Anti-angiogenic Effects of Bumetanide Revealed by DCE-MRI with a Biodegradable Macromolecular Contrast Agent in a Colon Cancer Model

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• 作者：Anthony S. Malamas ; Erlei Jin ; Qi Zhang ; John Haaga…
• 关键词：anti ; angiogenesis ; bumetanide ; cancer therapy ; DCE ; MRI ; polydisulfide
• 刊名：Pharmaceutical Research
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：32
• 期：9
• 页码：3029-3043
• 全文大小：7,265 KB
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• 作者单位：Anthony S. Malamas (1)
  Erlei Jin (1)
  Qi Zhang (2)
  John Haaga (3)
  Zheng-Rong Lu (1)
  
  1. Department of Biomedical Engineering, Case Western Reserve University, Wickenden 427, 10900 Euclid Avenue, Mail Stop 7207, Cleveland, Ohio, 44106, USA
  2. Provincial Key Lab of Fine Chemistry, Hainan University, Haikou, China
  3. Department of Radiology, University Hospitals Case Medical Center, Cleveland, Ohio, 44106, USA
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Pharmacy
  Biochemistry
  Medical Law
  Biomedical Engineering
  
• 出版者：Springer Netherlands
• ISSN：1573-904X

文摘

Purpose To assess the antiangiogenic effect of bumetanide with dynamic contrast enhanced (DCE)-MRI and a biodegradable macromolecular MRI contrast agent. Methods A new polydisulfide containing macrocyclic gadolinium (Gd(III)) chelates, poly([(Gd-DOTA)-DETA]-co-DTBP) (GODP), was synthesized as a safe biodegradable macromolecular MRI contrast agent for DCE-MRI. Nude mice bearing flank HT29 colon cancer xenografts were then treated daily with either bumetanide or saline for a total of 3?weeks. DCE-MRI was performed before and after the treatment weekly. The DCE-MRI data were analyzed using the adiabiatic approximation to the tissue homogeneity (AATH) model to assess the change of tumor vascularity in response to the treatment. Immunohistochemistry (IHC) and western blot were performed to study tumor angiogenic biomarkers and hypoxia. Results DCE-MRI with GODP revealed that bumetanide reduced vascular permeability and plasma volume fraction by a significantly greater extent than the saline control therapy after 3?weeks of therapy. These changes were verified by the significant decline of CD31 and VEGF expression in the bumetanide treatment group. Despite a significant regression in vascularity, the tumors remained highly proliferative. Overexpression of the transcription factor HIF-1α in response to elevated hypoxia is thought to be the driving force behind the uninterrupted tumor expansion. Conclusion This study demonstrated the effectiveness of DCE-MRI with GODP in detecting vascular changes following the administration of bumetanide. Bumetanide has the potential to curtail growth of the tumor vasculature and can be employed in future therapeutic strategies.