title: Histone deacetylase inhibitor-polymer conjugate nanoparticles for acid-responsive drug delivery.
abstract: We report the synthesis of acid-responsive polymeric nanoparticles (NPs) consisting of a polymer-histone deacetylase inhibitor conjugate. An innovative aspect of this drug delivery particle lies in the NP conjugation of a histone deacetylase (HDAC) inhibitor, CI-994 (Tacedinaline), introduced with a clickable acid-responsive prodrug during monomer synthesis, prior to polymerization. Another novelty lies in the selected norbornene (NB)-polyethylene oxide (PEO) macromonomer allowing standardization of the polymerization process by Ring-Opening Metathesis Polymerization (ROMP) and functionalization through azide-alkyne click chemistry. Herein we demonstrate that the synthesized polymer gave 300 nm core-shell spherical nanoparticles with low dispersity (0.04), high water dispersability thanks to the PEO shell and well controlled HDAC inhibitor prodrug loading. Bioluminescence Resonance Energy Transfer (BRET) assay in living cells and viability experiments demonstrated efficient cellular internalization without additional chemistry, drug release inside cells with restoration of the HDAC inhibition and induction of apoptosis. Such NPs should minimize drug release in vivo during blood circulation and trigger intracellular delivery after endocytosis, holding promises for improved efficacy of this class of epigenetic inhibitors. This standardized synthesis paves the way for multifunctional nanoparticles synthesis.
authors.affiliation: Inserm, U892, Nantes F-44000, France; CNRS, UMR 6299, Nantes F-44000, France; University of Nantes, Nantes F-44000, France.
authors.forename: Iza
authors.initials: I
authors.lastname: Denis
authors.affiliation: Institut de Chimie des Milieux et Matériaux de Poitiers, CNRS, UMR 7285, Poitiers. 4, Rue Michel Brunet, TSA 51106, B27 86073 Poitiers Cedex 9, France.
authors.forename: Fatima
authors.initials: F
authors.lastname: el Bahhaj
authors.affiliation: Laboratoire de Chimie des Polymères Organiques, CNRS, UMR 5629, Bordeaux, 16 Avenue Pey-Berland, F-33607 Pessac, France.
authors.forename: Floraine
authors.initials: F
authors.lastname: Collette
authors.affiliation: Institut de Chimie des Milieux et Matériaux de Poitiers, CNRS, UMR 7285, Poitiers. 4, Rue Michel Brunet, TSA 51106, B27 86073 Poitiers Cedex 9, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Delatouche
authors.affiliation: Inserm, U892, Nantes F-44000, France; CNRS, UMR 6299, Nantes F-44000, France; University of Nantes, Nantes F-44000, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Gueugnon
authors.affiliation: Inserm, U892, Nantes F-44000, France; CNRS, UMR 6299, Nantes F-44000, France; University of Nantes, Nantes F-44000, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pouliquen
authors.affiliation: Laboratoire de Chimie des Polymères Organiques, CNRS, UMR 5629, Bordeaux, 16 Avenue Pey-Berland, F-33607 Pessac, France.
authors.forename: Loic
authors.initials: L
authors.lastname: Pichavant
authors.affiliation: Laboratoire de Chimie des Polymères Organiques, CNRS, UMR 5629, Bordeaux, 16 Avenue Pey-Berland, F-33607 Pessac, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Héroguez
authors.affiliation: Inserm, U892, Nantes F-44000, France; CNRS, UMR 6299, Nantes F-44000, France; University of Nantes, Nantes F-44000, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Grégoire
authors.affiliation: Institut de Chimie des Milieux et Matériaux de Poitiers, CNRS, UMR 7285, Poitiers. 4, Rue Michel Brunet, TSA 51106, B27 86073 Poitiers Cedex 9, France. Electronic address: philippe.bertrand@univ-poitiers.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertrand
authors.affiliation: Inserm, U892, Nantes F-44000, France; CNRS, UMR 6299, Nantes F-44000, France; University of Nantes, Nantes F-44000, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanquart
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry* / Q000633:toxicity; D065546:Drug Liberation; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053758:Nanoparticles; D010316:Particle Size; D010655:Phenylenediamines / Q000737:chemistry* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*; D058105:Polymerization
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004337:Drug Carriers; D056572:Histone Deacetylase Inhibitors; D010655:Phenylenediamines; D011092:Polyethylene Glycols; C081895:tacedinaline
keywords: Controlled release; Drug delivery; Epigenetic inhibitor; Polymeric nanoparticle; Stimuli-responsive