Preclinical Evaluation of 68Ga-Labeled Heterodimers for Dual Integrin αvβ3 and PARP1-Targeted Tumor Imaging

Abstract Tumor heterogeneity limits the diagnostic performance of molecular imaging probes targeting a single biomarker. Here, we report the design, synthesis, and preclinical evaluation of 68Ga-labelled heterodimeric radiotracers co-targeting integrin αvβ3 and poly(ADP-ribose) polymerase 1 (PARP1) through a proposed “binding−anchoring” concept strategy. Conjugating the tumor-penetrating iRGD peptide with the PARP1 inhibitor niraparib and incorporating an albumin-binding moiety yielded the lead probe [68Ga] Ga-NY-Dual-IP. Molecular docking and surface plasmon resonance supported nanomolar target-binding capability of the corresponding non-radiolabeled precursors. In the 4T1 breast cancer model, [68Ga] Ga-NY-Dual-IP exhibited a tumor uptake of 7.29 ± 0.28% ID/g at 1 h, approximately 4−5-fold higher than that of the corresponding single-target probes. Cytotoxicity, haemolysis and histopathological analyses confirmed excellent biocompatibility. These findings established [68Ga] Ga-NY-Dual-IP as a promising PET probe for precise tumor imaging and potential clinical translation.