Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions

Radiolabelled meta-iodobenzylguanidine (MIBG) is selectively taken up by tumours of neuroendocrine origin, where its cellular localization is believed to be cytoplasmic. The radiopharmaceutical [(131)]MIBG is now widely used in the treatment of neuroblastoma, but other radioconjugates of benzylguanidine have been little studied. We have investigated the cytotoxic efficacy of beta, alpha and Auger electron-emitting radioconjugates in treating neuroblastoma cells grown in monolayer or spheroid culture. Using a no-carrier-added synthesis route, we produced I-123-, I-125-, I-131-, and At-211-labelled benzylguanidines and compared their in vitro toxicity to the neuroblastoma cell line SK-N-BE(2c) grown in monolayer and spheroid culture. The Auger electron-emitting conjugates ([(123)]MIBG and [(125)]MIBG) and the alpha-emitting conjugate ([At-211]MABG) were highly toxic to monolayers and small spheroids, whereas the beta-emitting conjugate [(131)]MIBG was relatively ineffective. The Auger emitters were more effective than expected if the cellular localization of MIBG is cytoplasmic. As dosimetrically predicted however, [At-211]MABG was found to be extremely potent in terms of both concentration of radioactivity and number of atoms ml(-1) administered. In contrast, the Auger electron emitters were ineffective in the treatment of larger spheroids, while the beta emitter showed greater efficacy. These findings suggest that short-range emitters would be well suited to the treatment of circulating tumour cells or small clumps, whereas beta emitters would be superior in the treatment of subclinical metastases or macroscopic tumours. These experimental results provide support for a clinical strategy of combinations ('cocktails') of radioconjugates in targeted radiotherapy.