Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 95, Issue -, Pages 369-376Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.03.037
Keywords
Polymeric nanoparticle; Epigenetic inhibitor; Drug delivery; Controlled release; Stimuli-responsive
Categories
Funding
- Agence Nationale de la Recherche (ANR) [ANR-08-PCVI-030]
- Region Poitou-Charentes for FEB grant
- Centre National de la Recherche Scientifique (CNRS)
- Ligue National Contre la Cancer for ID grant
- Ligue Contre le Cancer: committees of Morbihan, Sarthe, Vendee et Loire-Atlantique, Poitou-Charentes [ARSMESO44]
- Nantes University Hospital
- COST action [TD0905]
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We report the synthesis of acid responsive polymeric nanoparticles (NPs) consisting of a polymerhistone 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-allcyne 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. (C) 2015 Elsevier Masson SAS. All rights reserved.
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