Evaluation of treatment efficacy of the ¹⁶¹Tb- and ¹⁷⁷Lu-Labeled GRPR antagonists AMTG and RM2 in a mouse model of prostate cancer.

Abstract

Recent data on ¹⁶¹Tb-labeled radiopharmaceuticals indicate a benefit in treatment efficacy due to the emission of high-energy Auger and conversion electrons in addition to β particles. We aimed to investigate differences in therapeutic potential of the gastrin-releasing peptide receptor (GRPR) antagonists RM2 (DOTA-Pip⁵-D-Phe⁶-Gln⁷-Trp⁸-Ala⁹-Val¹⁰-Gly¹¹-His¹²-Sta¹³-Leu¹⁴-NH₂) and AMTG (DOTA-Pip⁵-D-Phe⁶-Gln⁷-α-Me-Trp⁸-Ala⁹-Val¹⁰-Gly¹¹-His¹²-Sta¹³-Leu¹⁴-NH₂) radiolabeled with ¹⁶¹Tb and ¹⁷⁷Lu in PC-3 tumor-bearing mice. We hypothesized that the superior in vivo stability of AMTG in combination with ¹⁶¹Tb would result in improved tumor control and overall survival as compared to RM2 and ¹⁷⁷Lu counterparts. Treatment studies in PC-3 tumor-bearing Nu/J mice were initiated once tumor volume was ~ 100 mm³. ¹⁶¹Tb- and ¹⁷⁷Lu-Labeling was completed at 90 °C within 10 min (1.0 M sodium acetate buffer, pH = 5.5, molar activity of ~ 50 MBq/nmol). Radiolabeled GRPR ligands were administered in treatment (PC-3 tumor-bearing, n = 6-7 per group) and toxicity (healthy animals, n = 3 per group) animals on day 0 and day 7 of the experiment (~ 15 MBq each). Treatment animals were sacrificed once tumor volume surpassed 1,500 mm³. Toxicity animals were sacrificed 45 d after injection and analyzed for complete blood count and metabolic panel. Animals were assigned to five groups (control, [¹⁷⁷Lu]Lu-RM2, [¹⁷⁷Lu]Lu-AMTG, [¹⁶¹Tb]Tb-RM2, [¹⁶¹Tb]Tb-AMTG). Each treatment group received a total activity amount of 26-31 MBq of the respective radiolabeled compound. All treatments resulted in improved tumor control and overall survival related to vehicle animals. [¹⁶¹Tb]Tb-AMTG had the longest median overall survival of 58.1 ± 5.4 d after initiation of treatment. No signs of long-term toxicity were observed during this study in any treatment group. The combination of Auger electrons with high in vivo stability of [¹⁶¹Tb]Tb-AMTG resulted in substantially improved tumor control and overall survival in PC-3 tumor-bearing mice, thus expanding the therapeutic potential of GRPR antagonists in GRPR-expressing malignancies.