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

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 Ac-225 and Bi-213 that specifically bind to nucleolin on the surface of proliferating tumour cells. The aim of our study was to determine the therapeutic efficacy of Ac-225-DOTA-F3 in comparison with that of Bi-213-DTPA-F3. ID50 values of Bi-213-DTPA-F3 and Ac-225-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. ID50 values of Bi-213-DTPA-F3 and Ac-225-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 x 10(7) MDA-MB-435 cells. Therapy with 6 x 1.85 kBq of Ac-225-DOTA-F3 or 6 x 1.85 MBq of Bi-213-DTPA-F3 prolonged median survival to 95 days and 97 days, respectively. While F3 labelled with short-lived Bi-213 (t (1/2) 46 min) reduced the tumour mass at early time-points up to 30 days after treatment, the antitumour effect of Ac-225-DOTA-F3 (t (1/2) 10 days) increased at later time-points. The difference in the fraction of necrotic cells after treatment with Ac-225-DOTA-F3 (43%) and with Bi-213-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 Ac-225-DOTA-F3 or Bi-213-DTPA-F3, protein casts were negligible (2%), indicating only minor damage to the kidney. Therapy with both Ac-225-DOTA-F3 and Bi-213-DTPA-F3 increased survival of mice with peritoneal carcinomatosis. Mild renal toxicity of both constructs favours future therapeutic application.