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Development and evaluation of a novel (99m)tc-labeled annexin A5 for early detection of response to chemotherapy.

Ogawa K, Ohtsuki K, Shibata T, Aoki M, Nakayama M, Kitamura Y, Ono M, Ueda M, Doue T, Onoguchi M, Shiba K, Odani A - PLoS ONE (2013)

Bottom Line: However, (99m)Tc-HYNIC-annexin A5 has characteristics of high uptake and long retention in non-target tissues such as kidney and liver.In biodistribution experiments, (99m)Tc-C3(BHam)2-annexin A5 had a much lower kidney accumulation of radioactivity than (99m)Tc-HYNIC-annexin A5.In the organs for metabolism, such as liver and kidney, radioactivity after the injection of (99m)Tc-HYNIC-annexin A5 was residual for a long time.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.

ABSTRACT
(99m)Tc-HYNIC-annexin A5 can be considered as a benchmark in the field of apoptosis imaging. However, (99m)Tc-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 (99m)Tc-labeled annexin A5 using a bis(hydroxamamide) derivative [C3(BHam)2] as a bifunctional chelating agent, and evaluated its usefulness as an imaging agent for detecting apoptosis. The amino group of C3(BHam)2 was converted to a maleimide group, and was coupled to thiol groups of annexin A5 pretreated with 2-iminothiolane. (99m)Tc labeling was performed by a ligand exchange reaction with (99m)Tc-glucoheptonate. Biodistribution experiments for both (99m)Tc-C3(BHam)2-annexin A5 and (99m)Tc-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 (99m)Tc-C3(BHam)2-annexin A5 just after the first treatment of 5-FU was evaluated. (99m)Tc-C3(BHam)2-annexin A5 was prepared with a radiochemical purity of over 95%. In biodistribution experiments, (99m)Tc-C3(BHam)2-annexin A5 had a much lower kidney accumulation of radioactivity than (99m)Tc-HYNIC-annexin A5. In the organs for metabolism, such as liver and kidney, radioactivity after the injection of (99m)Tc-HYNIC-annexin A5 was residual for a long time. On the other hand, radioactivity after the injection of (99m)Tc-C3(BHam)2-annexin A5 gradually decreased. In therapeutic experiments, tumor growth in the mice treated with 5-FU was significantly inhibited. Accumulation of (99m)Tc-C3(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 (99m)Tc-C3(BHam)2-annexin A5 may contribute to the efficient detection of apoptotic tumor response after chemotherapy.

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Correlation between TUNEL-positive cells and radioacitvity in tumor section.Correlation between the number of TUNEL-positive cells in each grid (0.45 mm×0.55 mm) of a tumoral section and 99mTc-C3(BHam)2-annexin A5 accumulation (%dose) determined by autoradiography in each corresponding grid of an adjacent section from mice treated with 5-FU (A) or non-treatment mice (B).
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pone-0081191-g007: Correlation between TUNEL-positive cells and radioacitvity in tumor section.Correlation between the number of TUNEL-positive cells in each grid (0.45 mm×0.55 mm) of a tumoral section and 99mTc-C3(BHam)2-annexin A5 accumulation (%dose) determined by autoradiography in each corresponding grid of an adjacent section from mice treated with 5-FU (A) or non-treatment mice (B).

Mentions: Autoradiographic images of tumoral sections at 4 hours after injection of 99mTc-C3(BHam)2-annexin A5 and corresponding TUNEL-staining images in adjacent sections are shown in Figure 6. These images show that the accumulation of radioactivity in tumors of 5-FU treated mice was higher compared to that in non-treatment control mice. Moreover, the sites of higher accumulation of radioactivity and the sites of intense positive TUNEL staining seem to match. To investigate whether the intratumoral localization of 99mTc-C3(BHam)2-annexin A5 correlated with the sites of drug-induced apoptosis cells, we divided the autoradiographic and TUNEL-staining images of tumor sections using grids (grid size; 0.45 mm×0.55 mm) and determined the radioactivity and number of TUNEL-positive cells in each grid. The results showed that the intratumoral accumulations of radioactivity correlated well with the counts of TUNEL-staining positive cells in corresponding grids (Figure 7).


