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Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer
Abstract
Advanced ovarian cancer currently has few therapeutic options. Poly(ADP-ribose) polymerase (PARP) inhibitors bind to nuclear PARP and trap the protein-inhibitor complex to DNA. This work investigates a theranostic PARP inhibitor for targeted radiopharmaceutical therapy of ovarian cancer in vitro and PET imaging of healthy mice in vivo. Methods: [77Br]RD1 was synthesized and assessed for pharmacokinetics and cytotoxicity in human and murine ovarian cancer cell lines. [76Br]RD1 biodistribution and organ uptake in healthy mice were quantified through longitudinal PET/CT imaging and ex vivo radioactivity measurements. Organ-level dosimetry following [76/77Br]RD1 administration was calculated using RAPID, an in-house platform for absorbed dose in mice, and OLINDA for equivalent and effective dose in human. Results: The maximum specific binding (Bmax), equilibrium dissociation constant (Kd), and nonspecific binding slope (NS) were calculated for each cell line. These values were used to calculate the cell specific activity uptake for cell viability studies. The half maximal effective concentration (EC50) was measured as 0.17 (95 % CI: 0.13–0.24) nM and 0.46 (0.13–0.24) nM for PARP(+) and PARP(–) expressing cell lines, respectively. The EC50 was 0.27 (0.21–0.36) nM and 0.30 (0.22–0.41) nM for BRCA1(–) and BRCA1(+) expressing cell lines, respectively. When measuring the EC50 as a function of cellularmore »
- Authors:
-
- Univ. of Wisconsin, Madison, WI (United States). School of Medicine and Public Health
- Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine
- Univ. of Wisconsin, Madison, WI (United States). Carbone Cancer Center
- Publication Date:
- Research Org.:
- Univ. of Wisconsin, Madison, WI (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Office of Isotope R&D and Production (IRP); National Cancer Institute (NCI)
- Contributing Org.:
- University of Wisconsin Carbone Cancer Center (UWCCC) Biostatistics Shared Resource; UWCCC Small Animal Imaging & Radiotherapy Facility
- OSTI Identifier:
- 1993381
- Grant/Contract Number:
- SC0020960; W81XWH2110351; T32CA009206; UL1TR002373; P01 CA250972-01; U01 CA233102-01
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nuclear Medicine and Biology
- Additional Journal Information:
- Journal Volume: 122-123; Journal ID: ISSN 0969-8051
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 62 RADIOLOGY AND NUCLEAR MEDICINE; Bromine-77; Bromine-76; Meitner-Auger radionuclide therapy; positron emission tomography; PARP-1 inhibitor; theranostic; ovarian cancer therapy
Citation Formats
Hoffman, Sabrina L. V., Mixdorf, J. C., Kwon, O., Johnson, T. R., Makvandi, M., Lee, H., Aluicio-Sarduy, E., Barnhart, T. E., Jeffery, J. J., Patankar, M. S., Engle, J. W., Bednarz, B. P., and Ellison, P. A. Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer. United States: N. p., 2023.
Web. doi:10.1016/j.nucmedbio.2023.108368.
Hoffman, Sabrina L. V., Mixdorf, J. C., Kwon, O., Johnson, T. R., Makvandi, M., Lee, H., Aluicio-Sarduy, E., Barnhart, T. E., Jeffery, J. J., Patankar, M. S., Engle, J. W., Bednarz, B. P., & Ellison, P. A. Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer. United States. https://doi.org/10.1016/j.nucmedbio.2023.108368
Hoffman, Sabrina L. V., Mixdorf, J. C., Kwon, O., Johnson, T. R., Makvandi, M., Lee, H., Aluicio-Sarduy, E., Barnhart, T. E., Jeffery, J. J., Patankar, M. S., Engle, J. W., Bednarz, B. P., and Ellison, P. A. Wed .
"Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer". United States. https://doi.org/10.1016/j.nucmedbio.2023.108368.
@article{osti_1993381,
title = {Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer},
author = {Hoffman, Sabrina L. V. and Mixdorf, J. C. and Kwon, O. and Johnson, T. R. and Makvandi, M. and Lee, H. and Aluicio-Sarduy, E. and Barnhart, T. E. and Jeffery, J. J. and Patankar, M. S. and Engle, J. W. and Bednarz, B. P. and Ellison, P. A.},
abstractNote = {Advanced ovarian cancer currently has few therapeutic options. Poly(ADP-ribose) polymerase (PARP) inhibitors bind to nuclear PARP and trap the protein-inhibitor complex to DNA. This work investigates a theranostic PARP inhibitor for targeted radiopharmaceutical therapy of ovarian cancer in vitro and PET imaging of healthy mice in vivo. Methods: [77Br]RD1 was synthesized and assessed for pharmacokinetics and cytotoxicity in human and murine ovarian cancer cell lines. [76Br]RD1 biodistribution and organ uptake in healthy mice were quantified through longitudinal PET/CT imaging and ex vivo radioactivity measurements. Organ-level dosimetry following [76/77Br]RD1 administration was calculated using RAPID, an in-house platform for absorbed dose in mice, and OLINDA for equivalent and effective dose in human. Results: The maximum specific binding (Bmax), equilibrium dissociation constant (Kd), and nonspecific binding slope (NS) were calculated for each cell line. These values were used to calculate the cell specific activity uptake for cell viability studies. The half maximal effective concentration (EC50) was measured as 0.17 (95 % CI: 0.13–0.24) nM and 0.46 (0.13–0.24) nM for PARP(+) and PARP(–) expressing cell lines, respectively. The EC50 was 0.27 (0.21–0.36) nM and 0.30 (0.22–0.41) nM for BRCA1(–) and BRCA1(+) expressing cell lines, respectively. When measuring the EC50 as a function of cellular activity uptake and nuclear dose, the EC50 ranges from 0.020 to 0.039 Bq/cell and 3.3–9.2 Gy, respectively. Excretion through the hepatobiliary and renal pathways were observed in mice, with liver uptake of 2.3 ± 0.4 %ID/g after 48 h, contributing to estimated absorbed dose values in mice of 19.3 ± 0.3 mGy/MBq and 290 ± 10 mGy/MBq for [77Br]RD1 and [76Br]RD1, respectively. Conclusion: [77Br]RD1 cytotoxicity was dependent on PARP expression and independent of BRCA1 status. Finally, the in vitro results suggest that [77Br]RD1 cytotoxicity is driven by the targeted Meitner-Auger electron (MAe) radiotherapeutic effect of the agent. Further studies investigating the theranostic potential, organ dose, and tumor uptake of [76/77Br]RD1 are warranted.},
doi = {10.1016/j.nucmedbio.2023.108368},
journal = {Nuclear Medicine and Biology},
number = ,
volume = 122-123,
place = {United States},
year = {Wed Jul 19 00:00:00 EDT 2023},
month = {Wed Jul 19 00:00:00 EDT 2023}
}
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