Abstract
Gastrin-releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclide therapy (TRT). We optimized the bombesin-derived GRPR-antagonist PEG(2) -RM26 for labeling with (177) Lu and further determined the effect of treatment with (177) Lu-labeled peptide alone or in combination with the anti-HER2 antibody trastuzumab in a murine model. The PEG(2) -RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide-chelator conjugates were labeled with (177) Lu and characterized in vitro and in vivo. A preclinical therapeutic study was performed in PC-3 xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA-PEG(2) -RM26, (C) (177) Lu-DOTAGA-PEG(2) -RM26, (D) trastuzumab or (E) (177) Lu-DOTAGA-PEG(2) -RM26 in combination with trastuzumab. (177) Lu-DOTAGA-PEG(2) -RM26 demonstrated quantitative labeling yield at high molar activity (450 GBq/μmol), high in vivo stability (5 min pi >98% of radioligand remained when coinjected with phosphoramidon), high affinity to GRPR (K(D) = 0.4 ± 0.2 nM), and favorable biodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with (177) Lu-DOTAGA-PEG(2) -RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorter than for treated groups (Group C 66 days, Group E 74 days). Trastuzumab together with radionuclide therapy significantly improved survival. No treatment-related toxicity was observed. In conclusion, based on in vitro and in vivo characterization of the four (177) Lu-labeled PEG(2) -RM26 analogs, we concluded that (177) Lu-DOTAGA-PEG(2) -RM26 was the most promising analog for TRT. Radiotherapy using (177) Lu-DOTAGA-PEG(2) -RM26 effectively inhibited tumor growth in vivo in a murine prostate cancer model. Anti-HER2 therapy additionally improved survival.