Alternative application routes for small animal theranostics

Ziel/Aim With growing theranostic applications and translational research, small animal models need to be optimized for feasible and tolerable repeated small ligand application. Here we aim to assess application routes s.c., i.p. and p.o. as alternative to i.v. application in healthy mice and models of PSMA, SSTR and FAPI-expressing cancer.

Methodik/Methods Healthy and tumor-bearing mice were applied with Ga-68-PSMA (RM1-PSMA prostate cancer (PC) allograft), Ga-68-DOTATOC (RM1-SSTR neuroendocrine tumor (NET) allograft) and Ga-68-FAPI (HT-1080 fibrosarcoma (FS) xenograft) via i.v., i.p., s.c. and p.o. routes. PET in vivo biodistribution was assessed until 4h p.i. and ex vivo measurement of tumors/organs 5h p.i. Readouts included tumor/organ uptake in %IA/g and calculation of residual local vs. systemic biodistribution over time. Healthy animals were monitored for up to 7 days after small ligand application for signs of stress or adverse reactions.

Ergebnisse/Results I.v., i.p., and s.c. application demonstrated <10 % residual activity at the injection site with near equivalent organ biodistribution starting from 1h p.i. with <1 % IA/g for liver, spleen, blood and bone marrow and 13.9 %±1.2 for kidneys. Focal tumor uptake in models for NET, PC and FS was noted respectively for i.v. (5.3 % ± 0.67; 0.8 % ±0.44; 1.3 % ± 0.2) i.p. (9.8 % ± 1; 0.7 %±0.2;0.99 % ± 0.1) and s.c. (10.8 % ± 1.57; 1.8 % ± 0.53; 2.18 % ± 1.1) for 1h p.i. Absolute tumor uptake/tumor to liver ratios were higher for s.c./i.p. vs. i.v. applications 5h p.i. (NET: 25/27 vs. 13.6; PC: 11.9/5.1 vs. 3.7; FS: 11.9/5.1 vs. 5.6).P.o. application resulted in ≤50 % systemic activity 4h p.i. No short-term and long-term adverse effects were noted after radioligand application in healthy mice.

Schlussfolgerungen/Conclusions Small animal theranostic via i.v., i.p., and s.c. application routes are feasible and tolerable. In addition, s.c. administration of small radioligands in mouse models for cancer led to a delayed tracer delivery with higher absolute tumor and tumor-to-organ uptake, which warrants further translational assessment.

Publication History

Article published online:
08 April 2021