Evaluation of effect of repeated alpha-particle-emitting meta-211At-astato-benzylguanidine (211At-MABG) treatments on tumor growth in a pheochromocytoma xenograft

Introduction: Given the limited treatment approaches currently available for patients with metastatic pheochromocytoma and paraganglioma (PPGL), new effective approaches are being sought. Treatment using ¹³¹I-meta-iodobenzylguanidine (¹³¹I-MIBG) has limited survival benefits in metastatic PPGL but is currently considered one of the standard therapeutic approaches. In theory, the alpha-particle-emitting radiopharmaceutical meta-²¹¹At-astato-benzylguanidine (²¹¹At-MABG) could be a very effective targeted treatment of metastatic PPGL with limited side effects. Our preliminary study showed that ²¹¹At-MABG induced a significantly greater tumor volume reduction than the vehicle treatment 14 days after their administration. This tumor-reducing effect of ²¹¹At-MABG is similar to that of ¹³¹I-MIBG, which is one of the current treatment options (Zhao et al, SNMMI 2020, Pub #1316). The purpose of this study was to further evaluate the tumor growth suppression by repeated treatments with ²¹¹At-MABG in a rat pheochromocytoma mouse model, and to compare it with that by single treatment with ²¹¹At-MABG.

Methods: Rat pheochromocytoma (PC-12) cells were subcutaneously inoculated into male BALB/c nu/nu nude mice. When the tumor volume reached approximately 300 mm³, the mice were randomly assigned to groups with single (n=5) and repeated (n=5) dose treatments with ²¹¹At-MABG and vehicle solvent (control) (n=5). Our preliminary results showed that the tumor volume was significantly suppressed for 14 days after a single dose treatment with 1.11 MBq ²¹¹At-MABG which was the maximum tolerated dose in normal BALB/c mice in the single-dose toxicity study. From this result, the second ²¹¹At-MABG administration was decided to be on the 14th day after the first administration. In the single and repeated dose treatment with ²¹¹At-MABG, the mice were intravenously administered 1.11 MBq of ²¹¹At-MABG. The mice with repeated dose treatments received 1.11 MBq of ²¹¹At-MABG again on the 14th day after the first administration. The tumor size was measured once every 2 days for 3 weeks. When the surface of the tumor tissue was ruptured, the tumor size measurement was stopped and the mice were euthanized.

Results: In the vehicle control group, the surface of the tumor tissue ruptured 20 days after the first administration; thus, the tumor size measurement was stopped and the mice were euthanized. The tumor volume significantly increased over time (at first administration, 283.6±59.0 mm³; at second administration, 4097.0±1562.9 mm³, and at the time of euthanization, 6085.3±2383.8 mm³, P<0.001). In the group with single dose treatment, the surface of the tumor tissue was ruptured 24 days after the first administration; thus, the tumor size measurement was stopped and the mice were euthanized. Compared with the vehicle control group, the tumor volume was significantly suppressed until 10 days after the second administration in the group with repeated dose treatments (P<0.001). However, in the single dose treated group, the tumor volume gradually increased over time 14 days after the administration (P<0.001). There was no significant change in percentage tumor volume between the single and repeated dose treated groups at the second administration (57.9±47.9 for single treatment vs 65.7±76.0 for repeated treatments, P=NS). In contrast, there was a significant change in percentage tumor volume between the single and repeated dose treated groups 10 days after the second administration at the time of euthanization (387.2±226.2 for single treatment vs 88.9±138.7 for repeated treatments, P<0.001).

Conclusions: Our results demonstrate that the repeated dose treatments with ²¹¹At-MABG suppressed tumor growth for a longer period than the single dose treatment. Therefore, the therapeutic effect of repeated treatments is expected in the future clinical application of ²¹¹At-MABG for the treatment of metastatic PPGL.