Synthesis and In Vitro and In Vivo Evaluation of Hypoxia-Enhanced 111In-Bombesin Conjugates for Prostate Cancer Imaging

Journal of Nuclear Medicine

Wen Shi¹  Yinnong Jia¹  Jered C. Garrison¹  Zhengyuan Zhou¹  Sunny M. Ogbomo¹  Nilesh K. Wagh¹  Susan K. Brusnahan¹ 

关键词: tumor hypoxia;    bombesin;    BB2 receptor;    prostate cancer;    2-nitroimidazole;   

DOI  :  10.2967/jnumed.112.117986

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Receptor-targeted agents, such as gastrin-releasing peptide receptor (BB2r)–targeted peptides, have been investigated extensively in preclinical and clinical studies. In an attempt to increase the effectiveness of diagnostic or radiotherapeutic agents, we have begun to explore the incorporation of the hypoxia-selective prodrug 2-nitroimidazole into receptor-targeted peptides. Hypoxia is a well-known characteristic of many solid tumors, including breast, prostate, and pancreatic cancers. The aim of this approach is to use the hypoxia-trapping capability of 2-nitroimidazoles to increase the retention of the agent in hypoxic, BB2r-positive tumors. We have demonstrated that incorporation of one or more 2-nitroimidazoles into the BB2r-targeted peptide significantly increases the in vitro retention of the agent in hypoxic prostate cancer cells. The study described herein represents our first investigation of the in vivo properties of these hypoxia-enhanced BB2r-targeted agents in a PC-3 xenograft mouse model. Methods: Four 111In-labeled BB2r-targeted conjugates111In-1, 111In-2, 111In-3, and 111In-4, composed of 2-nitroimidazole moieties of 0, 1, 2, and 3, respectivelywere synthesized, labeled, and purified. The BB2r binding affinities, externalization, and protein-association properties of these radioconjugates were assessed using the BB2r-positive PC-3 human prostate cancer cell line under hypoxic and normoxic environments. The in vivo biodistribution and micro-SPECT/CT imaging of the 111In-1, 111In-2, and 111In-4 radioconjugates were investigated in PC-3 tumor–bearing severely combined immunodeficient mice. Results: All conjugates and natIn-conjugates demonstrated nanomolar binding affinities. 111In-1, 111In-2, 111In-3, and 111In-4 demonstrated 41.4%, 60.7%, 69.1%, and 69.4% retention, correspondingly, of internalized radioactivity under hypoxic conditions relative to 34.8%, 35.3%, 33.2%, and 29.7% retention, respectively, under normoxic conditions. Protein-association studies showed significantly higher levels of association under hypoxic conditions for 2-nitroimidazole–containing BB2r-targeted radioconjugates than for controls. On the basis of the initial 1-h uptake in the PC-3 tumors, 111In-1, 111In-2, and 111In-4 demonstrated tumor retentions of 1.5%, 6.7%, and 21.0%, respectively, by 72 h after injection. Micro-SPECT/CT imaging studies of 111In-1, 111In-2, and 111In-4 radioconjugates resulted in clear delineation of the tumors. Conclusion: On the basis of the in vitro and in vivo studies, the BB2r-targeted agents that incorporated 2-nitroimidazole moieties demonstrated improved retention. These results indicate that further exploration into the potential of hypoxia-selective trapping agents for BB2r-targeted agents, as well as other targeted compounds, is warranted.

【 授权许可】

Unknown