Administration Routes for SSTR-/PSMA- and FAP-Directed Theranostic Radioligands in Mice

The NETTER-1, VISION, and TheraP trials proved the efficacy of repeat intravenous application of small radioligands. Application by subcuta-neous, intraperitoneal, or oral routes is an important alternative and may yield comparable or favorable organ and tumor radioligand uptake. Here, we assessed organ and tumor biodistribution for various radioligand application routes in healthy mice and models of cancer expressing somatostatin receptor (SSTR), prostate-specific membrane antigen (PSMA), and fibroblast activation protein (FAP). Methods: Healthy and tumor-bearing male C57BL/6 or NOD SCID y-mice, respectively, were administered a mean of 6.0 ?? 0.5 MBq of 68Ga-DOTATOC (RM1-SSTR allograft), 5.3 ?? 0.3 MBq of 68Ga-PSMA11 (RM1-PSMA allograft), or 4.8 ?? 0.2 MBq of 68Ga-FAPI46 (HT1080-FAP xenograft) by intravenous, intraperitoneal, subcutaneous, or oral routes. In vivo PET images and ex vivo biodistribution in tumor, organs, and the injection site were assessed up to 5 h after injection. Healthy mice were monitored for up to 7 d after the last scan for signs of stress or adverse reactions. Results: After intravenous, intraperito-neal, and subcutaneous radioligand administration, average residual activity at the injection site was less than 17 percentage injected activity per gram (%IA/g) at 1 h after injection, less than 10 %IA/g at 2 h after injection, and no more than 4 %IA/g at 4 h after injection for all radioligands. After oral administration, at least 50 %IA/g remained within the intestines until 4 h after injection. Biodistribution in organs of healthy mice was nearly equivalent after intravenous, intraperito-neal, and subcutaneous application at 1 h after injection and all sub-sequent time points (???1 %IA/g for liver, blood, and bone marrow; 11.2 ?? 1.4 %IA/g for kidneys). In models for SSTR-, PSMA-and FAP-expressing cancer, tumor uptake was increased or equivalent for intraperitoneal/subcutaneous versus intravenous injection at 5 h after injection (ex vivo): SSTR, 7.2 ?? 1.0 %IA/g (P = 0.0197)/6.5 ?? 1.3 %IA/g (P = 0.0827) versus 2.9 ?? 0.3 %IA/g, respectively; PSMA, 3.4 ?? 0.8 %IA/g (P = 0.9954)/3.9 ?? 0.8 %IA/g (P = 0.8343) versus 3.3 ?? 0.7% IA/g, respectively; FAP, 1.1 ?? 0.1 %IA/g (P = 0.9805)/ 1.1 ?? 0.1 %IA/g (P = 0.7446) versus 1.0 ?? 0.2 %IA/g, respectively. Conclusion: In healthy mice, biodistribution of small theranostic ligands after intraperitoneal/subcutaneous application is nearly equivalent to that after intravenous injection. Subcutaneous administra-tion resulted in the highest absolute SSTR tumor and tumor-to-organ uptake as compared with the intravenous route, warranting further clinical assessment.

Automated summary

The study assessed the biodistribution of various radioligand application routes in mice, and found that subcutaneous and intraperitoneal administration had comparable biodistribution to intravenous injection. Subcutaneous administration resulted in the highest tumor uptake, suggesting its potential in clinical assessment.