213Bi-[DOTA0,Tyr3]octreotide peptide receptor radionuclide therapy of pancreatic tumors in a preclinical animal model

Purpose: The somatostatin analogue [ DOTA(0), Tyr(3)] octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) beta-emitters, such as Lu-177 or Y-90, for tumor therapy. In this study, DOTATOC labeled with the high-LET alpha-emitter, Bi-213, was evaluated. Experimental Design: The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of Bi-213-DOTATOC (specific activity 7.4 MBq/mu g) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1 and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq Bi-213-DOTATOC was determined in a rat pancreatic carcinoma model. Results: Radiolabeling of the Bi-213-DOTATOC was achieved with radiochemical purity >95% and an incorporation yield >= 99.9%. Biodistribution data showed specific binding to somatostatin receptor -expressing tissues. Administration of free Bi-213, compared with Bi-213-DOTATOC, resulted in higher radioactivity accumulation at 3 hours postinjection in the kidneys [34.47 +/- 1.40% injected dose/g (ID/g) tissue versus 11.15 +/- 0.46%, P < 0.0001] and bone marrow (0.31 +/- 0.01% ID/g versus 0.06 +/- 0.02%, P < 0.0324). A significant decrease in tumor growth rate was observed in rats treated with >11 MBq of Bi-213-DOTATOC 10 days postinjection compared with controls (P < 0.025). Treatment with >20 MBq of Bi-213-DOTATOC showed significantly greater tumor reduction when compared with animals receiving <11 MBq (P < 0.02). Conclusions: Bi-213-DOTATOC showed dose-related antitumor effects with minimal treatment-related organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. Bi-213-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.