PARP-1-Targeted Auger Emitters Display High-LET Cytotoxic Properties In Vitro but Show Limited Therapeutic Utility in Solid Tumor Models of Human Neuroblastoma.

The currently available therapeutic radiopharmaceutical for high-risk neuroblastoma, I-metaiodobenzylguanidine, is ineffective at targeting micrometastases because of the low-linear-energy-transfer (LET) properties of high-energy β-particles. In contrast, Auger radiation has high-LET properties with nanometer ranges in tissue, efficiently causing DNA damage when emitted near DNA. The aim of this study was to evaluate the cytotoxicity of targeted Auger therapy in preclinical models of high-risk neuroblastoma. We used a radiolabled poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor called I-KX1 to deliver Auger radiation to PARP-1, a chromatin-binding enzyme overexpressed in neuroblastoma. The in vitro cytotoxicity of I-KX1 was assessed in 19 neuroblastoma cell lines, followed by in-depth pharmacologic analysis in a sensitive and resistant pair of cell lines. Immunofluorescence microscopy was used to characterize I-KX1-induced DNA damage. Finally, in vitro and in vivo microdosimetry was modeled from experimentally derived pharmacologic variables. I-KX1 was highly cytotoxic in vitro across a panel of neuroblastoma cell lines, directly causing double-strand DNA breaks. On the basis of subcellular dosimetry, I-KX1 was approximately twice as effective as I-KX1, whereas cytoplasmic I-metaiodobenzylguanidine demonstrated low biological effectiveness. Despite the ability to deliver a focused radiation dose to the cell nuclei, I-KX1 remained less effective than its α-emitting analog At-MM4 and required significantly higher activity for equivalent in vivo efficacy based on tumor microdosimetry. Chromatin-targeted Auger therapy is lethal to high-risk neuroblastoma cells and has the potential to be used in micrometastatic disease. This study provides the first evidence for cellular lethality from a PARP-1-targeted Auger emitter, calling for further investigation into targeted Auger therapy.