Hypoxia-abled biomarkers could be a boon for prostate cancer imaging
The gastrin-releasing peptide receptor (BB2r) has become a popular target in prostate cancer imaging, but low local retention of tracers at the tumor site impedes imaging. Hypoxia-enhanced targeting of these receptors may be just what the doctor ordered for better tumor-tracer retention, according to a study published July 29th in the Journal of Nuclear Medicine.
Zhengyuan Zhou, a researcher and PhD candidate in the department of Pharmaceutical Sciences and College of Pharmacy at the University of Nebraska Medical Center in Omaha, Neb., and colleagues conducted the first study of in vivo hypoxia-enhanced BB2-r targeted tracers in mice and found that the inclusion of 2-nitroimidazole moieties showed better local tumor affinity with I-111 bombesin and could potentially be investigated with other agents to improve BB2r targeting of prostate tumors.
“Hypoxia is a well known characteristic of many solid tumors, including breast, prostate, and pancreatic cancers,” wrote Zhou et al. “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.”
Hypoxia imaging may help clinicians get past the hurdle to sufficient retention of BB2r-targeted tracers that high efflux and diffusion rates present in tumors. Here 2-nitroimidazoles have been incorporated into the structure of the BB2r-targeted peptides for hypoxia-enhanced BB2r targets. These have been found to improve receptor binding in hopoxic PC-3 human prostate cancer cells.
Scientists developed four I-111 labeled BB2r-targeted conjugates—In-111-1, 2, 3 and 4—with different 2-nitroimidazole moieties and tested their binding affinities and other properties of externalization and protein association in BB2r-positive PC-3 human prostate cancer cell-bearing mice in both hypoxic and normomoxic conditions. Micro-SPECT/CT imaging was performed to gauge the in vivo biodistribution of the agents.
Results of the study indicated that I-111-1 had 44.4 percent retention, the second had 60.6 percent retention, the third 69.1 percent and I-111-4 showed 69.4 percent retention of radioactivity in hypoxic tumors. In contrast, the same agents in normoxic environments demonstrated 34.8, 35.3, 33.2 and 29.7 percent retention, respectively.
“The 2-nitroimidazole–trapping moieties containing BB2r-targeted agents demonstrated significantly higher retention and protein-association properties in hypoxic than in normoxic PC-3 cells,” wrote the authors. “In vivo biodistribution studies revealed great potential of incorporated trapping moieties to increase the residence time of BB2r-targeted agents in a PC-3 xenograft tumor. Further works are needed to clarify the mechanisms of increased retention effects at the molecular level and to correlate the tumor hypoxia burden with the retention efficacy.”