Celina Ansari MD, Presenter: Nothing to Disclose

Ken Ito PhD, Abstract Co-Author: Nothing to Disclose

Su Hyun Hong, Abstract Co-Author: Nothing to Disclose

Sanjiv Sam Gambhir MD, PhD, Abstract Co-Author: Research Grant, Bayer AG Research Grant, General Electric Company Research Grant, sanofi-aventis Group Research Consultant, Bracco Group Research Consultant, CytomX Therapeutics Research Consultant, Spectrum Dynamics Ltd Research Consultant, Enlight Biosciences Research Consultant, ImaginAb, Inc Research Consultant, FUJIFILM Holdings Corporation Speaker, Bracco Group Speaker, CytomX Therapeutics, Inc Speaker, Spectrum Dynamics Ltd Speaker, Enlight Biosciences Speaker, ImaginAb, Inc Speaker, FUJIFILM Holdings Corporation Stockholder, CellSight Technologies, Inc Stockholder, Endra, Inc Stockholder, Enlight Biosciences Stockholder, ImaginAb, Inc Stockholder, Lumen Therapeutics, LLC Stockholder, MagArray, Inc Stockholder, NinePoint Medical, Inc Stockholder, Prolume, Ltd Stockholder, RefleXion Medical Inc Stockholder, Spectrum Dynamics Ltd Stockholder, FUJIFILM Holdings Corporation Advisory Board, Enlight Biosciences Advisory Board, ImaginAb, Inc Advisory Board, FUJIFILM Holdings Corporation Spouse, Employee, CellSight Technologies, Inc

Lisa Coussens, Abstract Co-Author: Nothing to Disclose

Heike E. Daldrup-Link MD, Abstract Co-Author: Nothing to Disclose

The limited transendothelial permeability of macromolecules across tumor microvessels represents a significant challenge for the development of novel, multifunctional and tumor-specific diagnostic and therapeutic drugs. Purpose of this study was to evaluate, if inhibition of the type I TGFb receptor Alk5 leads to enhanced tumor microvascular permeability of macromolecular contrast agents.

Mice with transgenic MMTV-PyMT adenocarcinomas underwent optical imaging and MR imaging studies before and after intravenous injection of indocyanine green (ICG, n = 16), gadovosfeset trisodium (n=16) and ferumoxytol (n=8) before and after treatment with Alk5-inhibitor (ALK5 kinase inhibitor [3-(pyridin-2-yl)-4-(4-quinonyl)]-1H-pyrazole (Calbiochem, San Diego, CA)). The tumor enhancement on imaging studies before and after Alk5-inhibition was compared with a t-test and correlated with intravital microscopy studies and histopathology.

All imaging studies revealed markedly increased tumor enhancement after Alk5 inhibition, for macromolecular contrast agents of a wide range of sizes. Quantitative ICG-fluorescence intensity data as well as gadofosveset and ferumoxytol-induced changes in tumor relaxation rates were significantly increased after Alk5-inhibition (p<0.05). Intravital microscopy and histopathology confirmed increased transendothelial microvascular permeability and increased interstitial accummulation of macromolecular diagnostic drugs in Alk5-inhibitor treated tumors compared to untreated controls (p<0.05). The tumor vascular density did not change before and after Alk-5 inhibition.

Alk5-inhibition leads to significantly enhanced tumor microvascular permeability of a variety of macromolecular contrast agents.

By exploiting a novel endogenous pathway that regulates vascular permeability, we anticipate significantly facilitating novel tumor-specific diagnostic and therapeutic approaches.

Ansari, C, Ito, K, Hong, S, Gambhir, S, Coussens, L, Daldrup-Link, H, Overcoming Barriers of Drug Delivery to Tumors via Alk5-inhibition.  Radiological Society of North America 2012 Scientific Assembly and Annual Meeting, November 25 - November 30, 2012 ,Chicago IL. http://archive.rsna.org/2012/12029119.html