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Oncotarget. 2017 Sep 26;8(70):114495-114505. doi: 10.18632/oncotarget.21274. eCollection 2017 Dec 29.

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.

Author information

1
Department of Oncology, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 221002, China.
2
Deparment of Oncology, School of Medicine, Jiangsu University, Zhengjiang, Jiangsu, 212013, China.
3
Department of General Surgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, 223000, China.
4
Center of Research Laboratory, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, 222000, China.
5
The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, 210008, China.

Abstract

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.

KEYWORDS:

TFAP2E; drug delivery; epigenetic drugs; hypermethylation; nanoparticles

Conflict of interest statement

CONFLICTS OF INTEREST The authors have no competing interests to declare.

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