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

• Published in: European journal of nuclear medicine and molecular imaging 2012-04, Vol.39 (4), p.602
• Main Authors: Essler, Markus, Gärtner, Florian C, Neff, Frauke, Blechert, Birgit, Senekowitsch-schmidtke, Reingard, Bruchertseifer, Frank, Morgenstern, Alfred, Seidl, Christof
• Format: Article
• Language: English
• Subjects: Cancer; Isotopes; Nuclear medicine; Peptides; Radiation therapy
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-011-2023-6

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 ^sup 225^Ac and ^sup 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 ^sup 225^Ac-DOTA-F3 in comparison with that of ^sup 213^Bi-DTPA-F3. ID^sub 50^ values of ^sup 213^Bi-DTPA-F3 and ^sup 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. ID^sub 50^ values of ^sup 213^Bi-DTPA-F3 and ^sup 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^sup 7^ MDA-MB-435 cells. Therapy with 6×1.85 kBq of ^sup 225^Ac-DOTA-F3 or 6×1.85 MBq of ^sup 213^Bi-DTPA-F3 prolonged median survival to 95 days and 97 days, respectively. While F3 labelled with short-lived ^sup 213^Bi (t ^sub 1/2^ 46 min) reduced the tumour mass at early time-points up to 30 days after treatment, the antitumour effect of ^sup 225^Ac-DOTA-F3 (t ^sub 1/2^ 10 days) increased at later time-points. The difference in the fraction of necrotic cells after treatment with ^sup 225^Ac-DOTA-F3 (43%) and with ^sup 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 ^sup 225^Ac-DOTA-F3 or ^sup 213^Bi-DTPA-F3, protein casts were negligible (2%), indicating only minor damage to the kidney. Therapy with both ^sup 225^Ac-DOTA-F3 and ^sup 213^Bi-DTPA-F3 increased survival of mice with peritoneal carcinomatosis. Mild renal toxicity of both constructs favours future therapeutic application.[PUBLICATION ABSTRACT]