Pretargeted approach for tumor PET imaging using supramolecular nanoparticles with in vivo bioorthogonal chemistry

Objectives The aim of this study is to employ a pretargeted approach that leverages the power of a supramolecular nanoparticle (SNP) vector and in vivo bioorthogonal chemistry for improved tumor PET imaging.

Methods A reactive bioorthogonal motif (a trans-cyclooctene group, TCO) was encapsulated into an SNP vector (TCO-SNPs) constructed from adamantane-grafted polyamidoamine dendrimers, adamantane-functionalized polyethylene glycol, and β-cyclodextrin-grafted branched polyethylenimine. A complementary bioorthogonal motif (a tetrazine group, Tz) was radiolabeled with 18F to afford a radiolabeled reporter (18F-Tz). Transmission electron microscope (TEM) was used for directly examining the morphology and size of SNPs. Static microPET scans were performed at various time points after iv injection of 18F-Tz in U87MG glioblastoma mouse xenografts.

Results The TEM measurements indicated that the size of SNPs was about 100 nm. The total synthesis time for 18F-Tz, including final high-performance liquid chromatography purification, was about 150 min. The decay-corrected radiochemical yield was 12±3% (n = 6). PET imaging results showed that the U87MG tumors can be clearly visualized as early as at 30 min postinjection of 18F-Tz, suggesting that the in vivo bioconjugation of TCO-grafted molecular building block and 18F-Tz was very rapid. Good tumor retention of radioactivity was observed from PET imaging. At 2 h pi, the tumor-to-muscle (T/M) ratio can reach 2.94±0.48. Ex vivo studies further confirmed the in vivo imaging findings.

Conclusions We have demonstrated a new pretargeted approach to achieve improved tumor PET imaging. The new strategy decouples a tumor-targeting agent (such as nanoparticles) from a radiolabeled imaging agent, leading to a superb capability of optimizing the PKs of both nanoparticles and radiolabeled imaging agents to obtain optimal in vivo imaging performances.

Research Support This work was supported by the USC Department of Radiology.