European Journal of Medicinal Chemistry 2015-05-05

Histone deacetylase inhibitor-polymer conjugate nanoparticles for acid-responsive drug delivery.

Iza Denis, Fatima el Bahhaj, Floraine Collette, Régis Delatouche, Fabien Gueugnon, Daniel Pouliquen, Loic Pichavant, Valérie Héroguez, Marc Grégoire, Philippe Bertrand, Christophe Blanquart

Index: Eur. J. Med. Chem. 95 , 369-76, (2015)

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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. Copyright © 2015 Elsevier Masson SAS. All rights reserved.