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Whole-body organ-level and kidney micro-dosimetric evaluations of (64)Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin ((64)Cu-MM-302) in rodents and primates

BACKGROUND: Features of the tumor microenvironment influence the efficacy of cancer nanotherapeutics. The ability to directly radiolabel nanotherapeutics offers a valuable translational tool to obtain biodistribution and tumor deposition data, testing the hypothesis that the extent of delivery predi...

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Autores principales: Gaddy, Daniel F, Lee, Helen, Zheng, Jinzi, Jaffray, David A, Wickham, Thomas J, Hendriks, Bart S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404468/
https://www.ncbi.nlm.nih.gov/pubmed/25918676
http://dx.doi.org/10.1186/s13550-015-0096-0
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author Gaddy, Daniel F
Lee, Helen
Zheng, Jinzi
Jaffray, David A
Wickham, Thomas J
Hendriks, Bart S
author_facet Gaddy, Daniel F
Lee, Helen
Zheng, Jinzi
Jaffray, David A
Wickham, Thomas J
Hendriks, Bart S
author_sort Gaddy, Daniel F
collection PubMed
description BACKGROUND: Features of the tumor microenvironment influence the efficacy of cancer nanotherapeutics. The ability to directly radiolabel nanotherapeutics offers a valuable translational tool to obtain biodistribution and tumor deposition data, testing the hypothesis that the extent of delivery predicts therapeutic outcome. In support of a first in-human clinical trial with (64)Cu-labeled HER2-targeted liposomal doxorubicin ((64)Cu-MM-302), a preclinical dosimetric analysis was performed. METHODS: Whole-body biodistribution and pharmacokinetic data were obtained in mice that received (64)Cu-MM-302 and used to estimate absorbed radiation doses in normal human organs. PET/CT imaging revealed non-uniform distribution of (64)Cu signal in mouse kidneys. Kidney micro-dosimetry analysis was performed in mice and squirrel monkeys, using a physiologically based pharmacokinetic model to estimate the full dynamics of the (64)Cu signal in monkeys. RESULTS: Organ-level dosimetric analysis of mice receiving (64)Cu-MM-302 indicated that the heart was the organ receiving the highest radiation absorbed dose, due to extended liposomal circulation. However, PET/CT imaging indicated that (64)Cu-MM-302 administration resulted in heterogeneous exposure in the kidney, with a focus of (64)Cu activity in the renal pelvis. This result was reproduced in primates. Kidney micro-dosimetry analysis illustrated that the renal pelvis was the maximum exposed tissue in mice and squirrel monkeys, due to the highly concentrated signal within the small renal pelvis surface area. CONCLUSIONS: This study was used to select a starting clinical radiation dose of (64)Cu-MM-302 for PET/CT in patients with advanced HER2-positive breast cancer. Organ-level dosimetry and kidney micro-dosimetry results predicted that a radiation dose of 400 MBq of (64)Cu-MM-302 should be acceptable in patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-015-0096-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-44044682015-04-27 Whole-body organ-level and kidney micro-dosimetric evaluations of (64)Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin ((64)Cu-MM-302) in rodents and primates Gaddy, Daniel F Lee, Helen Zheng, Jinzi Jaffray, David A Wickham, Thomas J Hendriks, Bart S EJNMMI Res Original Research BACKGROUND: Features of the tumor microenvironment influence the efficacy of cancer nanotherapeutics. The ability to directly radiolabel nanotherapeutics offers a valuable translational tool to obtain biodistribution and tumor deposition data, testing the hypothesis that the extent of delivery predicts therapeutic outcome. In support of a first in-human clinical trial with (64)Cu-labeled HER2-targeted liposomal doxorubicin ((64)Cu-MM-302), a preclinical dosimetric analysis was performed. METHODS: Whole-body biodistribution and pharmacokinetic data were obtained in mice that received (64)Cu-MM-302 and used to estimate absorbed radiation doses in normal human organs. PET/CT imaging revealed non-uniform distribution of (64)Cu signal in mouse kidneys. Kidney micro-dosimetry analysis was performed in mice and squirrel monkeys, using a physiologically based pharmacokinetic model to estimate the full dynamics of the (64)Cu signal in monkeys. RESULTS: Organ-level dosimetric analysis of mice receiving (64)Cu-MM-302 indicated that the heart was the organ receiving the highest radiation absorbed dose, due to extended liposomal circulation. However, PET/CT imaging indicated that (64)Cu-MM-302 administration resulted in heterogeneous exposure in the kidney, with a focus of (64)Cu activity in the renal pelvis. This result was reproduced in primates. Kidney micro-dosimetry analysis illustrated that the renal pelvis was the maximum exposed tissue in mice and squirrel monkeys, due to the highly concentrated signal within the small renal pelvis surface area. CONCLUSIONS: This study was used to select a starting clinical radiation dose of (64)Cu-MM-302 for PET/CT in patients with advanced HER2-positive breast cancer. Organ-level dosimetry and kidney micro-dosimetry results predicted that a radiation dose of 400 MBq of (64)Cu-MM-302 should be acceptable in patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-015-0096-0) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2015-04-14 /pmc/articles/PMC4404468/ /pubmed/25918676 http://dx.doi.org/10.1186/s13550-015-0096-0 Text en © Gaddy et al.; licensee Springer. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
spellingShingle Original Research
Gaddy, Daniel F
Lee, Helen
Zheng, Jinzi
Jaffray, David A
Wickham, Thomas J
Hendriks, Bart S
Whole-body organ-level and kidney micro-dosimetric evaluations of (64)Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin ((64)Cu-MM-302) in rodents and primates
title Whole-body organ-level and kidney micro-dosimetric evaluations of (64)Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin ((64)Cu-MM-302) in rodents and primates
title_full Whole-body organ-level and kidney micro-dosimetric evaluations of (64)Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin ((64)Cu-MM-302) in rodents and primates
title_fullStr Whole-body organ-level and kidney micro-dosimetric evaluations of (64)Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin ((64)Cu-MM-302) in rodents and primates
title_full_unstemmed Whole-body organ-level and kidney micro-dosimetric evaluations of (64)Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin ((64)Cu-MM-302) in rodents and primates
title_short Whole-body organ-level and kidney micro-dosimetric evaluations of (64)Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin ((64)Cu-MM-302) in rodents and primates
title_sort whole-body organ-level and kidney micro-dosimetric evaluations of (64)cu-loaded her2/erbb2-targeted liposomal doxorubicin ((64)cu-mm-302) in rodents and primates
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404468/
https://www.ncbi.nlm.nih.gov/pubmed/25918676
http://dx.doi.org/10.1186/s13550-015-0096-0
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