Development and Evaluation of a Novel Tc-99m-Labeled Annexin A5 for Early Detection of Response to Chemotherapy

作者：Ogawa Kazuma^*; Ohtsuki Katsuichi; Shibata Tomomi; Aoki Miho; Nakayama Morio; Kitamura Yoji; Ono Masahiro; Ueda Masashi; Doue Tomoki; Onoguchi Masahisa; Shiba Kazuhiro; Odani Akira

来源：PLos One, 2013, 8(12): e81191.

DOI：10.1371/journal.pone.0081191

Tc-99m-HYNIC-annexin A5 can be considered as a benchmark in the field of apoptosis imaging. However, Tc-99m-HYNIC-annexin A5 has characteristics of high uptake and long retention in non-target tissues such as kidney and liver. To minimize this problem, we developed a novel Tc-99m-labeled annexin A5 using a bis(hydroxamamide) derivative [C-3(BHam)(2)] as a bifunctional chelating agent, and evaluated its usefulness as an imaging agent for detecting apoptosis. The amino group of C-3(BHam)(2) was converted to a maleimide group, and was coupled to thiol groups of annexin A5 pretreated with 2-iminothiolane. Tc-99m labeling was performed by a ligand exchange reaction with Tc-99m-glucoheptonate. Biodistribution experiments for both Tc-99m-C-3(BHam)(2)-annexin A5 and Tc-99m-HYNIC-annexin A5 were performed in normal mice. In addition, in tumor-bearing mice, the relationship between the therapeutic effects of chemotherapy (5-FU) and the tumor accumulation of Tc-99m-C-3(BHam)(2)-annexin A5 just after the first treatment of 5-FU was evaluated. Tc-99m-C-3(BHam)(2)-annexin A5 was prepared with a radiochemical purity of over 95%. In biodistribution experiments, Tc-99m-C-3(BHam)(2)-annexin A5 had a much lower kidney accumulation of radioactivity than Tc-99m-HYNIC-annexin A5. In the organs for metabolism, such as liver and kidney, radioactivity after the injection of Tc-99m-HYNIC-annexin A5 was residual for a long time. On the other hand, radioactivity after the injection of Tc-99m-C-3(BHam)(2)-annexin A5 gradually decreased. In therapeutic experiments, tumor growth in the mice treated with 5-FU was significantly inhibited. Accumulation of Tc-99m-C-3(BHam)(2)-annexin A5 in tumors significantly increased after 5-FU treatment. The accumulation of radioactivity in tumor correlated positively with the counts of TUNEL-positive cells. These findings suggest that Tc-99m-C-3(BHam)(2)-annexin A5 may contribute to the efficient detection of apoptotic tumor response after chemotherapy.

• 出版日期2013-12-4