title: Targeting a G-protein-coupled receptor overexpressed in endocrine tumors by magnetic nanoparticles to induce cell death.
abstract: Nanotherapy using targeted magnetic nanoparticles grafted with peptidic ligands of receptors overexpressed in cancers is a promising therapeutic strategy. However, nanoconjugation of peptides can dramatically affect their properties with respect to receptor recognition, mechanism of internalization, intracellular trafficking, and fate. Furthermore, investigations are needed to better understand the mechanism whereby application of an alternating magnetic field to cells containing targeted nanoparticles induces cell death. Here, we designed a nanoplatform (termed MG-IONP-DY647) composed of an iron oxide nanocrystal decorated with a ligand of a G-protein coupled receptor, the cholecystokinin-2 receptor (CCK2R) that is overexpressed in several malignant cancers. MG-IONP-DY647 did not stimulate inflammasome of Raw 264.7 macrophages. They recognized cells expressing CCK2R with a high specificity, subsequently internalized via a mechanism involving recruitment of β-arrestins, clathrin-coated pits, and dynamin and were directed to lysosomes. Binding and internalization of MG-IONP-DY647 were dependent on the density of the ligand at the nanoparticle surface and were slowed down relative to free ligand. Trafficking of CCK2R internalized with the nanoparticles was slightly modified relative to CCK2R internalized in response to free ligand. Application of an alternating magnetic field to cells containing MG-IONP-DY647 induced apoptosis and cell death through a lysosomal death pathway, demonstrating that cell death is triggered even though nanoparticles of low thermal power are internalized in minute amounts by the cells. Together with pioneer findings using iron oxide nanoparticles targeting tumoral cells expressing epidermal growth factor receptor, these data represent a solid basis for future studies aiming at establishing the proof-of-concept of nanotherapy of cancers using ligand-grafted magnetic nanoparticles specifically internalized via cell surface receptors.
authors.affiliation: EA 4552, Université de Toulouse 3 , Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Sanchez
authors.forename: Darine
authors.initials: D
authors.lastname: El Hajj Diab
authors.forename: Vincent
authors.initials: V
authors.lastname: Connord
authors.forename: Pascal
authors.initials: P
authors.lastname: Clerc
authors.forename: Etienne
authors.initials: E
authors.lastname: Meunier
authors.forename: Bernard
authors.initials: B
authors.lastname: Pipy
authors.forename: Bruno
authors.initials: B
authors.lastname: Payré
authors.forename: Reasmey P
authors.initials: RP
authors.lastname: Tan
authors.forename: Michel
authors.initials: M
authors.lastname: Gougeon
authors.forename: Julian
authors.initials: J
authors.lastname: Carrey
authors.forename: Véronique
authors.initials: V
authors.lastname: Gigoux
authors.forename: Daniel
authors.initials: D
authors.lastname: Fourmy
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D004701:Endocrine Gland Neoplasms / Q000378:metabolism* / Q000473:pathology; D005290:Ferric Compounds / Q000378:metabolism; D005755:Gastrins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008280:Magnetics; D051379:Mice; D053758:Nanoparticles; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D005290:Ferric Compounds; D005755:Gastrins; D043562:Receptors, G-Protein-Coupled; C000499:ferric oxide