title: Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles.
abstract: Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The effect and mechanism of 5-FU loaded EGF grafted HMSNs (EGF-HMSNs-5-FU) in overcoming acquired drug resistance in SW480/ADR cells were studied. The EGF-HMSNs were demonstrated to be specifically internalized in EGFR overexpressed SW480/ADR cells via a receptor-mediated endocytosis and can escape from endo-lysosomes. The EGF-HMSNs-5-FU exhibited much higher cytotoxicity on SW480/ADR cells than HMSNs-5-FU and free 5-FU while the plain HMSNs did not show significant cytotoxicity. The mechanism of EGF-HMSNs-5-FU in overcoming drug resistance in SW480/ADR cells could be attributed to the specific internalization of EGF-HMSNs-5-FU in EGFR overexpressed cells which can lead to high intracellular drug accumulation and cause cell death through S phase arrest.
authors.affiliation: Institute for Frontier Materials, Deakin University, Waurn Ponds, VIC 3216, Australia. lingxue.kong@deakin.edu.au.
authors.forename: Lijue
authors.initials: L
authors.lastname: Chen
authors.forename: Xiaodong
authors.initials: X
authors.lastname: She
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.forename: Sarah
authors.initials: S
authors.lastname: Shigdar
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.forename: Lingxue
authors.initials: L
authors.lastname: Kong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D001672:Biocompatible Materials / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000737:chemistry*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry*; D016062:Porosity; D060888:Real-Time Polymerase Chain Reaction; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D012822:Silicon Dioxide / Q000737:chemistry*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001672:Biocompatible Materials; D004337:Drug Carriers; D004815:Epidermal Growth Factor; D012822:Silicon Dioxide; D042943:Dihydrouracil Dehydrogenase (NADP); C512478:EGFR protein, human; D066246:ErbB Receptors; D005472:Fluorouracil