Abstract
BackgroundFeatures 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.MethodsWhole-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.ResultsOrgan-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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0096-0) contains supplementary material, which is available to authorized users.
Highlights
Features of the tumor microenvironment influence the efficacy of cancer nanotherapeutics
MM-302 is a HER2-targeted liposomal doxorubicin designed for selective uptake into HER2-overexpressing
MM-302 was designed to build on PEGylated liposomal doxorubicin (PLD) by retaining the improved cardiac safety profile of PLD relative to conventional doxorubicin and improving anti-tumor activity through immunotargeting of HER2
Summary
Features of the tumor microenvironment influence the efficacy of cancer nanotherapeutics. 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. 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. 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. 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.
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