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

Purpose: Targeted delivery of alpha-particle emitting radionuclides is a promising novel option in cancer therapy. We generated stable conjugates of the vascular tumor-homing peptide F3 both with 225Ac and 213Bi to specifically target tumor cells. The aim of our study was to determine therapeutic efficacy of 225Ac-DOTA-F3 in comparison with 213Bi-DTPA-F3. Experimental Design: ID50 values of 213Bi-DTPA-F3 and 225Ac-DOTA-F3 were detrmined via clonogenic assays. Therapeutic efficacy of both constructs was assayed after repeated treatment of mice with intraperitoneal MDA-MB-435 xenograft tumors. Therapy monitoring was performed by bioluminescence imaging. Nephrotoxic effects were analyzed by histology. Results: ID50 values of 213Bi-DTPA-F3 and 225Ac-DOTA-F3 were 53 kBq/ml and 67 Bq/ml, respectively. Median survival of control mice treated with PBS was 60 days after i.p. inoculation of 1x107 MDA-MB-435 cells. Therapy with 6 x 1.85 kBq 225Ac-DOTA-F3 or 6 x 1.85 MBq 213Bi-DTPA-F3 prolonged median survival to 95 days and 97 days, respectively. While 213Bi-DTPA-F3 reduced the tumor mass at early time points until 30 days after treatment, 225Ac-DOTA-F3 showed a prolonged anti-tumour effect. No significant difference concerning the fraction of necrotic cells was found after treatment with 225Ac-DOTA-F3 (43%) or 213Bi-DTPA-F3 (36%). Though histological analysis of the kidney samples revealed acute tubule necrosis and tubular edema in some 10-30% after treatment with 225Ac-DOTA-F3 or 213Bi-DTPA-F3, protein casts were negligible (2%), indicating only a minor damage of the kidney. Conclusions: Therapy with both 225Ac-DOTA-F3 and 213Bi-DTPA-F3 increased survival of mice with peritoneal carcinomatosis. Mild renal toxicity of both constructs favours future therapeutic application.

ESSLER M.;  GAERTNER F. C.;  NEFF Frauke;  BLECHERT B.;  SENEKOWITSCH-SCHMIDTKE R.;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  SEIDL C.; 

2012-04-20

SPRINGER

JRC68042

1619-7070,   

http://www.springerlink.com/content/321l261540033028/,    https://publications.jrc.ec.europa.eu/repository/handle/JRC68042,   

10.1007/s00259-011-2023-6,