Modifying pancreatic tumor stroma with angiotensin II receptor blockers to improve verteporfin delivery

摘要

While most cancer therapy options rely on a systemic delivery of pharmacologic drugs into the tumor site, physiologic barriers intrinsic to solid tumors seriously limit drug distribution. In pancreatic ductal adenocarcinoma (PDAC) tumors, it is well-characterized that tumor stroma with a dense desmoplasia hinders drug uptake due to the overproduction of extracellular matrix (ECM) macromolecules such as collagen and hyaluronan. These major components of the ECM exert a high pressure on blood vessels thus collapsing them. This study focused on reducing the overexpression of cancer associated fibroblasts (CAF) by administering an angiotensin II receptor blocker, losartan, to examine its effects on tumor microenvironment modulation for photodynamic therapy. Treatments were conducted on orthotopic xenograft models of AsPC-1 tumor line, which represented the dense stroma of PDAC with highly disordered collagen bundles. Drug delivery efficiency was examined by quantifying verteporfin uptake and vascular patency. Results showed that pancreatic tumor stroma can be modulated by angiotensin II receptor blockers. Losartan treated mice showed an increase in verteporfin uptake and patent vessel area. Collagen structure change was observed which required more texture analysis to quantify. Tumor size between the two groups did not show significant shrinkage, which indicated the importance of treatment start time especially for malignant tumors with narrow treatment windows such as AsPC-1. The enhancement of drug uptake and vascular perfusion suggested that photodynamic therapeutic outcome could be improved by targeting the tumor stroma to improve verteporfin uptake.