Biodistribution of the Bombesin Receptor-Targeted Radiopharmaceutical Precursor BBN/C1-C2 in a Prostate Cancer Model

Gastrin-releasing peptide receptor (GRPR) is a G protein-coupled receptor expressed in the central nervous system, the gastrointestinal tract, the pancreas, and the adrenal cortical tissue regulating their physiological functions. In addition to normal tissues, GRPR is overexpressed in many solid cancers. At present, several radiolabeled ligands targeting GRPR have been introduced into clinical practice for cancer diagnostics and radioligand therapy. However, there were found the high uptake of radiopharmaceuticals in normal organs and low bioavailability of the drugs caused by their stability. Therefore, GRPR radioantagonists with improved proteolytic stability and longer residence time in tumor foci with low uptake in non-target organs are currently being sought to improve the therapeutic efficacy. The aim of the study was to analyze the biodistribution of the BBN/C1-C2 molecule created on the basis of bombesin and knottin and its accumulation dynamics in the tumor in an in vivo model.

The study analyzed the biodistribution of Cy7.5-labeled BBN/C1-C2 peptide based on bombesin and knottin U5-Sth1a and produced using solid-phase peptide synthesis. The investigation was carried out on a mouse model Nu/Nu with a prostate cancer solid tumor (PC-3 culture) transplanted into the right side, expressing GRPR, using real-time surface fluorescent imaging on days 2 and 5 after intravenous administration of the molecules under study.

The biodistribution analysis showed the selective binding of the BBN/C1-C2 molecule to a tumor, as well as its holding power on the tumor surface for up to 5 days without internalization into cells with low accumulation in normal organs and tissues.

We managed to obtain a stable molecule; however, U5-Sth1a toxin tropic to ion channels was used as a scaffold, so the resulting molecule retained the domain responsible for attaching to the target channel and typical for knottin. In the future, when using the molecule as a ligand for radiotherapy, it can have a negative effect on the patient's heart due to the supplementary radiation load. In this regard, the BBN/C1-C2 molecule requires the extension study.