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Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer
Auger radiopharmaceutical therapy is a promising strategy for micrometastatic disease given high linear energy transfer and short range in tissues, potentially limiting normal tissue toxicities. We previously demonstrated anti-tumor efficacy of a small-molecule Auger electron emitter targeting the p...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053212/ https://www.ncbi.nlm.nih.gov/pubmed/32194842 http://dx.doi.org/10.7150/thno.38882 |
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author | Shen, Colette J. Minn, Il Hobbs, Robert F. Chen, Ying Josefsson, Anders Brummet, Mary Banerjee, Sangeeta R. Brayton, Cory F. Mease, Ronnie C. Pomper, Martin G. Kiess, Ana P. |
author_facet | Shen, Colette J. Minn, Il Hobbs, Robert F. Chen, Ying Josefsson, Anders Brummet, Mary Banerjee, Sangeeta R. Brayton, Cory F. Mease, Ronnie C. Pomper, Martin G. Kiess, Ana P. |
author_sort | Shen, Colette J. |
collection | PubMed |
description | Auger radiopharmaceutical therapy is a promising strategy for micrometastatic disease given high linear energy transfer and short range in tissues, potentially limiting normal tissue toxicities. We previously demonstrated anti-tumor efficacy of a small-molecule Auger electron emitter targeting the prostate-specific membrane antigen (PSMA), 2-[3-[1-carboxy-5-(4-[(125)I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid), or (125)I-DCIBzL, in a mouse xenograft model. Here, we investigated the therapeutic efficacy, long-term toxicity, and biodistribution of (125)I-DCIBzL in a micrometastatic model of prostate cancer (PC). Methods: To test the therapeutic efficacy of (125)I-DCIBzL in micrometastatic PC, we used a murine model of human metastatic PC in which PSMA+ PC3-ML cells expressing firefly luciferase were injected intravenously in NSG mice to form micrometastatic deposits. One week later, 0, 0.37, 1.85, 3.7, 18.5, 37, or 111 MBq of (125)I-DCIBzL was administered (intravenously). Metastatic tumor burden was assessed using bioluminescence imaging (BLI). Long-term toxicity was evaluated via serial weights and urinalysis of non-tumor-bearing mice over a 12-month period, as well as final necropsy. Results: In the micrometastatic PC model, activities of 18.5 MBq (125)I-DCIBzL and above significantly delayed development of detectable metastatic disease by BLI and prolonged survival in mice. Gross metastases were detectable in control mice and those treated with 0.37-3.7 MBq (125)I-DCIBzL at a median of 2 weeks post-treatment, versus 4 weeks for those treated with 18.5-111 MBq (125)I-DCIBzL (P<0.0001 by log-rank test). Similarly, treatment with ≥18.5 MBq (125)I-DCIBzL yielded a median survival of 11 weeks, compared with 6 weeks for control mice (P<0.0001). At 12 months, there was no appreciable toxicity via weight, urinalysis, or necropsy evaluation in mice treated with any activity of (125)I-DCIBzL, which represents markedly less toxicity than the analogous PSMA-targeted α-particle emitter. Macro-to-microscale dosimetry modeling demonstrated lower absorbed dose in renal cell nuclei versus tumor cell nuclei due to lower levels of drug uptake and cellular internalization in combination with the short range of Auger emissions. Conclusion: PSMA-targeted radiopharmaceutical therapy with the Auger emitter (125)I-DCIBzL significantly delayed development of detectable metastatic disease and improved survival in a micrometastatic model of PC, with no long-term toxicities noted at 12 months, suggesting a favorable therapeutic ratio for treatment of micrometastatic PC. |
format | Online Article Text |
id | pubmed-7053212 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-70532122020-03-19 Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer Shen, Colette J. Minn, Il Hobbs, Robert F. Chen, Ying Josefsson, Anders Brummet, Mary Banerjee, Sangeeta R. Brayton, Cory F. Mease, Ronnie C. Pomper, Martin G. Kiess, Ana P. Theranostics Research Paper Auger radiopharmaceutical therapy is a promising strategy for micrometastatic disease given high linear energy transfer and short range in tissues, potentially limiting normal tissue toxicities. We previously demonstrated anti-tumor efficacy of a small-molecule Auger electron emitter targeting the prostate-specific membrane antigen (PSMA), 2-[3-[1-carboxy-5-(4-[(125)I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid), or (125)I-DCIBzL, in a mouse xenograft model. Here, we investigated the therapeutic efficacy, long-term toxicity, and biodistribution of (125)I-DCIBzL in a micrometastatic model of prostate cancer (PC). Methods: To test the therapeutic efficacy of (125)I-DCIBzL in micrometastatic PC, we used a murine model of human metastatic PC in which PSMA+ PC3-ML cells expressing firefly luciferase were injected intravenously in NSG mice to form micrometastatic deposits. One week later, 0, 0.37, 1.85, 3.7, 18.5, 37, or 111 MBq of (125)I-DCIBzL was administered (intravenously). Metastatic tumor burden was assessed using bioluminescence imaging (BLI). Long-term toxicity was evaluated via serial weights and urinalysis of non-tumor-bearing mice over a 12-month period, as well as final necropsy. Results: In the micrometastatic PC model, activities of 18.5 MBq (125)I-DCIBzL and above significantly delayed development of detectable metastatic disease by BLI and prolonged survival in mice. Gross metastases were detectable in control mice and those treated with 0.37-3.7 MBq (125)I-DCIBzL at a median of 2 weeks post-treatment, versus 4 weeks for those treated with 18.5-111 MBq (125)I-DCIBzL (P<0.0001 by log-rank test). Similarly, treatment with ≥18.5 MBq (125)I-DCIBzL yielded a median survival of 11 weeks, compared with 6 weeks for control mice (P<0.0001). At 12 months, there was no appreciable toxicity via weight, urinalysis, or necropsy evaluation in mice treated with any activity of (125)I-DCIBzL, which represents markedly less toxicity than the analogous PSMA-targeted α-particle emitter. Macro-to-microscale dosimetry modeling demonstrated lower absorbed dose in renal cell nuclei versus tumor cell nuclei due to lower levels of drug uptake and cellular internalization in combination with the short range of Auger emissions. Conclusion: PSMA-targeted radiopharmaceutical therapy with the Auger emitter (125)I-DCIBzL significantly delayed development of detectable metastatic disease and improved survival in a micrometastatic model of PC, with no long-term toxicities noted at 12 months, suggesting a favorable therapeutic ratio for treatment of micrometastatic PC. Ivyspring International Publisher 2020-02-03 /pmc/articles/PMC7053212/ /pubmed/32194842 http://dx.doi.org/10.7150/thno.38882 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Shen, Colette J. Minn, Il Hobbs, Robert F. Chen, Ying Josefsson, Anders Brummet, Mary Banerjee, Sangeeta R. Brayton, Cory F. Mease, Ronnie C. Pomper, Martin G. Kiess, Ana P. Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer |
title | Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer |
title_full | Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer |
title_fullStr | Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer |
title_full_unstemmed | Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer |
title_short | Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer |
title_sort | auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053212/ https://www.ncbi.nlm.nih.gov/pubmed/32194842 http://dx.doi.org/10.7150/thno.38882 |
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