Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 7; pp. 2909 - 2914
• Main Authors: Diop-Frimpong, Benjamin, Chauhan, Vikash P, Krane, Stephen, Boucher, Yves, Jain, Rakesh K
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15.02.2011; National Acad Sciences
• Subjects: Analysis of Variance; angiotensin II; Animals; antagonists; Antineoplastics; Biological Sciences; biopsy; breast neoplasms; Breast Neoplasms - drug therapy; Cancer; Carcinoma - drug therapy; collagen; Collagen - biosynthesis; Collagens; DNA Primers - genetics; Dosage; dose response; Dose-Response Relationship, Drug; doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Drug Delivery Systems - methods; Drug therapy; Female; fibroblasts; Fluorescence Recovery After Photobleaching; herpes simplex; Humans; Immunohistochemistry; Losartan - pharmacokinetics; Losartan - pharmacology; Medical treatment; Mice; Mice, SCID; nanomedicine; Nanoparticles; Nanoscience; Nanotechnology - methods; Oncolytic Virotherapy - methods; Pancreatic neoplasms; Pancreatic Neoplasms - drug therapy; patients; Pharmacology; Physical Sciences; Polyethylene Glycols - administration & dosage; Polymerase Chain Reaction; Protein synthesis; Proteins; Receptors; Simplexvirus; skin neoplasms; Skin Neoplasms - drug therapy; Tumors; Viruses
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1018892108

The dense collagen network in tumors significantly reduces the penetration and efficacy of nanotherapeutics. We tested whether losartan—a clinically approved angiotensin II receptor antagonist with noted antifibrotic activity—can enhance the penetration and efficacy of nanomedicine. We found that losartan inhibited collagen I production by carcinoma-associated fibroblasts isolated from breast cancer biopsies. Additionally, it led to a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic, and skin tumors in mice. Furthermore, losartan improved the distribution and therapeutic efficacy of intratumorally injected oncolytic herpes simplex viruses. Finally, it also enhanced the efficacy of i.v. injected pegylated liposomal doxorubicin (Doxil). Thus, losartan has the potential to enhance the efficacy of nanotherapeutics in patients with desmoplastic tumors.