Furin-Guided Intracellular 68Ga Nanoparticle Formation Enhancing Tumor MicroPET Imaging.

Positron-emission tomography (PET) is routinely used in the clinic for tumor imaging with ultrahigh sensitivity, but tumor-targeted PET imaging probes are quite few. In this work, we rationally designed a furin-responsive radiotracer Acetyl-Arg-Val-Arg-Arg-Cys(StBu)-Lys(DOTA-68Ga)-CBT (CBT-68Ga) and demonstrated that coinjection of the radiotracer with its cold analogue CBT-Ga instructed the formation of 68Ga nanoparticles in furin-overexpressing MDA-MB-468 cancer cells, which significantly enhanced microPET imaging of the tumor in vivo. In vitro results showed that CBT-Ga subjected to furin-initiated CBT-Cys condensation reaction and self-assembly to form the nanoparticles CBT-Ga-NPs with an average diameter of 258.3 nm. In vivo microPET imaging results indicate that the mice coinjected with CBT-68Ga and CBT-Ga, which warrants 68Ga nanoparticle formation in their MDA-MB-468 tumors, had a tumor/liver ratio 9.1-fold of that of the mice only injected with CBT-68Ga. We envisioned that, by replacing the RVRR substrate of CBT-68Ga with other enzyme-specific ones and using the strategy of intracellular nanoparticle formation, a series of radioactive probes could be developed for more sensitive and precise tumor microPET imaging in the near future.