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

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

doi:10.1172/jci.insight.85608

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

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

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Article number	e85608
Journal	JCI Insight
Volume	1
Issue number	6
DOIs	https://doi.org/10.1172/jci.insight.85608
State	Published - May 5 2016
Externally published	Yes

Bibliographical note

Funding 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).

Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access

10.1172/jci.insight.85608

OpenUrl availability

Full text

Cite this

@article{1681ba4765714ca08c0198aff78708e9,

title = "Alk5 inhibition increases delivery of macromolecular and protein-bound contrast agents to tumors",

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.",

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

note = "Funding 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). Publisher Copyright: {\textcopyright} 2016 American Society for Clinical Investigation. All rights reserved.",

year = "2016",

month = may,

day = "5",

doi = "10.1172/jci.insight.85608",

language = "English (US)",

volume = "1",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "6",

}

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 - Funding 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). 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.

UR - http://www.scopus.com/inward/record.url?scp=85083249846&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85083249846&partnerID=8YFLogxK

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 -

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

Abstract

Bibliographical note

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this