title: Conatumumab (AMG 655) coated nanoparticles for targeted pro-apoptotic drug delivery.
abstract: Colloidal nanoparticle drug delivery systems have attracted much interest for their ability to enable effective formulation and delivery of therapeutic agents. The selective delivery of these nanoparticles to the disease site can be enhanced by coating the surface of the nanoparticles with targeting moieties, such as antibodies. In this current work, we demonstrate that antibodies on the surface of the particles can also elicit key biological effects. Specifically, we demonstrate the induction of apoptosis in colorectal HCT116 cancer cells using PLGA nanoparticles coated with Conatumumab (AMG 655) death receptor 5-specific antibodies (DR5-NP). We show that DR5-NP preferentially target DR5-expressing cells and present a sufficient density of antibody paratopes to induce apoptosis via DR5, unlike free AMG 655 or non-targeted control nanoparticles. We also demonstrate that DR5-targeted nanoparticles encapsulating the cytotoxic drug camptothecin are effectively targeted to the tumour cells, thereby producing enhanced cytotoxic effects through simultaneous drug delivery and apoptosis induction. These results demonstrate that antibodies on nanoparticulate surfaces can be exploited for dual modes of action to enhance the therapeutic utility of the modality.
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Francois
authors.initials: F
authors.lastname: Fay
authors.forename: Kirsty M
authors.initials: KM
authors.lastname: McLaughlin
authors.forename: Donna M
authors.initials: DM
authors.lastname: Small
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scott
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006801:Humans; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D053758:Nanoparticles
chemical_list: D000911:Antibodies, Monoclonal; C554537:conatumumab