title: Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors.
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.
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Lei
authors.initials: L
authors.lastname: Miao
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|UNC & NCSU Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Lin
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Luo
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Lina
authors.initials: L
authors.lastname: Liu
authors.affiliation: UNC & NCSU Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Yin
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
authors.forename: Shihao
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Leafh@email.unc.edu.|UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects*; D002295:Carcinoma, Transitional Cell / Q000473:pathology; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D041681:NIH 3T3 Cells; D058726:Nanoconjugates; D009374:Neoplasms, Experimental / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000473:pathology; D016133:Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*; D059016:Tumor Microenvironment / Q000187:drug effects*; D001749:Urinary Bladder Neoplasms / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D058726:Nanoconjugates; D053221:TNF-Related Apoptosis-Inducing Ligand