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Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors
Open accessAbstract
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.
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“Increased mechanical stress can collapse blood vessels, leading to hypoxia, thereby promoting more aggressive cancer phenotypes, and reducing drug delivery89,100–105.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [100]
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Metadata
- Authors
- Diop-Frimpong, B., Chauhan, V. P., Krane, S., Boucher, Y., & Jain, R. K.
- Affiliations
- Harvard University (US)
- Corresponding author
- Jain, Rakesh K.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-01-31
- Volume
- 108
- Issue
- 7
- Pages
- 2909-2914
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3041115
- OpenAlex
- W2098054841
- Cited by
- 733
- References
- 54
- Citations by year
- 2026: 38 · 2025: 51 · 2024: 63 · 2023: 55 · 2022: 65 · 2021: 77 · 2020: 84 · 2019: 47 · 2018: 43 · 2017: 51 · 2016: 40 · 2015: 40 · 2014: 20 · 2013: 28 · 2012: 24
- FWCI
- 10.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- U.S. Department of Defense (W81XWH1010016, W81XWH)
- AstraZeneca
- FibroGen
- Astellas Pharma
- National Cancer Institute (W81XWH-10-1-0016, R01 CA 85140, R01CA98706, R01CA085140, P01CA080124, R01CA098706, P01-CA-80124)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- losartan, collagen I synthesis, desmoplasia, tumor stroma, nanotherapeutics, drug penetration, oncolytic herpes simplex virus, pegylated liposomal doxorubicin, cancer-associated fibroblasts, breast cancer, pancreatic cancer, skin cancer, antifibrotic agents, tumor microenvironment
- MeSH terms
- Analysis of Variance, Animals, Breast Neoplasms, Carcinoma, Collagen, Dose-Response Relationship, Drug, Doxorubicin, Female, Humans, Immunohistochemistry, Pancreatic Neoplasms, Polyethylene Glycols, Skin Neoplasms, Polymerase Chain Reaction, Drug Delivery Systems, Mice, SCID, DNA Primers, Simplexvirus, Losartan, Nanotechnology, Fluorescence Recovery After Photobleaching, Oncolytic Virotherapy, Mice
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