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 [⁸⁹Zr]Zr-DFO-Per, [⁸⁹Zr]Zr-DFO-Per-F(ab')₂ and [⁸⁹Zr]Zr-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 ([¹³¹I]I-Tyr-d-peptide-PEG₁₁-Tz) was introduced. Through a series of in vivo studies, we observed prolonged retention of [¹³¹I]I-Tyr-d-peptide-PEG₁₁-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.

Theranostic  /  Radionuclide targeting delivery system  /  Bioorthogonal click chemistry  /  [¹³¹I]I-Tyr-d-peptide-PEG₁₁-Tz  /  HER2  /  Nuclear medicine  /  Pretargeting  /  Radionuclide therapy