title: Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Diop-Frimpong
authors.forename: Vikash P
authors.initials: VP
authors.lastname: Chauhan
authors.forename: Stephen
authors.initials: S
authors.lastname: Krane
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D002277:Carcinoma / Q000188:drug therapy*; D003094:Collagen / Q000096:biosynthesis*; D017931:DNA Primers / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D036681:Fluorescence Recovery After Photobleaching; D006801:Humans; D007150:Immunohistochemistry; D019808:Losartan / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D036103:Nanotechnology / Q000379:methods*; D050130:Oncolytic Virotherapy / Q000379:methods; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000008:administration & dosage; D016133:Polymerase Chain Reaction; D018139:Simplexvirus; D012878:Skin Neoplasms / Q000188:drug therapy
chemical_list: D017931:DNA Primers; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D003094:Collagen; D019808:Losartan