The currently available therapeutic radiopharmaceutical for high-risk neuroblastoma, ¹³¹I-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. Methods: We used a radiolabled poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor called ¹²⁵I-KX1 to deliver Auger radiation to PARP-1, a chromatin-binding enzyme overexpressed in neuroblastoma. The in vitro cytotoxicity of ¹²⁵I-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 ¹²⁵I-KX1–induced DNA damage. Finally, in vitro and in vivo microdosimetry was modeled from experimentally derived pharmacologic variables. Results:¹²⁵I-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, ¹²⁵I-KX1 was approximately twice as effective as ¹³¹I-KX1, whereas cytoplasmic ¹²⁵I-metaiodobenzylguanidine demonstrated low biological effectiveness. Despite the ability to deliver a focused radiation dose to the cell nuclei, ¹²⁵I-KX1 remained less effective than its α-emitting analog ²¹¹At-MM4 and required significantly higher activity for equivalent in vivo efficacy based on tumor microdosimetry. Conclusion: 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.

Theranostics are emerging as a pillar of cancer therapy that enable the use of single molecule constructs for diagnostic and therapeutic application. As poly adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) is overexpressed in various cancer types, and is localized to the nucleus, PARP-1 can be safely targeted with Auger emitters to induce DNA damage in tumors. Here, we investigated a radioiodinated PARP inhibitor, [¹²⁵I]KX1, and show drug target specific DNA damage and subsequent killing of BRCA1 and non-BRCA mutant ovarian cancer cells at sub-pharmacological concentrations several orders of magnitude lower than traditional PARP inhibitors. Furthermore, we demonstrated that viable tumor tissue from ovarian cancer patients can be used to screen tumor radiosensitivity ex-vivo, enabling the direct assessment of therapeutic efficacy. Finally, we showed tumors can be imaged by single-photon computed tomography (SPECT) with PARP theranostic, [¹²³I]KX1, in a human ovarian cancer xenograft mouse model. These data support the utility of PARP-1 targeted radiopharmaceutical therapy as a theranostic option for PARP-1 overexpressing ovarian cancers.

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Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) with alpha-emitting ²²⁵Ac-PSMA-617 has shown clinical efficacy even in cases of failed therapy with beta-emitting ¹⁷⁷Lu-PSMA-617. We investigated the efficacy of ²²⁵Ac-PSMA-617 relative to ¹⁷⁷Lu-PSMA-617 using subcellular dosimetry. A 3-dimensional model of prostate cancer was constructed. For each decay, the absorbed and equivalent radiation dose to the cell nuclei was calculated. The relative efficacy per administered activity was calculated by taking into account the differences in residence time and tumor uptake. As the tumor size increased, the absorbed dose from ²²⁵Ac-PSMA-617 increased linearly (R2: 0.99) and reached an asymptote near the maximum alpha range (85 µm), whereas the absorbed dose from ¹⁷⁷Lu-PSMA-617 continued to increase linearly (R2: 0.99). The equivalent dose per decay was 2,320, 2,900, and 823-fold higher in favor of ²²⁵Ac-PSMA-617 compared to ¹⁷⁷Lu-PSMA-617 in a single cell, 100 µm-radius micrometastasis, and macroscopic tumor, respectively. Per administered activity, the relative efficacy of ²²⁵Ac-PSMA-617 compared to ¹⁷⁷Lu-PSMA-617 in respective tumor sizes was at least 3,480, 4,350, and 1,230-fold higher, and possibly 11,800, 14,900, and 4,200-fold higher considering differences in tumor uptake. At commonly administered 1,000-fold lower activity of ²²⁵Ac-PSMA-617 relative to ¹⁷⁷Lu-PSMA-617, the equivalent radiation dose deposited by ²²⁵Ac-PSMA-617 is higher in measurable disease and much higher in microscopic disease compared to ¹⁷⁷Lu-PSMA-617.