title: Efficient drug delivery and induction of apoptosis in colorectal tumors using a death receptor 5-targeted nanomedicine.
abstract: Death Receptor 5 (DR5) is a pro-apoptotic cell-surface receptor that is a potential therapeutic target in cancer. Despite the potency of DR5-targeting agents in preclinical models, the translation of these effects into the clinic remains disappointing. Herein, we report an alternative approach to exploiting DR5 tumor expression using antibody-targeted, chemotherapy-loaded nanoparticles. We describe the development of an optimized polymer-based nanotherapeutic incorporating both a functionalized polyethylene glycol (PEG) layer and targeting antibodies to limit premature phagocytic clearance whilst enabling targeting of DR5-expressing tumor cells. Using the HCT116 colorectal cancer model, we show that following binding to DR5, the nanoparticles activate caspase 8, enhancing the anti-tumor activity of the camptothecin payload both in vitro and in vivo. Importantly, the combination of nanoparticle-induced DR5 clustering with camptothecin delivery overcomes resistance to DR5-induced apoptosis caused by loss of BAX or overexpression of anti-apoptotic FLIP. This novel approach may improve the clinical activity of DR5-targeted therapeutics while increasing tumor-specific delivery of systemically toxic chemotherapeutics.
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, UK; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schmid
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, UK; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK; Current address: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Fay
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, UK.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Small
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, UK.
authors.forename: Jakub
authors.initials: J
authors.lastname: Jaworski
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Riley
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Tegazzini
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: Fenning
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, UK.
authors.forename: David S
authors.initials: DS
authors.lastname: Jones
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, UK; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK. Electronic address: c.scott@qub.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scott
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D002166:Camptothecin / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D050997:Nanomedicine; D053758:Nanoparticles / Q000008:administration & dosage*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D002166:Camptothecin