Design of pH responsive clickable prodrugs applied to histone deacetylase inhibitors: A new strategy for anticancer therapy

• Published in: European journal of pharmaceutics and biopharmaceutics Vol. 85; no. 3; pp. 862 - 872
• Main Authors: Delatouche, Régis, Denis, Iza, Grinda, Marion, Bahhaj, Fatima El, Baucher, Estelle, Collette, Floraine, Héroguez, Valérie, Grégoire, Marc, Blanquart, Christophe, Bertrand, Philippe
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-11-2013; Elsevier
• Subjects: Acetylation; Adenocarcinoma - drug therapy; Antineoplastic Agents - chemistry; Bioluminescence; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival; Chemical Sciences; Chemistry, Pharmaceutical - methods; Click chemistry; Click Chemistry - methods; Drug Design; Energy Transfer; Epigenesis, Genetic; Histone acetylation; Histone Deacetylase Inhibitors - chemistry; Histones - chemistry; Humans; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Kinetics; Luminescence; Lung Neoplasms - drug therapy; Mesothelioma - drug therapy; Neoplasms - drug therapy; pH response; Prodrug; Prodrugs - chemistry; Bioluminescence; Histone acetylation; pH response; Click chemistry; Prodrug; Cancer
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2013.03.006

The aim of this study was to develop clickable prodrugs bearing a tunable pH responsive linker designed for acidic pH-mediated release of histone deacetylase inhibitors. HDACi are an important class of molecules belonging to the epigenetic modulators used for innovative cancer strategies. The behavior of these prodrugs was determined by a bioluminescence resonance energy transfer assay in living tumor cells. This work demonstrated that this innovative type of clickable prodrugs entered cancer cells and showed restored anti proliferative properties attributed to the effective release of the HDAC inhibitors. A correlation between kinetic studies, dose responses, and biological activities was obtained, making such clickable prodrugs good candidates for new strategies in epigenetic-oriented anticancer therapies.