Denis Iza, El Bahhaj Fatima, Collette Floraine, Delatouche Régis, Gueugnon Fabien, Pouliquen Daniel, Pichavant Loic, Héroguez Valérie, Grégoire Marc, Bertrand Philippe, Blanquart Christophe
Inserm, UMR 892 , Nantes F-44000, France.
Biomacromolecules. 2014 Dec 8;15(12):4534-43. doi: 10.1021/bm501338r. Epub 2014 Nov 7.
In vivo histone deacetylase (HDAC) inhibition by vorinostat under clinically acceptable dosing is limited by its poor pharmacokinetics properties. A new type of nontoxic pH-responsive delivery system has been synthesized by ring-opening metathesis polymerization, allowing for the selective distribution of vorinostat in mesothelioma tumors in vivo and subsequent histone reacetylation. The delivery system is synthesized by generic click chemistry, possesses native stealth properties for passive tumor targeting, and does not need additional chemistry for cellular internalization. Although vorinostat alone at 50 mg/kg in mice showed no effect, our new delivery system with 2 mg/kg vorinostat promoted histone reacetylation in tumors without side effects, demonstrating that our strategy improves the activity of this HDAC inihibitor in vivo.
在临床可接受的给药剂量下，伏立诺他对体内组蛋白脱乙酰酶（HDAC）的抑制作用受到其不良药代动力学性质的限制。通过开环易位聚合反应合成了一种新型无毒pH响应递送系统，该系统可使伏立诺他在体内间皮瘤肿瘤中选择性分布，并随后实现组蛋白再乙酰化。该递送系统通过通用点击化学合成，具有天然的隐形特性用于被动肿瘤靶向，且细胞内化无需额外的化学反应。虽然单独给予小鼠50mg/kg伏立诺他没有效果，但我们含有2mg/kg伏立诺他的新型递送系统可促进肿瘤中的组蛋白再乙酰化且无副作用，这表明我们的策略提高了这种HDAC抑制剂在体内的活性。
