Preclinical Evaluation of a Trop2-Targeted Peptide Probe for PET Imaging of Triple-Negative Breast Cancer

Trophoblast cell surface antigen 2 (Trop2) has been extensively characterized as a clinically relevant pan-cancer biomarker that is overexpressed in multiple malignancies, including triple-negative breast cancer (TNBC). In this study, we employed computational simulation strategies to develop peptide WP8 derived from midkine (MDK), a particular ligand of Trop2, and designed a Trop2-targeting radiotracer [⁶⁸Ga]Ga-NOTA-PEG₂-WP8 for positron emission tomography (PET) imaging of Trop2 expression. This radiotracer exhibits nanomolar affinity for Trop2, along with favorable stability and pharmacokinetic properties. Dynamic PET imaging revealed that [⁶⁸Ga]Ga-NOTA-PEG₂-WP8 displays significant and specific uptake in Trop2-positive TNBC tissues, enabling rapid and precise identification of Trop2 expression. Notably, this radiotracer demonstrated high sensitivity in detecting the response of TNBC tumor to Trop2-targeting antibody-drug conjugates (ADCs). Collectively, these findings indicate that the peptide-based radiotracer [⁶⁸Ga]Ga-NOTA-PEG₂-WP8 holds considerable potential as a noninvasive tool for accurately monitoring of Trop2 expression before, during, and after ADC-based therapies.