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.
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, USA.
authors.forename: Heike E
authors.initials: HE
authors.lastname: Daldrup-Link
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, USA.
authors.forename: Suchismita
authors.initials: S
authors.lastname: Mohanty
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, USA.
authors.forename: Celina
authors.initials: C
authors.lastname: Ansari
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Lenkov
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Aubie
authors.initials: A
authors.lastname: Shaw
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Ito
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, USA.
authors.forename: Su Hyun
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe University, Frankfurt, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Pisani
authors.affiliation: Department of Surgery, UCSF, San Francisco, California, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Boudreau
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, USA; Department of Bioengineering, Stanford University, Stanford, California, USA; Department of Materials Science and Engineering, Stanford University, Stanford, California, USA.
authors.forename: Sanjiv Sam
authors.initials: SS
authors.lastname: Gambhir
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Coussens