title: High-order TRAIL oligomer formation in TRAIL-coated lipid nanoparticles enhances DR5 cross-linking and increases antitumour effect against colon cancer.
abstract: During the last years, a great effort has been invested into developing new TRAIL formulations with increased bioactivity, trying to overcome the resistance to conventional soluble TRAIL (sTRAIL) exhibited by many primary tumours. In our group, we have generated artificial lipid nanoparticles decorated with sTRAIL (LUV-TRAIL), emulating the physiological TRAIL-containing exosomes by which T-cells release TRAIL upon activation. We already demonstrated that LUV-TRAIL has greater cytotoxicity against both chemoresistant haematologic tumour cells and epithelial carcinoma cells compared to a form of sTRAIL similar to that used in clinical trials. In this study we have tested LUV-TRAIL in several human colon cancer cell lines with different sensitivity to sTRAIL. LUV-TRAIL significantly improved sTRAIL cytotoxicity in all colon cancer cell lines tested. Trying to ascertain the molecular mechanism by which LUV-TRAIL exhibited improved cytotoxicity, we demonstrated that TRAIL-coated lipid nanoparticles were able to activate DR5 more efficiently than sTRAIL, and this relied on LUV-TRAIL ability to promote DR5 clustering on the cell surface. Moreover, we show that TRAIL molecules are arranged in higher order oligomers only in LUV-TRAIL, which may explain their enhanced DR5 clustering ability. Finally, LUV-TRAIL showed significantly better antitumour activity than sTRAIL in an in vivo model using HCT-116 xenograft tumours in nude mice, validating its potential clinical application.
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain; Instituto de Investigación Sanitaria de Aragón (ISS), Spain. Electronic address: diego_demiguel@hotmail.com.
authors.forename: Diego
authors.initials: D
authors.lastname: De Miguel
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain; Instituto de Investigación Sanitaria de Aragón (ISS), Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gallego-Lleyda
authors.affiliation: Instituto de Investigación Sanitaria de Aragón (ISS), Spain; Grupo de Mecánica Estructural y Modelado de Materiales (GEMM), Instituto de Investigación en Ingeniería de Aragón, (I3A), Spain; Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Ayuso
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Pejenaute-Ochoa
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Vidal
authors.initials: V
authors.lastname: Jarauta
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain; Instituto de Investigación Sanitaria de Aragón (ISS), Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Marzo
authors.affiliation: Instituto de Investigación Sanitaria de Aragón (ISS), Spain; Grupo de Mecánica Estructural y Modelado de Materiales (GEMM), Instituto de Investigación en Ingeniería de Aragón, (I3A), Spain; Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Spain.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Fernández
authors.affiliation: Instituto de Investigación Sanitaria de Aragón (ISS), Spain; Grupo de Mecánica Estructural y Modelado de Materiales (GEMM), Instituto de Investigación en Ingeniería de Aragón, (I3A), Spain; Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Ochoa
authors.affiliation: Departamento de Anatomía e Histología Humanas, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Conde
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain; Instituto de Investigación Sanitaria de Aragón (ISS), Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Anel
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain; Instituto de Investigación Sanitaria de Aragón (ISS), Spain; Instituto de Nanociencia de Aragón, Zaragoza, Spain. Electronic address: lumartin@unizar.es.
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez-Lostao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003432:Cross-Linking Reagents / Q000008:administration & dosage* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004339:Drug Compounding; D019008:Drug Resistance, Neoplasm; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008055:Lipids / Q000737:chemistry*; D008297:Male; D008819:Mice, Nude; D053758:Nanoparticles; D011487:Protein Conformation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000737:chemistry; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D008055:Lipids; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D051028:bcl-2-Associated X Protein
keywords: Colorectal cancer; DR5 cross-linking; Immunotherapy; Lipid nanoparticles; TRAIL