Preparation and Application of a Bioorganic Nanoparticle-Enhanced PDL1-Targeted Small-Molecule Probe.

Programmed death ligand 1 (PDL1) is a specific molecular target for the diagnosis and immunotherapy of solid tumors. PET imaging can be used for noninvasive assessments of PDL1 expression in tumors to aid in therapy selection. The most frequently reported small-molecule radiotracer of PDL1 is limited by low imaging specificity, short residence time, and singular functionality. Here, we combined a biocompatible melanin nanoprobe with the PDL1-binding peptide WL12 to construct a novel radiotracer, 124 I-WPMN, to enhance PDL1 targeting. The radiochemical purity of 124 I-WPMN was >95%, and uptake in A549 PDL1 cells was 1.49 ± 0.08% at 2 h. The uptake was blocked by WL12 (0.39 ± 0.03%, P < 0.0001). This novel radiotracer showed a higher affinity for PDL1 ( K d = 18.5 nM) than 68 Ga-NOTA-WL12 ( K d = 24.0 nM). Micro-PET/CT imaging demonstrated specific uptake and a high signal-to-noise ratio in an A549 PDL1 xenograft mouse model with a tumor-to-muscle ratio of 27.31 ± 7.03 at 2 h. The levels increased or remained steady for more than 72 h, and tumor uptake was significantly higher than 68 Ga-NOTA-WL12, at 6.08 ± 0.62 at 2 h. Prolonged retention of 124 I-WPMN makes it possible to conduct PET/MRI imaging over long periods and to perform various imaging techniques. A clear advantage of 124 I-WPMN over 68 Ga-NOTA-WL12 was observed for PDL1-targeted PET imaging after nanoparticle modification, supporting the utility of 124 I-WPMN PET imaging as an effective diagnostic tool for optimizing PDL1-targeted therapies.