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EJNMMI Research
Published in: EJNMMI Research 1/2015

Open Access 01-12-2015 | Original research

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

Authors: Daniel F Gaddy, Helen Lee, Jinzi Zheng, David A Jaffray, Thomas J Wickham, Bart S Hendriks

Published in: EJNMMI Research | Issue 1/2015

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Abstract

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 64Cu-labeled HER2-targeted liposomal doxorubicin (64Cu-MM-302), a preclinical dosimetric analysis was performed.

Methods

Whole-body biodistribution and pharmacokinetic data were obtained in mice that received 64Cu-MM-302 and used to estimate absorbed radiation doses in normal human organs. PET/CT imaging revealed non-uniform distribution of 64Cu 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 64Cu signal in monkeys.

Results

Organ-level dosimetric analysis of mice receiving 64Cu-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 64Cu-MM-302 administration resulted in heterogeneous exposure in the kidney, with a focus of 64Cu 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 64Cu-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 64Cu-MM-302 should be acceptable in patients.
Appendix
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Metadata
Title
Whole-body organ-level and kidney micro-dosimetric evaluations of 64Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin (64Cu-MM-302) in rodents and primates
Authors
Daniel F Gaddy
Helen Lee
Jinzi Zheng
David A Jaffray
Thomas J Wickham
Bart S Hendriks
Publication date
01-12-2015
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2015
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-015-0096-0

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