Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer

Hoffman, Sabrina; Mixdorf, Jason C.; Kwon, Ohyun; Johnson, T.R.; Makvandi, Mehran; Lee, Ho; Aluicio‐Sarduy, Eduardo; Barnhart, Todd; Jeffery, Justin J.; Patankar, Manish S.; Engle, Jonathan W.; Bednarz, Bryan; Ellison, Paul A.

doi:10.1016/j.nucmedbio.2023.108368

Cited by 5 publications

(4 citation statements)

References 52 publications

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“…In addition, PARP-mediated uptake of PARP inhibitors labeled with b-, a-, or Auger electron-emitting radionuclides can be used for radioligand therapy of PARP-expressing tumors. In a series of preclinical studies, it has been shown that 123 I-, 125 I-, 131 I-, 77 Br-, or 211 At-labeled compounds, all variations on olaparib-or rucapariblike structures, are able to cause DNA damage in cancer cells, thereby reducing viability and clonogenic survival and inhibiting tumor growth in subcutaneous or orthotopic xenograft tumors in mice (9,(21)(22)(23)(24)(25)(26). To date, no clinical trial has been performed to evaluate the safety and efficacy of PARP inhibitor radioligand therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Two radiolabeled compounds are furthest along the translational pipeline, with clinical trials under way: [ 18 F]fluorthanatrace (14-17) and [ 18 F]PARPi (6,(18)(19)(20). Radionuclide therapy targeting PARP with a-, b-, and Auger electron emitters has been described using 123 I-, 125 I-, 131 I-, 125 I-, 77 Br-, or 211 At-labeled compounds that resemble olaparib-or rucaparib-like structures (9,(21)(22)(23)(24)(25)(26)(27).…”

mentioning

confidence: 99%

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[¹²³I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

Chan,

Chen,

Guibbal

et al. 2023

J Nucl Med

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

[¹²³I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

Chan,

Chen,

Guibbal

et al. 2023

J Nucl Med

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“…Along the trajectory drawn by the previously mentioned paper [29], a further research study recently evaluated the potential of another radio-brominated rucaparib-derivative, namely [ 77 Br]RD1, as potential AE-based therapeutic tool in ovarian cancer. Notably, the authors employed [ 76 Br]RD1 as a diagnostic companion to assess biodistribution and pre-therapeutic biomarker (PARP-1) evaluation through PET/CT, leveraging physical properties of bromine-76 (t1/2 = 16.2 h, 55% β+) [30].…”

Section: Ovarian Cancermentioning

confidence: 99%

PARP-Targeted Radiotheranostics with Auger Electrons: An Updated Overview

Filippi,

Urso,

Evangelista

2024

CIMB

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Auger electrons (AEs) represent an intriguing topic in the field of radionuclide therapy. They are emitted by several radionuclides commonly used in nuclear medicine (indium-111, iodine-123, iodine-125), allowing for highly localized energy deposition and thus exerting a radiotoxic effect on specific cellular and sub-cellular targets. However, due to their short range in matter, AEs have had limited use in therapeutic applications so far. In recent years, the synthesis of various radiopharmaceuticals capable of binding to the enzyme poly(ADP-ribose) polymerase 1 has reignited interest in this type of therapy, laying the groundwork for a theranostic approach based on radionuclides emitting AEs. The enzyme PARP-1 operates enzymatically in close proximity to DNA that represents the prime target of radionuclide therapies. Following this trend, several PARP-targeted radiopharmaceuticals for AE-based theranostics have been developed. We provide an updated overview of preclinical studies focused on the applications of this new theranostic approach in glioblastoma, breast, prostate and ovarian carcinoma, and pancreatic adenocarcinoma.

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“…We have previously reported on a theranostic poly-ADP ribose polymerase (PARP) inhibitor for targeted RPT of ovarian cancer in vitro and positron emission tomography (PET) imaging of healthy mice in vivo [34,35]. This RPT agent has also been investigated for radiotherapeutic efficacy in preclinical murine models of prostate cancer [36].…”

Section: Br-77 Examplementioning

confidence: 99%

Monte Carlo-Based Nanoscale Dosimetry Holds Promise for Radiopharmaceutical Therapy Involving Auger Electron Emitters

Kwon,

Hoffman,

Ellison

et al. 2024

Cancers

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Radiopharmaceutical therapy (RPT) is evolving as a promising strategy for treating cancer. As interest grows in short-range particles, like Auger electrons, understanding the dose–response relationship at the deoxyribonucleic acid (DNA) level has become essential. In this study, we used the Geant4-DNA toolkit to evaluate DNA damage caused by the Auger-electron-emitting isotope I-125. We compared the energy deposition and single strand break (SSB) yield at each base pair location in a short B-form DNA (B-DNA) geometry with existing simulation and experimental data, considering both physical direct and chemical indirect hits. Additionally, we evaluated dosimetric differences between our high-resolution B-DNA target and a previously published simple B-DNA geometry. Overall, our benchmarking results for SSB yield from I-125 decay exhibited good agreement with both simulation and experimental data. Using this simulation, we then evaluated the SSB and double strand break (DSB) yields caused by a theranostic Br-77-labeled poly ADP ribose polymerase (PARP) inhibitor radiopharmaceutical. The results indicated a predominant contribution of chemical indirect hits over physical direct hits in generating SSB and DSB. This study lays the foundation for future investigations into the nano-dosimetric properties of RPT.

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Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer

Cited by 5 publications

References 52 publications

[¹²³I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

[¹²³I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

PARP-Targeted Radiotheranostics with Auger Electrons: An Updated Overview

Monte Carlo-Based Nanoscale Dosimetry Holds Promise for Radiopharmaceutical Therapy Involving Auger Electron Emitters

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Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer

Cited by 5 publications

References 52 publications

[123I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

[123I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

PARP-Targeted Radiotheranostics with Auger Electrons: An Updated Overview

Monte Carlo-Based Nanoscale Dosimetry Holds Promise for Radiopharmaceutical Therapy Involving Auger Electron Emitters

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[¹²³I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

[¹²³I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer