| Summary: | <p>Molecular radiotherapy using <sup>177</sup>Lu-DOTATATE is a most effective treatment for somatostatin receptor–expressing neuroendocrine tumors. Despite its frequent and successful use in the clinic, little or no radiobiologic considerations are made at the time of treatment planning or delivery. On positive uptake on octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiologic and DNA damage effects in the tumor. Here, we visualized and quantified the extent of DNA damage response after <sup>177</sup>Lu-DOTATATE therapy using SPECT imaging with <sup>111</sup>In-anti-γH2AX-TAT. This work was a proof-of-principle study of this in vivo noninvasive biodosimeter with β-emitting therapeutic radiopharmaceuticals. <strong>Methods:</strong> Six cell lines were exposed to external-beam radiotherapy (EBRT) or <sup>177</sup>Lu-DOTATATE, after which the number of γH2AX foci and the clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor–positive tumor xenografts were treated with <sup>177</sup>Lu-DOTATATE or sham-treated and coinjected with <sup>111</sup>In-anti-γH2AX-TAT, <sup>111</sup>In-IgG-TAT control, or vehicle. <strong>Results:</strong> Clonogenic survival after external-beam radiotherapy was cell-line–specific, indicating varying levels of intrinsic radiosensitivity. Regarding in vitro cell lines treated with <sup>177</sup>Lu-DOTATATE, clonogenic survival decreased and γH2AX foci increased for cells expressing high levels of somatostatin receptor subtype 2. Ex vivo measurements revealed a partial correlation between <sup>177</sup>Lu-DOTATATE uptake and γH2AX focus induction between different regions of CA20948 xenograft tumors, suggesting that different parts of the tumor may react differentially to <sup>177</sup>Lu-DOTATATE irradiation. <strong>Conclusion:</strong> <sup>111</sup>In-anti-γH2AX-TAT allows monitoring of DNA damage after <sup>177</sup>Lu-DOTATATE therapy and reveals heterogeneous damage responses.</p>
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