TY - JOUR T1 - Targeted <sup>125</sup>I Auger electron radiotherapy for the treatment of triple-negative breast cancer JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 126 LP - 126 VL - 59 IS - supplement 1 AU - Ian Marsh AU - Benjamin Titz AU - Justin Jeffery AU - Robert Moskwa AU - Bryan Bednarz AU - Joseph Grudzinski Y1 - 2018/05/01 UR - http://jnm.snmjournals.org/content/59/supplement_1/126.abstract N2 - 126Objectives: Triple negative breast cancer (TNBC) is typically associated with a poor prognosis that is largely attributable to the absence of effective molecularly-targeted therapies. Micrometastases contribute to poor prognosis by increasing recurrence rate. The Auger electrons emitted by radioisotopes such as I-125 have a high linear energy transfer and short mean free path in tissue (&lt;10 µm), making them optimal for treating micrometastases while sparing normal tissues. This study investigated the therapeutic potential of an I-125-radiolabeled cancer cell-selective phospholipid ether analog against TNBC cells in vivo. Methods: The broad spectrum cancer targeting agent, NM404, was radiolabeled with I-125 via a cGMP method with &gt;95% radiochemical purity. To estimate [I-125]-NM404 in vivo dosimetry and identify potential dose limiting organs, the biodistribution of the analog compound [I-124]-NM404 was investigated using microPET/CT in conjunction with a Monte Carlo dosimetry platform. In vivo antitumor efficacy was tested by injecting nude mice bearing MDA-MB-231-luc orthotopic xenografts with 74 MBq of [I-125]-NM404 or an equivalent amount of non-radiolabeled NM404. Longitudinal tumor measurements for the xenografts were made using calipers for 52 days. Results: Longitudinal [I-124]-NM404 PET imaging showed marked tumor uptake and retention in the pharmacokinetic profile. The hepatobiliary clearance of NM404 is confirmed by elevated concentrations in the liver and the prolonged blood clearance is corroborated by elevated concentrations in the lungs. [I-124]-NM404 PET-based Monte Carlo tumor dosimetry predicted a mean (n=4) integral absorbed dose of 0.26 ± 0.02 Gy/MBq of [I-125]-NM404, which was larger than all normal tissues. Activites of up to 74 MBq, which was proven to be safe in prior maximum tolerated dose finding studies, was estimated to deliver 19.3 ± 1.7 Gy to the tumor. The single dose of [I-125]-NM404 induced a tumor growth inhibition of orthotopic primary TNBC xenografts by approximately 60% relative to control (p&lt;0.001). Conclusion: The significant antitumor efficacy of molecularly targeted radionuclide therapy with [I-125]-NM404 observed in in vivo preclinical orthotopic TNBC xenografts suggests promise for the treatment of TNBC micrometastases. ER -