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Alk5 inhibition increases delivery of macromolecular and protein-bound contrast agents to tumors
Heike E. Daldrup-Link, … , Sanjiv Sam Gambhir, Lisa M. Coussens
Heike E. Daldrup-Link, … , Sanjiv Sam Gambhir, Lisa M. Coussens
Published May 5, 2016
Citation Information: JCI Insight. 2016;1(6):e85608. https://doi.org/10.1172/jci.insight.85608.
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Research Article Oncology

Alk5 inhibition increases delivery of macromolecular and protein-bound contrast agents to tumors

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Abstract

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.

Authors

Heike E. Daldrup-Link, Suchismita Mohanty, Celina Ansari, Olga Lenkov, Aubie Shaw, Ken Ito, Su Hyun Hong, Matthias Hoffmann, Laura Pisani, Nancy Boudreau, Sanjiv Sam Gambhir, Lisa M. Coussens

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Figure 2

Alk5 inhibition leads to increased iron oxide nanoparticle accumulation and enhancement of MMTV-PyMT tumors on MR images.

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Alk5 inhibition leads to increased iron oxide nanoparticle accumulation ...
(A) Representative axial T2-weighted MR images before and after i.v. injection of ferumoxytol nanoparticles show stronger negative (dark) tumor enhancement after Alk5 inhibition (arrow) compared with untreated tumors (arrowhead). (B) Corresponding quantitative changes in tumor R2 relaxation rates after ferumoxytol injection, measured as R2precontrast – R2postcontrast and displayed as means for 4 animals in each group ± SD. ANOVA was used to compare the differences between various groups. *P < 0.05, between MR enhancement of Alk5 inhibitor-treated tumors compared with untreated controls. Results are representative of 3 independent experiments. Alk5, activin-like kinase 5; Alk5i, Alk5 inhibition; MMTV-PyMT, mouse mammary tumor virus–driven expression of the polyoma middle T oncogene; MR, magnetic resonance.

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