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Published on: January 11, 2020
Administration Routes for SSTR-/PSMA- and FAP-Directed Theranostic Radioligands in Mice
Jasmin M Klose1, Jasmin Wosniack1, Janette Iking1
1Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Abstract:
The NETTER-1, VISION, and TheraP trials proved the efficacy of repeat intravenous application of small radioligands. Application by subcutaneous, 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 γ-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, intraperitoneal, 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, intraperitoneal, and subcutaneous application at 1 h after injection and all subsequent 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 administration resulted in the highest absolute SSTR tumor and tumor-to-organ uptake as compared with the intravenous route, warranting further clinical assessment.
Insights
New research shows that subcutaneous and intraperitoneal injections of radioligands are effective alternatives to intravenous administration for cancer imaging and therapy. These routes offer comparable or improved tumor uptake, especially for somatostatin receptor (SSTR) targeted agents.
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Therapy
- Oncology
Background:
- Intravenous administration of small radioligands is established for cancer theranostics (NETTER-1, VISION, TheraP trials).
- Alternative administration routes like subcutaneous, intraperitoneal, or oral may offer comparable or improved radioligand uptake.
- Investigating biodistribution across different routes is crucial for optimizing theranostic agent delivery.
Purpose of the Study:
- To evaluate and compare organ and tumor biodistribution of radioligands via intravenous, intraperitoneal, subcutaneous, and oral routes.
- To assess the efficacy of non-intravenous routes in mouse models of somatostatin receptor (SSTR), prostate-specific membrane antigen (PSMA), and fibroblast activation protein (FAP) expressing cancers.
Main Methods:
- Healthy and tumor-bearing mice received 68Ga-DOTATOC, 68Ga-PSMA11, or 68Ga-FAPI46 via intravenous, intraperitoneal, subcutaneous, or oral routes.
- In vivo PET imaging and ex vivo biodistribution were assessed up to 5 hours post-injection.
- Tumor and organ uptake, as well as injection site activity, were quantified.
Main Results:
- Intraperitoneal and subcutaneous routes showed comparable or increased tumor uptake versus intravenous injection for SSTR, PSMA, and FAP targets.
- Subcutaneous administration yielded the highest absolute SSTR tumor uptake and tumor-to-organ ratios.
- Oral administration resulted in significant intestinal retention, unlike other routes.
Conclusions:
- Peritoneal and subcutaneous administration of small theranostic ligands demonstrate nearly equivalent biodistribution to intravenous injection in healthy mice.
- Subcutaneous delivery is particularly promising, showing superior SSTR tumor uptake and tumor-to-organ ratios.
- These findings support further clinical investigation of non-intravenous radioligand administration.
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