS
  The average size of the unconjugated nanobubbles (NBs-Blank) and NBs-Her was 447.1 ± 18.4 and 613.0 ± 25.4 nm, respectively. In cell culture, the NBs-Her adhered to Her-2-positive cells significantly better than to Her-2-negative cells (p < 0.05). In vivo, the peak intensity and the half-time to washout of the NBs-Her were significantly greater than those of the NBs-Blank (p < 0.05). In addition, contrast-enhanced ultrasound imaging quality was improved through the use of the NBs-Her. The nanobubbles were able to penetrate into tumor tissue to allow extravascular imaging, but did not penetrate normal skeletal muscle.
  
  
  CONCLUSIONS
  The Herceptin-conjugated nanobubble had many properties that made it useful for in vivo imaging, including longer circulation time and better tumor selectivity. This platform may be able to provide targeted delivery of therapeutic drugs or genes.
authors.affiliation: Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen University, Guangzhou, 510120, People's Republic of China.
authors.forename: Qiongchao
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Shaoyun
authors.initials: S
authors.lastname: Hao
authors.affiliation: Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen University, Guangzhou, 510120, People's Republic of China.
authors.forename: Jiyi
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Bing
authors.initials: B
authors.lastname: Ou
authors.affiliation: Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Zizhuo
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yinfeng Road No. 33, HaiZhu District, Guangzhou, 510260, Guangdong, People's Republic of China.
authors.forename: Fengtao
authors.initials: F
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China. bmluo123@126.com.
authors.forename: Baoming
authors.initials: B
authors.lastname: Luo
authors.affiliation: Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China. zhihui181@126.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008819:Mice, Nude; D045423:Microbubbles; D049329:Nanostructures / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D016217:Ultrasonography, Mammary; D023041:Xenograft Model Antitumor Assays
chemical_list: D003287:Contrast Media; D010743:Phospholipids; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Breast cancer; Contrast-enhanced ultrasound; Herceptin; Nanobubble; Phospholipid