Efficacy of decitabine-loaded gelatinases-stimuli nanoparticles in overcoming cancer drug resistance is mediated via its enhanced demethylating activity to transcription factor AP-2 epsilon
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Yi-Dong Hong1,2,*, Jian Zhang3,*, Ming Zhuang1,*, Wei Li4, Puy-Uan Wu5, Ru-Tian Li5, Nan Hu1, Bao-Xiang Bian1, Zi-Yan Song1 and Feng-Lei Wu1
1Department of Oncology, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 221002, China
2Deparment of Oncology, School of Medicine, Jiangsu University, Zhengjiang, Jiangsu, 212013, China
3Department of General Surgery, Huai'an First People's Hospital, Nanjing Medical University, Huai’an, Jiangsu, 223000, China
4Center of Research Laboratory, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 222000, China
5The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, 210008, China
Feng-Lei Wu, email: [email protected]
Keywords: TFAP2E, hypermethylation, epigenetic drugs, nanoparticles, drug delivery
Received: May 27, 2017 Accepted: September 08, 2017 Published: September 26, 2017
Hypermethylation of the transcription factor AP-2 epsilon (TFAP2E) gene affects 5-fluorouridine (5-FU) resistance in gastric cancer (GC) patients. The epigenetic inhibitor 5-Aza-2’-deoxycytidine (DAC), which reverses DNA methylation by targeting DNA methyltransferases (DNMTs), has potential to sensitize GC to 5-FU. Nevertheless, DNA demethylation only DAC transiently occurs since DAC is unstable in aqueous solutions, which limits its potential. Here we developed intelligent nanoparticles (NPs) comprising gelatinase with polyethylene glycol (PEG) and poly-ε-caprolactone) (PCL) to specifically deliver DAC (DAC-TNPs) to tumors. DAC-carrying PEG-PCL NPs (DAC-NPs) lacking gelatinase features served as controls. 72 hours after administration of DAC-TNPs or DAC-NPs, 5-FU was sequentially applied to GC cells and human GC xenografts in nude mice. Both in vitro and in vivo evaluations demonstrated that the combination treatment of DAC-TNPs and 5-FU greatly improved tumor suppression in GC cells and mouse xenograft models with hypermethylation TFAP2E (MKN45 cells). We thus propose that the sequential administration of DAC-TNPs and 5-FU could be significant in the development of novel targeted therapies.
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