title: Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor.
abstract: Chemotherapy for pancreatic cancer is hampered by the tumor's physio-pathological complexity. Here we show a targeted nanomedicine using a new ligand, the CKAAKN peptide, which had been identified by phage display, as an efficient homing device within the pancreatic pathological microenvironment. Taking advantage of the squalenoylation platform, the CKAAKN peptide was conjugated to squalene (SQCKAAKN) and then co-nanoprecipitated with the squalenoyl prodrug of gemcitabine (SQdFdC) giving near monodisperse nanoparticles (NPs) for safe intravenous injection. By interacting with a novel target pathway, the Wnt-2, the CKAAKN functionalization enabled nanoparticles: (i) to specifically interact with both tumor cells and angiogenic vessels and (ii) to simultaneously promote pericyte coverage, thus leading to the normalization of the vasculature likely improving the tumor accessibility for therapy. All together, this approach represents a unique targeted nanoparticle design with remarkable selectivity towards pancreatic cancer and multiple mechanisms of action.
authors.affiliation: Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France; CNRS UMR 8612, Institut Galien Paris-Sud, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France; Department of Drug Science and Technology, University of Torino, 9 Via Pietro Giuria, 10125 Torino, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Valetti
authors.affiliation: Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, Strada Provinciale 142, Km. 3.95, 10060 Candiolo (Torino), Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Maione
authors.affiliation: Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France; CNRS UMR 8612, Institut Galien Paris-Sud, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Simona
authors.initials: S
authors.lastname: Mura
authors.affiliation: Department of Drug Science and Technology, University of Torino, 9 Via Pietro Giuria, 10125 Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Stella
authors.affiliation: Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France; CNRS UMR 8612, Institut Galien Paris-Sud, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaële
authors.affiliation: Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France; CNRS UMR 8612, Institut Galien Paris-Sud, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Noiray
authors.affiliation: Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France; CNRS UMR 8612, Institut Galien Paris-Sud, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Vergnaud
authors.affiliation: Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France; CNRS UMR 8612, Institut Galien Paris-Sud, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Vauthier
authors.affiliation: Department of Drug Science and Technology, University of Torino, 9 Via Pietro Giuria, 10125 Torino, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Cattel
authors.affiliation: Department of Drug Science and Technology, University of Torino, 9 Via Pietro Giuria, 10125 Torino, Italy; Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, Strada Provinciale 142, Km. 3.95, 10060 Candiolo (Torino), Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Giraudo
authors.affiliation: Université Paris-Sud, Faculté de Pharmacie, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France; CNRS UMR 8612, Institut Galien Paris-Sud, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France. Electronic address: patrick.couvreur@u-psud.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000627:therapeutic use; D013185:Squalene / Q000737:chemistry* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D010455:Peptides; D011355:Prodrugs; D003841:Deoxycytidine; D013185:Squalene; D000093542:Gemcitabine
keywords: Gemcitabine; Pancreatic cancer; Squalene nanoparticles; Targeted nanoparticles; Tumor-targeting peptide