Figure 4.

Schematic representation of a new approach for pretargeted PET imaging that leverages the utilities of supramolecular nanoparticles (SNPs) and bioorthogonal chemistry: (a) Supramolecular synthetic strategy is employed for preparing the tumor-targeting agent (TCO⊂SNPs); (b) after intravenous injection, the tumor EPR effect drives preferential accumulation of TCO⊂SNPs in tumor; (c) after TCO⊂SNPs have accumulated in tumor, TCO⊂SNPs disassemble to release a TCO-grafted molecular building block, TCO/CD-PEI; (d) a radiolabeled reporter (⁶⁴Cu-Tz) is then injected for bioorthogonal reaction with tumor-retained TCO/CD-PEI; (e) the unreacted ⁶⁴Cu-Tz was cleared quickly from the body; (f) the resulting dihydropyrazine (DHP) conjugation adduct (⁶⁴Cu-DHP/CD-PEI) confines radioactivity in tumor, resulting in high-contrast tumor PET imaging. (g) Chemical structures of the bioorthogonal reactions between TCO/CD-PEI and ⁶⁴Cu-Tz (adapted from Hou et al., 2016).