Synthesis and characterization of hypoxia trapping incorporated 177Lu-bombesin analogs for prostate cancer

Objectives The gastrin-releasing peptide receptor (BB2r) has been a promising target due to the highly up-regulated receptor expression in a variety of human cancers including prostate cancer. Bombesin (BBN) is a widely used targeting peptide as a result of its high affinity and specificity towards the BB2r. Unfortunately, one of the major challenges for BBN-targeted drugs is the significant clearance from tumor, thereby reducing the theranostic efficacy. In most solid tumors, regions of hypoxia are present throughout the tissue due to chaotic vascular architecture. Bioreductive hypoxia targeting agents, such as nitroimidazoles, are selectively reduced under hypoxic conditions and become trapped in the hypoxic cell. In an attempt to increase the effectiveness of small targeted ligand based theranostic agents, we designed BB2r-targeted agents that include 2-nitroimidazoles as hypoxia trapping moieties to increase the retention of the drug in hypoxic tumor cells.

Methods Four 177Lu-labeled BB2r-targeted agents (0-3) were synthesized. The BB2r binding affinity, partition coefficient, efflux and protein association studies were assessed using the PC-3 cancer cell line under hypoxic and normoxic conditions. The biodistribution and microSPECT/CT imaging studies were carried out using PC-3 tumor bearing SCID mice.

Results All conjugates demonstrated nanomolar binding affinities and hydrophilic nature under physiological conditions. 177Lu-0-3 demonstrated 39, 71, 72 and 70 % retention of internalized radioactivity under hypoxic conditions relative to 33, 32, 32 and 29 % retention under normoxic conditions. Size exclusion chromatography revealed significantly higher radioactive signals associated with macromolecules for the 2-nitroimidazole containing 177Lu-conjugates under hypoxic conditions. 117Lu-0-3 demonstrated tumor retentions of 7, 13, 22 and 24 % by 144 h post-injection.

Conclusions The improved retention resulted in higher tumor to non-target ratios which provide significant benefits for diagnostic imaging and radiotherapy.