BASIC SCIENCE INVESTIGATIONS In Vitro Cytotoxicity of 211At-Astatide and 131I-Iodide to Glioma Tumor Cells Expressing the Sodium/Iodide Symporter

The sodium/iodide symporter (NIS) has been identified as an attractive target for cancer therapy. The efficacy of 131I-iodide for NIS-expressing tumor therapy may be limited by a combination of poor cellular retention and unfavorable physical characteristics (long physical half-life and low linear-energy-transfer [LET] radiative emissions). On the other hand, 211At-astatide is also transported by NIS and offers several therapeutic advantages over 131I-iodide due to its physical characteristics (short half-life, high LET -particle emissions). The objective of this study was to directly compare the radiotoxicity of both radionuclides using a NIS-transfected cultured cell model. Methods: Cytotoxicity was determined by colony-forming assays. Also, a first-order pharmacokinetic model was used to simulate the closed compartmental system between the medium and cells. Experimental data were then fitted to this model and used to estimate the transfer coefficients between medium and cells, km , and between cells and medium, kc. Using the pharmacokinetic model, the cumulated activity concentrations in the medium and cells were calculated. Monte Carlo transport methods were then used to assess absorbed doses from 131I and 211At. Results: 211At-Astatide was significantly more cytotoxic than 131I-iodide in this closed compartmental system. For 211At-astatide, absorbed doses per unit administered activity were 54to 65-fold higher than for 131I-iodide. Both NIS-expressing and control cells showed increased sensitivity to 211At over 131I, with significantly lower D0 (absorbed dose required to reduce the survival fraction to e 1) and SF2 (2-Gy survival fraction) values, highlighting the higher intrinsic cytotoxicity of -particles. However, NIS-independent (nonspecific) binding of 211At-astatide was higher than that of 131I-iodide, therefore, yielding a lower absorbed dose ratio between NIS-transfected and -nontransfected cells. Conclusion: Treatment of NIS-expressing cells with 211At-astatide resulted in higher absorbed doses and increased cytotoxicity per unit administered activity than that observed with 131I-iodide. These results suggest that 211At-astatide may be a promising treatment strategy for the therapy of NIS-expressing tumors.