Nanoparticle-Mediated Target Delivery of TRAIL as Gene Therapy for Glioblastoma.
Human tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is an attractive cancer therapeutic because of its ability to induce apoptosis in tumor cells while having a negligible effect on normal cells. However, the short serum half-life of TRAIL and lack of efficient in vivo administration approaches have largely hindered its clinical use. Using nanoparticles (NPs) as carriers in gene therapy is considered as an alternative approach to increase TRAIL delivery to tumors as transfected cells would be induced to secrete TRAIL into the tumor microenvironment. To enable effective delivery of plasmid DNA encoding TRAIL into glioblastoma (GBM), we developed a targeted iron oxide NP coated with chitosan-polyethylene glycol-polyethyleneimine copolymer and chlorotoxin (CTX) and evaluated its effect in delivering TRAIL in vitro and in vivo. NP-TRAIL successfully delivers TRAIL into human T98G GBM cells and induces secretion of 40 pg mL(-1) of TRAIL in vitro. Transfected cells show threefold increased apoptosis as compared to the control DNA bound NPs. Systemic administration of NP-TRAIL-CTX to mice bearing T98G-derived flank xenografts results in near-zero tumor growth and induces apoptosis in tumor tissue. Our results suggest that NP-TRAIL-CTX can potentially serve as a targeted anticancer therapeutic for more efficient TRAIL delivery to GBM.
Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.
Kui
K
Wang
Department of Neurological Surgery, University of Washington, Seattle, WA, 98195, USA.
Forrest M
FM
Kievit
Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.
Mike
M
Jeon
Department of Neurological Surgery, University of Washington, Seattle, WA, 98195, USA.
John R
JR
Silber
Department of Neurological Surgery, University of Washington, Seattle, WA, 98195, USA.
Richard G
RG
Ellenbogen
Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.|Department of Neurological Surgery, University of Washington, Seattle, WA, 98195, USA.
Miqin
M
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D048271:Chitosan / Q000008:administration & dosage; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005909:Glioblastoma / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053758:Nanoparticles / Q000008:administration & dosage*; D010957:Plasmids / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011094:Polyethyleneimine / Q000008:administration & dosage; D012604:Scorpion Venoms / Q000008:administration & dosage; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*; D014162:Transfection / Q000379:methods; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D012604:Scorpion Venoms; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C091539:Chlorotoxin; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D048271:Chitosan
TRAIL; apoptosis; gene therapy; glioblastoma; transfection