TY - JOUR
T1 - Alk5 inhibition increases delivery of macromolecular and protein-bound contrast agents to tumors
AU - Daldrup-Link, Heike E.
AU - Mohanty, Suchismita
AU - Ansari, Celina
AU - Lenkov, Olga
AU - Shaw, Aubie
AU - Ito, Ken
AU - Hong, Su Hyun
AU - Hoffmann, Matthias
AU - Pisani, Laura
AU - Boudreau, Nancy
AU - Gambhir, Sanjiv Sam
AU - Coussens, Lisa M.
N1 - Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/5/5
Y1 - 2016/5/5
N2 - Limited transendothelial permeability across tumor microvessels represents a significant bottleneck in the development of tumor-specific diagnostic agents and theranostic drugs. Here, we show an approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-β receptor, activin-like kinase 5 (Alk5), in tumors. Alk5 inhibition significantly increased tumor contrast agent delivery and enhancement on imaging studies, while healthy organs remained relatively unaffected. Imaging data correlated with significantly decreased tumor interstitial fluid pressure, while tumor vascular density remained unchanged. This immediately clinically translatable concept involving Alk5 inhibitor pretreatment prior to an imaging study could be leveraged for improved tumor delivery of macromolecular and nanoparticle-based imaging probes and, thereby, facilitate development of more sensitive imaging tests for cancer diagnosis, enhanced tumor characterization, and personalized, image-guided therapies.
AB - Limited transendothelial permeability across tumor microvessels represents a significant bottleneck in the development of tumor-specific diagnostic agents and theranostic drugs. Here, we show an approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-β receptor, activin-like kinase 5 (Alk5), in tumors. Alk5 inhibition significantly increased tumor contrast agent delivery and enhancement on imaging studies, while healthy organs remained relatively unaffected. Imaging data correlated with significantly decreased tumor interstitial fluid pressure, while tumor vascular density remained unchanged. This immediately clinically translatable concept involving Alk5 inhibitor pretreatment prior to an imaging study could be leveraged for improved tumor delivery of macromolecular and nanoparticle-based imaging probes and, thereby, facilitate development of more sensitive imaging tests for cancer diagnosis, enhanced tumor characterization, and personalized, image-guided therapies.
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U2 - 10.1172/jci.insight.85608
DO - 10.1172/jci.insight.85608
M3 - Article
AN - SCOPUS:85083249846
SN - 2379-3708
VL - 1
JO - JCI Insight
JF - JCI Insight
IS - 6
M1 - e85608
ER -