Small-Animal PET of Tumors with 64Cu-Labeled RGD-Bombesin Heterodimer

Journal of Nuclear Medicine

Zi-Bo Li¹  Shuanglong Liu¹  Xiaoyuan Chen¹  Qizhen Cao¹  Fan Wang¹  Zhaofei Liu¹ 

关键词: RGD-BBN heterodimer;    bombesin;    positron emission tomography (PET);    gastrin-releasing peptide receptor (GRPR);    integrin α_vβ₃;    ⁶⁴Cu;   

DOI  :  10.2967/jnumed.108.061739

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

The overexpression of gastrin-releasing peptide receptor (GRPR) in various tumor types suggests that GRPR is an attractive target for cancer imaging and therapy with radiolabeled bombesin analogs. We recently reported the ability of 18F-labeled RGD-bombesin heterodimer to be used for dual integrin αvβ3– and GRPR-targeted imaging. To further investigate the synergistic effect of the dual-receptor targeting of peptide heterodimers, we evaluated 64Cu-labeled RGD-bombesin for PET imaging of tumors. Methods: RGD-bombesin was coupled with 1,4,7,10-tetraazacyclododecane-N, N′, N′′, N′′′-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and the conjugates were labeled with 64Cu. The in vitro and in vivo characteristics of 64Cu-NOTA-RGD-bombesin were compared with those of 64Cu-NOTA-RGD, 64Cu-NOTA-bombesin, and 64Cu-DOTA-RGD-bombesin. Results: 64Cu-NOTA-RGD-bombesin and 64Cu-DOTA-RGD-bombesin had comparable dual integrin αvβ3– and GRPR-binding affinities in vitro, both of which were slightly lower than RGD for integrin binding and bombesin for GRPR binding. 64Cu-NOTA-RGD-bombesin possessed significantly higher tumor uptake than did 64Cu-NOTA-RGD, 64Cu-NOTA-bombesin, the mixture of 64Cu-NOTA-RGD and 64Cu-NOTA-bombesin, or 64Cu-DOTA-RGD-bombesin in PC-3 prostate cancer. 64Cu-NOTA-RGD-bombesin also showed improved in vivo kinetics such as lower liver and intestinal activity accumulation than did the bombesin tracers. 64Cu-NOTA-RGD-bombesin also outperformed 64Cu-NOTA-RGD in a 4T1 murine mammary carcinoma model that expresses integrin on tumor vasculature but no GRPR in tumor tissue, which had no uptake of 64Cu-NOTA-bombesin. Conclusion: Compared with other tracers, 64Cu-NOTA-RGD-bombesin showed favorable in vivo kinetics and enhanced tumor uptake, which warrants its further investigation for targeting tumors that express integrin or GRPR or that coexpress integrin and GRPR for imaging and therapeutic applications. The synergistic effect of RGD-bombesin heterodimers observed in this study also encourages further investigations of novel heterodimers recognizing other cell surface receptors for tumor targeting.

【 授权许可】

Unknown