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

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 lo...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-02, Vol.108 (7), p.2909-2914
Main Authors: Diop-Frimpong, Benjamin, Chauhan, Vikash P, Krane, Stephen, Boucher, Yves, Jain, Rakesh K
Format: Article
Language:English
Subjects:
Analysis of Variance
Animals
Antineoplastics
Biological Sciences
Breast Neoplasms - drug therapy
Cancer
Carcinoma - drug therapy
Collagen - biosynthesis
Collagens
DNA Primers - genetics
Dosage
Dose-Response Relationship, Drug
Doxorubicin - administration & dosage
Doxorubicin - analogs & derivatives
Drug Delivery Systems - methods
Drug therapy
Female
Fluorescence Recovery After Photobleaching
Humans
Immunohistochemistry
Losartan - pharmacokinetics
Losartan - pharmacology
Medical treatment
Mice
Mice, SCID
Nanoparticles
Nanoscience
Nanotechnology - methods
Oncolytic Virotherapy - methods
Pancreatic neoplasms
Pancreatic Neoplasms - drug therapy
Pharmacology
Physical Sciences
Polyethylene Glycols - administration & dosage
Polymerase Chain Reaction
Protein synthesis
Proteins
Receptors
Simplexvirus
Skin Neoplasms - drug therapy
Tumors
Viruses
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Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1018892108