The approval of radionuclide therapy strategies in nuclear medicine has revolutionized the treatment landscape for patients with advanced malignancies. Due to significant HER2 overexpression in some solid tumors, radionuclide therapy targeting HER2 is a viable strategy. The traditional monoclonal antibody (mAb) direct radiolabelling system may lead to off-target radiation exposure. To address this limitation, we employed the established inverse-electron demand Diels-Alder (IEDDA)-based pretargeting strategy and designed a novel tetrazine probe. First, we identified the optimal targeting molecule (Pertuzumab) and optimal metabolic time (48 h) through micro-positron emission tomography/computed tomography (PET/CT) scans and biodistribution studies of 89 ZrZr-DFO-Per, 89 ZrZr-DFO-Per-F(ab′) 2 and 89 ZrZr-DFO-Per-Fab. Next, TCO-Pertuzumab (TCO-Per) was administered to HER2-overexpressing SKOV3 tumor-bearing mice models, and after 48 h of circulation and clearance, a novel radiolabelled small molecule Tz ( 131 II-Tyr-D-peptide-PEG 11 -Tz) was introduced. Through a series of in vivo studies, we observed prolonged retention of 131 II-Tyr-D-peptide-PEG 11 -Tz in SKOV3 tumors with rapid renal clearance, along with promising therapeutic efficacy. Our study demonstrates that the novel tetrazine probe within a pretargeting delivery system overcomes limitations of traditional strategies and shows promise for clinical translation. Three lead molecules were evaluated to select the optimal candidate. Following the successful synthesis of Tyr-D-peptide-PEG 11 -Tz, a novel tetrazine probe was developed within a pretargeted delivery system for theranostic applications.
Ma et al. (Sun,) studied this question.