OpenSSL SSL_connect: Connection reset by peer in connection to v2.sherpa.ac.uk:443 PuSH - Publication Server of Helmholtz Zentrum München: Therapeutic efficacy and toxicity of <sup>225</sup>Ac-labelled vs. <sup>213</sup>Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis.

PuSH - Publication Server of Helmholtz Zentrum München

Essler, M.* ; Gärtner, F.C.* ; Neff, F. ; Blechert, B.* ; Senekowitsch-Schmidtke, R.* ; Bruchertseifer, F.* ; Morgenstern, A.* ; Seidl, C..*

Therapeutic efficacy and toxicity of 225Ac-labelled vs. 213Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis.

Eur. J. Nucl. Med. Mol. Imaging 39, 602-612 (2012)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
PURPOSE: Targeted delivery of alpha-particle-emitting radionuclides is a promising novel option in cancer therapy. We generated stable conjugates of the vascular tumour-homing peptide F3 both with (225)Ac and (213)Bi that specifically bind to nucleolin on the surface of proliferating tumour cells. The aim of our study was to determine the therapeutic efficacy of (225)Ac-DOTA-F3 in comparison with that of (213)Bi-DTPA-F3. METHODS: ID(50) values of (213)Bi-DTPA-F3 and (225)Ac-DOTA-F3 were determined via clonogenic assays. The therapeutic efficacy of both constructs was assayed by repeated treatment of mice bearing intraperitoneal MDA-MB-435 xenograft tumours. Therapy was monitored by bioluminescence imaging. Nephrotoxic effects were analysed by histology. RESULTS: ID(50) values of (213)Bi-DTPA-F3 and (225)Ac-DOTA-F3 were 53 kBq/ml and 67 Bq/ml, respectively. The median survival of control mice treated with phosphate-buffered saline was 60 days after intraperitoneal inoculation of 1 × 10(7) MDA-MB-435 cells. Therapy with 6 × 1.85 kBq of (225)Ac-DOTA-F3 or 6 × 1.85 MBq of (213)Bi-DTPA-F3 prolonged median survival to 95 days and 97 days, respectively. While F3 labelled with short-lived (213)Bi (t (1/2) 46 min) reduced the tumour mass at early time-points up to 30 days after treatment, the antitumour effect of (225)Ac-DOTA-F3 (t (1/2) 10 days) increased at later time-points. The difference in the fraction of necrotic cells after treatment with (225)Ac-DOTA-F3 (43%) and with (213)Bi-DTPA-F3 (36%) was not significant. Though histological analysis of kidney samples revealed acute tubular necrosis and tubular oedema in 10-30% of animals after treatment with (225)Ac-DOTA-F3 or (213)Bi-DTPA-F3, protein casts were negligible (2%), indicating only minor damage to the kidney. CONCLUSION: Therapy with both (225)Ac-DOTA-F3 and (213)Bi-DTPA-F3 increased survival of mice with peritoneal carcinomatosis. Mild renal toxicity of both constructs favours future therapeutic application.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Targeted radionuclide therapy; Phage display; Tumour-homing peptide F3; Peritoneal carcinomatosis; α-emitters 225Ac and 213Bi; TARGETED ALPHA-THERAPY; GASTRIC-CANCER CELLS; NEUROENDOCRINE TUMORS; RADIONUCLIDE THERAPY; MONOCLONAL-ANTIBODY; OVARIAN-CANCER; NUDE-MICE; RADIOIMMUNOTHERAPY; BI-213; DELIVERY
ISSN (print) / ISBN 1619-7070
e-ISSN 1432-105X
Journal European Journal of Nuclear Medicine and Molecular Imaging
Quellenangaben Volume: 39, Issue: 4, Pages: 602-612 Article Number: , Supplement: ,
Publisher Springer
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)