Denis Iza, el Bahhaj Fatima, Collette Floraine, Delatouche Régis, Gueugnon Fabien, Pouliquen Daniel, Pichavant Loic, Héroguez Valérie, Grégoire Marc, Bertrand Philippe, Blanquart Christophe
Inserm, U892, Nantes F-44000, France; CNRS, UMR 6299, Nantes F-44000, France; University of Nantes, Nantes F-44000, France.
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.
Eur J Med Chem. 2015 May 5;95:369-76. doi: 10.1016/j.ejmech.2015.03.037. Epub 2015 Mar 18.
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.
我们报道了由聚合物-组蛋白脱乙酰酶抑制剂缀合物组成的酸响应性聚合物纳米颗粒（NPs）的合成。这种药物递送颗粒的一个创新之处在于，在聚合之前的单体合成过程中，通过可点击的酸响应性前药引入了组蛋白脱乙酰酶（HDAC）抑制剂CI-994（他西那林）与NP的缀合。另一个新颖之处在于所选的降冰片烯（NB）-聚环氧乙烷（PEO）大分子单体，它允许通过开环易位聚合（ROMP）实现聚合过程的标准化，并通过叠氮化物-炔烃点击化学进行功能化。在此，我们证明合成的聚合物产生了300 nm的核壳球形纳米颗粒，具有低分散性（0.04），由于PEO壳而具有高水分散性，并且HDAC抑制剂前药负载得到良好控制。活细胞中的生物发光共振能量转移（BRET）测定和活力实验表明，无需额外的化学处理即可实现有效的细胞内化，细胞内药物释放并恢复HDAC抑制作用并诱导细胞凋亡。此类纳米颗粒应能在血液循环过程中最大限度地减少体内药物释放，并在胞吞作用后触发细胞内递送，有望提高这类表观遗传抑制剂的疗效。这种标准化合成方法为多功能纳米颗粒的合成铺平了道路。
