Targeted radiotherapy of multicell neuroblastoma spheroids with high specific activity [125I]meta-iodobenzylguanidine

Purpose: Iodine-125 induces cell death by a mechanism similar to that of high linear energy transfer (high-LET) radiation. This study investigates the cytotoxicity of high-specific-activity [I-125]meta-iodobenzylguanidine (I-125-mIBG) in human SK-N-MC neuroblastoma cells grown as three-dimensional multicellular spheroids. Materials and Methods: Spheroids were incubated with high-specific-activity I-125-mIBG (6 mCi/mu g, 1000 times that of the conventional specific activity used for autoradiography). Cytotoxicity was assessed by fluorescence viability markers and confocal microscopy for intact spheroids, fluorescence-activated cell sorting and clonogenic assay, and clonogenic assays for dispersed whole spheroids. Distribution of radioactive mIBG was determined by quantitative light-microscope autoradiography of spheroid cryostat sections. Dose estimation was based on temporal knowledge of the retained radioactivity inside spheroids, and of the radiolabel's emission characteristics. Findings were compared with those of spheroids treated under the same conditions with I-131-mIBG, cold mIBG, and free iodine-125. Results: I-125-mIBG exerted significant cell killing. Complete spheroids were eradicated when they were treated with 500 mu Ci of I-125-mIBG, while those treated with 500 mu Ci or 1000 mu Ci of I-131-mIBG were not, The observed difference in cytotoxicity between treatments with I-125- and I-131-mIBG could not be accounted for by the absorbed dose of spheroid alone. The peripheral, proliferating cell layer of the spheroids remained viable at the moderate radioactivity of 100 mu Ci for both isotopes. Cytotoxicity induced by I-125-mIBG was quantitatively comparable by the peripheral rim thickness to that of I-131-mIBG at the dose of 100 mu Ci. The peripheral rim thickness decreased most significantly in the first 17 hours after initial treatment, There was no statistical decrease in the rim thickness identified afterwards for the second, third, and fourth days of incubation. Conclusion: The cytotoxic effect of high-specific-activity I-125-mIBG appears to be comparable to, if not more efficient than that of conventionally used I-131-mIBG at the same level of total radioactivity. I-125-mIBG may improve the therapeutic index over that of I-131-mIBG in the clinical management of metastatic neuroblastoma due to the short range of Auger electrons. (C) 1998 Elsevier Science Inc.