Alpha- versus beta-particle radiopeptide therapy in a human prostate cancer model (213Bi-DOTA-PESIN and 213Bi-AMBA versus 177Lu-DOTA-PESIN).
Recurrent prostate cancer presents a challenge to conventional treatment, particularly so to address micrometastatic and small-volume disease. Use of α-radionuclide therapy is considered as a highly effective treatment in such applications due to the shorter range and exquisite cytotoxicity of α-particles as compared with β-particles. (213)Bi is considered an α-emitter with high clinical potential, due to its short half-life (45.6 minutes) being well matched for use in peptide-receptor radionuclide α-therapy; however, there is limited knowledge available within this context of use. In this study, two novel (213)Bi-labeled peptides, DOTA-PEG(4)-bombesin (DOTA-PESIN) and DO3A-CH(2)CO-8-aminooctanoyl-Q-W-A-V-G-H-L-M-NH(2) (AMBA), were compared with (177)Lu (β-emitter)-labeled DOTA-PESIN in a human androgen-independent prostate carcinoma xenograft model (PC-3 tumor). Animals were injected with (177)Lu-DOTA-PESIN, (213)Bi-DOTA-PESIN, or (213)Bi-AMBA to determine the maximum tolerated dose (MTD), biodistribution, and dosimetry of each agent; controls were left untreated or were given nonradioactive (175)Lu-DOTA-PESIN. The MTD of (213)Bi-DOTA-PESIN and (213)Bi-AMBA was 25 MBq (0.68 mCi) whereas (177)Lu-DOTA-PESIN showed an MTD of 112 MBq (3 mCi). At these dose levels, (213)Bi-DOTA-PESIN and (213)Bi-AMBA were significantly more effective than (177)Lu-DOTA-PESIN. At the same time, (177)Lu-DOTA-PESIN showed minimal, (213)Bi-DOTA-PESIN slight, and (213)Bi-AMBA marked kidney damage 20 to 30 weeks posttreatment. These preclinical data indicate that α-therapy with (213)Bi-DOTA-PESIN or (213)Bi-AMBA is more efficacious than β-therapy. Furthermore, (213)Bi-DOTA-PESIN has a better safety profile than (213)Bi-AMBA, and represents a possible new approach for use in peptide-receptor radionuclide α-therapy treating recurrent prostate cancer.
Division of Radiological Chemistry, University Hospital, Basel, Switzerland.
Damian
D
Wild
Michael
M
Frischknecht
Hanwen
H
Zhang
Alfred
A
Morgenstern
Frank
F
Bruchertseifer
Julie
J
Boisclair
Anne
A
Provencher-Bolliger
Jean-Claude
JC
Reubi
Helmut R
HR
Maecke
D000512:Alpha Particles / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001610:Beta Particles / Q000009:adverse effects / Q000627:therapeutic use*; D001729:Bismuth / Q000737:chemistry; D005260:Female; D006801:Humans; D008187:Lutetium / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D011868:Radioisotopes / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
D009842:Oligopeptides; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D008187:Lutetium; D001729:Bismuth