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.
Bibliographical noteFunding Information:
The authors thank the Small Animal Imaging Facility at Stanford for providing the equipment and infrastructure for this project. We thank members of the Daldrup-Link, Gambhir, and Coussens laboratories for valuable discussions. We acknowledge support from NIH National Cancer Institute (NCI) grant R01 CA140943 (to L.M. Coussens, H.E. Daldrup-Link, and N. Boudreau); grants R21 CA176519 (to H.E. Dal-drup-Link), R21 CA190196-01A1, R01 CA155331, and U54 CA163123 from the NCI; the Department of Defense Breast Cancer Research Program Era of Hope Scholar Expansion Award (BC10412); the Susan G. Komen Foundation; Stand Up To Cancer – Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant; and the Breast Cancer Research Foundation (to L.M. Coussens).
© 2016 American Society for Clinical Investigation. All rights reserved.