Dual‐Targeting of PD‐L1 and Integrin α_vβ₃ for Preclinical PET Imaging of Cancer

The dual-targeting strategy has demonstrated advantages in enhancing tumor uptake, improving imaging contrast, and ultimately increasing tumor detection rate. PD-L1 is overexpressed on multiple tumor cells and regulated by α_vβ₃-integrin. In this study, a dual-targeting radiotracer, [64Cu]-PEG-RGD-TPP-1, is developedfor PET/CT imaging of both PD-L1 and α_vβ₃-integrin simultaneously, achieving high contrast, enhanced tumor uptake, and prolonged tumor retention time. [⁶⁴Cu]-PEG-RGD-TPP-1 comprises the peptide TPP-1 and cyclic peptide c(RGDyC), linked via a PEG linker. The dual-targeting molecule had a moderate serum stability (≈60%) in vivo after 1 hr. This dual-targeting radiotracer is evaluated and compared with the single-targeting radiotracers [⁶⁴Cu]-PEG-TPP-1 and [⁶⁴Cu]-TPP-1. PET imaging and ex vivo biodistribution studies show that [⁶⁴Cu]-PEG-RGD-TPP-1 exhibits higher tumor uptake than its single-targeting counterparts. Moreover, the dual-targeting radiotracer demonstrated potential for ultrasmall tumor imaging and could be combined with X-ray irradiation to further enhance PET imaging contrast, thereby improving tumor-targeting efficiency. These findings suggest that [⁶⁴Cu]-PEG-RGD-TPP-1 is a promising noninvasive tracer for detecting tumors expressing PD-L1 and/or integrin a_vβ₃, with the prospect of clinical implementation.