title: Gelatinases-stimuli nanoparticles encapsulating 5-fluorouridine and 5-aza-2'-deoxycytidine enhance the sensitivity of gastric cancer cells to chemical therapeutics.
abstract: Aberrant methylation of the transcription factor AP-2 epsilon (TFAP2E) has been attributed to 5-fluorouridine (5-FU) sensitivity. 5-Aza-2'-deoxycytidine (DAC), an epigenetic drug that inhibits DNA methylation, is able to cause reactive expression of TFAP2E by demethylating activity. This property might be useful in enhancing the sensitivity of cancer cells to 5-FU. However, the effect of DAC is transient because of its instability. Here, we report the use of intelligent gelatinases-stimuli nanoparticles (NPs) to coencapsulate and deliver DAC and 5-FU to gastric cancer (GC) cells. The results showed that NPs encapsulating DAC, 5-FU, or both could be effectively internalized by GC cells. Furthermore, we found that the NPs enhanced the stability of DAC, resulting in improved re-expression of TFAP2E. Thus, the incorporation of DAC into NPs significantly enhanced the sensitivity of GC cells to 5-FU by inhibiting cell growth rate and inducing cell apoptosis. In conclusion, the results of this study clearly demonstrated that the gelatinases-stimuli NPs are an efficient means to simultaneously deliver epigenetic and chemotherapeutic drugs that may effectively inhibit cancer cell proliferation.
authors.affiliation: Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 321 Zhongshan Rd, Nanjing 210008, China; Department of Oncology, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China.
authors.forename: Feng-lei
authors.initials: FL
authors.lastname: Wu
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Rd, Nanjing 210008, China.
authors.forename: Ru-Tian
authors.initials: RT
authors.lastname: Li
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Rd, Nanjing 210008, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
authors.forename: Guo-Feng
authors.initials: GF
authors.lastname: Yue
authors.affiliation: Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 321 Zhongshan Rd, Nanjing 210008, China.
authors.forename: Hui-yu
authors.initials: HY
authors.lastname: Wang
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Rd, Nanjing 210008, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Rd, Nanjing 210008, China; Department of Oncology, The People' Hospital of Ma Anshan, Ma Anshan City 243000, Anhui, China.
authors.forename: Fang-bo
authors.initials: FB
authors.lastname: Cui
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Rd, Nanjing 210008, China.
authors.forename: Pu-yuan
authors.initials: PY
authors.lastname: Wu
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Rd, Nanjing 210008, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Rd, Nanjing 210008, China.
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Yu
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Rd, Nanjing 210008, China.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Qian
authors.affiliation: Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 321 Zhongshan Rd, Nanjing 210008, China. Electronic address: baoruiliu@nju.edu.cn.
authors.forename: Bao-Rui
authors.initials: BR
authors.lastname: Liu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D004789:Enzyme Activation; D044127:Epigenesis, Genetic / Q000187:drug effects; D005472:Fluorouracil / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D053758:Nanoparticles; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism
chemical_list: C493680:TFAP2E protein, human; D050656:Transcription Factor AP-2; D000077209:Decitabine; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D001374:Azacitidine; D005472:Fluorouracil
keywords: Drug delivery; Epigenetic drugs; Hypermethylation; Nanoparticles; TFAP2E