An HDAC-Targeted Imaging Probe LBH589鈥揅y5.5 for Tumor Detection and Therapy Evaluation

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• 作者：Qingqing Meng ; Zhiyi Liu ; Feng Li ; Jianjun Ma ; He Wang ; Yi Huan ; Zheng Li
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：July 6, 2015
• 年：2015
• 卷：12
• 期：7
• 页码：2469-2476
• 全文大小：456K
• ISSN：1543-8392

文摘

Histone deacetylases (HDACs) are overexpressed in various cancers. In vivo imaging to measure the expression and functions of HDACs in tumor plays an important role for tumor diagnosis and HDAC-targeted therapy evaluation. The development of stable and highly sensitive HDAC targeting probe is highly desirable. Near-infrared (NIR) fluorescence optical imaging is a powerful technology for visualizing disease at the molecular level in vivo with high sensitivity and no ionizing radiation. We report here the design, synthesis, and bioactivity evaluation of LBH589鈥揅y5.5 for in vivo NIR fluorescence imaging of HDACs. The IC₅₀ value of the resulting NIR probe to HDACs was determined to be 9.6 nM. In vitro fluorescence microscopic studies using a triple-negative breast cancer cell line, MDA-MB-231, established the binding specificity of LBH589鈥揅y5.5 to HDACs. An in vivo imaging study performed in MDA-MB-231 tumor xenografts demonstrated accumulation of the probe in tumor with good contrast from 2 h to 48 h postinjection. Furthermore, the fluorescent signal of LBH589鈥揅y5.5 in tumor was successfully blocked by coinjection of nonfluorescent LBH589 with the probe. In a following therapy evaluation study, the administration of SAHA, a clinically used HDAC inhibitor, decreased LBH589鈥揅y5.5 accumulation in tumor, demonstrating the potential application of LBH589鈥揅y5.5 for evaluating therapeutic response of HDAC inhibitors in cancer treatment.