Development and evaluation of a novel (99m)tc-labeled annexin A5 for early detection of response to chemotherapy.

Ogawa K, Ohtsuki K, Shibata T, Aoki M, Nakayama M, Kitamura Y, Ono M, Ueda M, Doue T, Onoguchi M, Shiba K, Odani A - PLoS ONE (2013)

Correlation between TUNEL-positive cells and radioacitvity in tumor section.Correlation between the number of TUNEL-positive cells in each grid (0.45 mm×0.55 mm) of a tumoral section and 99mTc-C3(BHam)2-annexin A5 accumulation (%dose) determined by autoradiography in each corresponding grid of an adjacent section from mice treated with 5-FU (A) or non-treatment mice (B).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852265&req=5

pone-0081191-g007: Correlation between TUNEL-positive cells and radioacitvity in tumor section.Correlation between the number of TUNEL-positive cells in each grid (0.45 mm×0.55 mm) of a tumoral section and 99mTc-C3(BHam)2-annexin A5 accumulation (%dose) determined by autoradiography in each corresponding grid of an adjacent section from mice treated with 5-FU (A) or non-treatment mice (B).
Mentions: Autoradiographic images of tumoral sections at 4 hours after injection of 99mTc-C3(BHam)2-annexin A5 and corresponding TUNEL-staining images in adjacent sections are shown in Figure 6. These images show that the accumulation of radioactivity in tumors of 5-FU treated mice was higher compared to that in non-treatment control mice. Moreover, the sites of higher accumulation of radioactivity and the sites of intense positive TUNEL staining seem to match. To investigate whether the intratumoral localization of 99mTc-C3(BHam)2-annexin A5 correlated with the sites of drug-induced apoptosis cells, we divided the autoradiographic and TUNEL-staining images of tumor sections using grids (grid size; 0.45 mm×0.55 mm) and determined the radioactivity and number of TUNEL-positive cells in each grid. The results showed that the intratumoral accumulations of radioactivity correlated well with the counts of TUNEL-staining positive cells in corresponding grids (Figure 7).

Bottom Line: However, (99m)Tc-HYNIC-annexin A5 has characteristics of high uptake and long retention in non-target tissues such as kidney and liver.In biodistribution experiments, (99m)Tc-C3(BHam)2-annexin A5 had a much lower kidney accumulation of radioactivity than (99m)Tc-HYNIC-annexin A5.In the organs for metabolism, such as liver and kidney, radioactivity after the injection of (99m)Tc-HYNIC-annexin A5 was residual for a long time.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.

ABSTRACT
(99m)Tc-HYNIC-annexin A5 can be considered as a benchmark in the field of apoptosis imaging. However, (99m)Tc-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 (99m)Tc-labeled annexin A5 using a bis(hydroxamamide) derivative [C3(BHam)2] as a bifunctional chelating agent, and evaluated its usefulness as an imaging agent for detecting apoptosis. The amino group of C3(BHam)2 was converted to a maleimide group, and was coupled to thiol groups of annexin A5 pretreated with 2-iminothiolane. (99m)Tc labeling was performed by a ligand exchange reaction with (99m)Tc-glucoheptonate. Biodistribution experiments for both (99m)Tc-C3(BHam)2-annexin A5 and (99m)Tc-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 (99m)Tc-C3(BHam)2-annexin A5 just after the first treatment of 5-FU was evaluated. (99m)Tc-C3(BHam)2-annexin A5 was prepared with a radiochemical purity of over 95%. In biodistribution experiments, (99m)Tc-C3(BHam)2-annexin A5 had a much lower kidney accumulation of radioactivity than (99m)Tc-HYNIC-annexin A5. In the organs for metabolism, such as liver and kidney, radioactivity after the injection of (99m)Tc-HYNIC-annexin A5 was residual for a long time. On the other hand, radioactivity after the injection of (99m)Tc-C3(BHam)2-annexin A5 gradually decreased. In therapeutic experiments, tumor growth in the mice treated with 5-FU was significantly inhibited. Accumulation of (99m)Tc-C3(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 (99m)Tc-C3(BHam)2-annexin A5 may contribute to the efficient detection of apoptotic tumor response after chemotherapy.

Show MeSH
Related in: MedlinePlus