title: Histone Deacetylase Inhibitors Delivery using Nanoparticles with Intrinsic Passive Tumor Targeting Properties for Tumor Therapy.
abstract: Fast clearance, metabolism and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo model of cancers. Specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. In this work, we describe a simple and flexible polymeric nanoparticle platform highly targeting the tumor in vivo and triggering impressive tumor weight reduction when functionalized with HDACi. Our nanoparticles were produced by Ring-Opening Metathesis Polymerization of azido-polyethylene oxide-norbornene macromonomers and functionalized using click chemistry. Using an orthotopic model of peritoneal invasive cancer, a highly selective accumulation of the particles in the tumor was obtained. A combination of epigenetic drugs involving a pH-responsive histone deacetylase inhibitor (HDACi) polymer conjugated to these particles gave 80% reduction of tumor weight without toxicity whereas the free HDACi has no effect. Our work demonstrates that the use of a nanovector with theranostic properties leads to an optimized delivery of potent HDACi in tumor and then, to an improvement of their anti-tumor properties in vivo.
authors.affiliation: 1. Institut de Chimie des Milieux et Matériaux de Poitiers, University of Poitiers, CNRS UMR 7285, 4 rue Michel Brunet TSA 51106, B27, Poitiers. F-86073 Poitiers cedex 9, France.
authors.forename: Fatima
authors.initials: F
authors.lastname: El Bahhaj
authors.affiliation: 2. Centre de Recherche contre le Cancer Nantes et Angers, University of Nantes, CNRS UMR 6299, Inserm, U892, 8 quai Moncousu, F-44000 Nantes cedex 1, France.
authors.forename: Iza
authors.initials: I
authors.lastname: Denis
authors.affiliation: 3. Laboratoire de Chimie des Polymères Organiques, University of Bordeaux, CNRS UMR 5629, 16 Avenue Pey-Berland, F-33607 Pessac, France.
authors.forename: Loic
authors.initials: L
authors.lastname: Pichavant
authors.affiliation: 1. Institut de Chimie des Milieux et Matériaux de Poitiers, University of Poitiers, CNRS UMR 7285, 4 rue Michel Brunet TSA 51106, B27, Poitiers. F-86073 Poitiers cedex 9, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Delatouche
authors.affiliation: 3. Laboratoire de Chimie des Polymères Organiques, University of Bordeaux, CNRS UMR 5629, 16 Avenue Pey-Berland, F-33607 Pessac, France.
authors.forename: Floraine
authors.initials: F
authors.lastname: Collette
authors.affiliation: 2. Centre de Recherche contre le Cancer Nantes et Angers, University of Nantes, CNRS UMR 6299, Inserm, U892, 8 quai Moncousu, F-44000 Nantes cedex 1, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Linot
authors.affiliation: 2. Centre de Recherche contre le Cancer Nantes et Angers, University of Nantes, CNRS UMR 6299, Inserm, U892, 8 quai Moncousu, F-44000 Nantes cedex 1, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pouliquen
authors.affiliation: 2. Centre de Recherche contre le Cancer Nantes et Angers, University of Nantes, CNRS UMR 6299, Inserm, U892, 8 quai Moncousu, F-44000 Nantes cedex 1, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Grégoire
authors.affiliation: 3. Laboratoire de Chimie des Polymères Organiques, University of Bordeaux, CNRS UMR 5629, 16 Avenue Pey-Berland, F-33607 Pessac, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Héroguez
authors.affiliation: 2. Centre de Recherche contre le Cancer Nantes et Angers, University of Nantes, CNRS UMR 6299, Inserm, U892, 8 quai Moncousu, F-44000 Nantes cedex 1, France; 4. Réseau Epigénétique du Cancéropôle Grand Ouest.
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanquart
authors.affiliation: 1. Institut de Chimie des Milieux et Matériaux de Poitiers, University of Poitiers, CNRS UMR 7285, 4 rue Michel Brunet TSA 51106, B27, Poitiers. F-86073 Poitiers cedex 9, France; 4. Réseau Epigénétique du Cancéropôle Grand Ouest.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertrand
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000493:pharmacokinetics*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008654:Mesothelioma / Q000188:drug therapy; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage*; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D004337:Drug Carriers; D056572:Histone Deacetylase Inhibitors
keywords: HDAC; cancer; epigenetic; mesothelioma.; peritoneal; polymeric nanoparticle; theranostics