Mucolytic Agents Can Enhance HER2 Receptor Accessibility for [89Zr]Trastuzumab, Improving HER2 Imaging in a Mucin-Overexpressing Breast Cancer Xenograft Mouse Model
Purpose Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([ 89 Zr]T) binding/uptake. Procedures The...
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Published in | Molecular imaging and biology Vol. 17; no. 5; pp. 697 - 703 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Springer US
01.10.2015
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | Purpose
Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([
89
Zr]T) binding/uptake.
Procedures
The effect of
N
-acetylcysteine (NAC) and MUC4 knockdown/stimulation on [
89
Zr]T binding/uptake were evaluated in MCF7(HER2−), BT474 and SKBr3(HER2+/MUC4−), and JIMT1(HER2+/MUC4+) cell lines. The results were then validated in SKBR3 and JIMT1 tumor-bearing nude mice with a microPET-CT and
ex vivo
analysis.
Results
Significant increases in [
89
Zr]T binding/uptake were observed in JIMT1 cells following MUC4 knockdown (62.4 ± 6.5 %) and exposure to NAC (62.8 ± 19.4 %). Compared to controls, mice treated with NAC showed a significant increase in [
89
Zr]T uptake in MUC4 tumors on microPET-CT (SUV
mean
(18.3 ± 4.7 %), SUV
max
(41.7 ± 8.4 %)) and individual organ counting (37.3 ± 18.3 %). In contrast, no significant differences were observed in SKBr3.
Conclusion
NAC can enhance [
89
Zr]T accumulation and improve the HER2 imaging of MUC4-overexpressing tumors. The potential positive impact on trastuzumab-based treatment deserves further investigation. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1536-1632 1860-2002 |
DOI: | 10.1007/s11307-015-0840-x |