213Bi-[DOTA0, Tyr3]octreotide peptide receptor radionuclide therapy of pancreatic tumors in a preclinical animal model.
OBJECTIVE
The somatostatin analogue [DOTA0, Tyr3]octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) beta-emitters, such as 177Lu or 90Y, for tumor therapy. In this study, DOTATOC labeled with the high-LET alpha-emitter, 213Bi, was evaluated.


METHODS
The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of 213Bi-DOTATOC (specific activity 7.4 MBq/microg) 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 213Bi-DOTATOC was determined in a rat pancreatic carcinoma model.


RESULTS
Radiolabeling of the 213Bi-DOTATOC was achieved with radiochemical purity >95% and an incorporation yield > or = 99.9%. Biodistribution data showed specific binding to somatostatin receptor-expressing tissues. Administration of free 213Bi, compared with 213Bi-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 213Bi-DOTATOC 10 days postinjection compared with controls (P < 0.025). Treatment with >20 MBq of 213Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving <11 MBq (P < 0.02).


CONCLUSIONS
213Bi-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. 213Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.
Norenberg
Jeffrey P
JP
College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131-0001, USA. jpnoren@unm.edu
Krenning
Boudewijn J
BJ
Konings
Inge R H M
IR
Kusewitt
Donna F
DF
Nayak
Tapan K
TK
Anderson
Tamara L
TL
de Jong
Marion
M
Garmestani
Kayhan
K
Brechbiel
Martin W
MW
Kvols
Larry K
LK
D000818:Animals; D001729:Bismuth / Q000627:therapeutic use* / Q000633:toxicity*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D008297:Male; D015282:Octreotide / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000633:toxicity; D010190:Pancreatic Neoplasms / Q000532:radiotherapy*; D011868:Radioisotopes; D051381:Rats; D011917:Rats, Inbred Lew; D017481:Receptors, Somatostatin / Q000187:drug effects*; D013997:Time Factors
D011868:Radioisotopes; D017481:Receptors, Somatostatin; C121107:octreotide, DOTA-Tyr(3)-; D015282:Octreotide; D001729:Bismuth