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

Department of Radiology, Duke University Medical Center, Durham, North Carolina

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, k_m^c, and between cells and medium, k_c^m. 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 54- to 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.

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