Cited by 215Nanoparticle-Based Drug DeliveryRNA Interference and Gene DeliveryBacterial Cancer Therapy

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Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors

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Miao, Lei, Liu, Qi, Lin, C. Michael, Luo, Cong, Wang, Yuhua, Liu, Lina, Yin, Weiyan, Hu, Shihao, Kim, William Y., Huang, Leaf·2017·Cancer Research

DOI 10.1158/0008-5472.can-16-0866PMC PMC5290135

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Abstract

The off-target distribution of anticancer nanoparticles to fibroblasts creates a barrier to the effective treatment of desmoplastic tumors. However, we hypothesized that this nanoparticle detriment might be exploited to target the expression of secreted cytotoxic proteins from tumor-associated fibroblasts (TAF) as an anticancer strategy. In addressing this hypothesis, plasmids encoding the secretable TNF-related factor sTRAIL were loaded into lipid-coated protamine DNA complexes and administered by infusion in a murine xenograft model of human desmoplastic bladder carcinoma. Three doses were sufficient to generate approximately 70% of TAFs as sTRAIL-producing cells. sTRAIL triggered apoptosis in tumor cell nests adjacent to TAFs. Furthermore, it reverted residual fibroblasts to a quiescent state due to insufficient activation, further compromising tumor growth and remodeling the microenvironment to favor second-wave nanotherapy. We confirmed the efficacy of this strategy in an orthotopic xenograft model of human pancreatic cancer, where the desmoplastic stroma is well known to be a major barrier to the delivery of therapeutic nanoparticles. Collectively, our results offer a proof of concept for the use of nanoparticles to modify TAFs as an effective strategy to treat desmoplastic cancers. Cancer Res; 77(3); 719–31. ©2016 AACR.

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Authors: Miao, L., Liu, Q., Lin, C. M., Luo, C., Wang, Y., Liu, L., Yin, W., Hu, S., Kim, W. Y., & Huang, L.
Affiliations: University of North Carolina at Chapel Hill (US)
Shenyang Pharmaceutical University (CN)
China Pharmaceutical University (CN)
Corresponding author: Huang, Leaf
ORCID: Miao, Lei
Liu, Qi
Lin, C. Michael
Luo, Cong
Wang, Yuhua
Liu, Lina
Yin, Weiyan
Hu, Shihao
Kim, William Y.
Huang, Leaf
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2017-01-31
Volume: 77
Issue: 3
Pages: 719-731
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-16-0866
PMC: PMC5290135
OpenAlex: W2555883270
Cited by: 215
References: 50
Citations by year: 2026: 13 · 2025: 16 · 2024: 16 · 2023: 16 · 2022: 26 · 2021: 29 · 2020: 31 · 2019: 31 · 2018: 21 · 2017: 16
FWCI: 9.26
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
UNC Libraries
Funders: NIH (CA149363, CA151652, and CA149387)
North Carolina Biotech Center Institutional (2005-IDG-1016)
Topics: Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
Keywords: cancer-associated fibroblasts, desmoplastic tumors, tumor microenvironment, lipid-coated nanoparticles, pancreatic cancer, nanoparticle delivery
MeSH terms: Cancer-Associated Fibroblasts, Animals, Urinary Bladder Neoplasms, Carcinoma, Transitional Cell, Flow Cytometry, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Neoplasms, Experimental, Pancreatic Neoplasms, Blotting, Western, Polymerase Chain Reaction, Apoptosis, Xenograft Model Antitumor Assays, NIH 3T3 Cells, Cell Line, Tumor, Mice, TNF-Related Apoptosis-Inducing Ligand, Nanoconjugates, Tumor Microenvironment

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Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors

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