Synthesis and characterization of boron fenbufen and its F-18 labeled homolog for boron neutron capture therapy of COX-2 overexpressed cholangiocarcinoma

Publication date: 30 September 2017
Source:European Journal of Pharmaceutical Sciences, Volume 107
Author(s): Chun-Nan Yeh, Chi-Wei Chang, Yi-Hsiu Chung, Shi-Wei Tien, Yong-Ren Chen, Tsung-Wen Chen, Ying-Cheng Huang, Hsin-Ell Wang, You-Cheng Chou, Ming-Huang Chen, Kun-Chun Chiang, Wen-Sheng Huang, Chung-Shan Yu
Boron neutron capture therapy (BNCT) is a binary therapy that employs neutron irradiation on the boron agents to release high-energy helium and alpha particles to kill cancer cells. An optimal response to BNCT depends critically on the time point of maximal ¹⁰B accumulation and highest tumor to normal ratio (T/N) for performing the neutron irradiation. The aggressive cholangiocarcinoma (CCA) representing a liver cancer that overexpresses COX-2 enzyme is aimed to be targeted by COX-2 selective boron carrier, fenbufen boronopinacol (FBPin). Two main works were performed including: 1) chemical synthesis of FBPin as the boron carrier and 2) radiochemical labeling with F-18 to provide the radiofluoro congener, m-[¹⁸F]fluorofenbufen ester boronopinacol (m-[¹⁸F]FFBPin), to assess the binding affinity, cellular accumulation level and distribution profile in CCA rats. FBPin was prepared from bromofenbufen via 3 steps with 82% yield. The binding assay employed [¹⁸F]FFBPin to compete FBPin for binding to COX-1 (IC50=0.91±0.68μM) and COX-2 (IC50=0.33±0.24μM). [¹⁸F]FFBPin-derived 60-min dynamic PET scans predict the ¹⁰B-accumulation of 0.8–1.2ppm in liver and 1.2–1.8ppm in tumor and tumor to normal ratio=1.38±0.12. BNCT was performed 40–55min post intravenous administration of FBPin (20–30mg) in the CCA rats. CCA rats treated with BNCT display more tumor reduction than that by NCT with respect of 2-[¹⁸F]fluoro-2-deoxy glucose uptake in the tumor region of interest, 20.83±3.00% (n=12) vs. 12.83±3.79% (n=10), P=0.05. The visualizing agent [¹⁸F]FFBPin resembles FBPin to generate the time-dependent boron concentration profile. Optimal neutron irradiation period is thus determinable for BNCT. A boron-substituted agent based on COX-2-binding features has been prepared. The moderate COX-2/COX-1 selectivity index of 2.78 allows a fair tumor selectivity index of 1.38 with a mild cardiovascular effect. The therapeutic effect from FBPin with BNCT warrants a proper COX-2 targeting of boron NSAIDs.

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