title: Synergism through combination of chemotherapy and oxidative stress-induced autophagy in A549 lung cancer cells using redox-responsive nanohybrids: a new strategy for cancer therapy.
abstract: A combination of various therapeutic approaches has emerged as a promising strategy for cancer treatment. A safe and competent nano-delivery system is thus in urgent demand to facilitate the simultaneous transport of various therapeutic agents to cancer cells and a tumor region to achieve synergistic effect. Gold nanoparticles (GNPs) and mesoporous silica nanoparticle (MSNs) were fabricated herein as potential candidates for drug delivery. Serving as gatekeepers, GNPs (5 nm in diameter) were attached onto the amino-functionalized MSNs (denoted as NMSNs) via a relatively weak gold-nitrogen bonding. The resulting nanohybrids (denoted as GCMSNs) were uptaken by cells, and the detachment of GNPs and subsequent intracellular drug release from NMSNs were achieved by competitive binding of intracellular glutathione to GNPs. In addition to the function of gatekeeping, GNPs also play another role as the oxidative stress elicitor. Our in vitro studies revealed that GCMSNs induced higher oxidative stress in lung cancer cells (A549) than in normal cells (3T3-L1). This growth inhibitory effect found in the cancer cells was likely induced by mitochondria dysfunction originated from the GCMSN-induced, oxidative stress-triggered mitochondria-mediated autophagy. The redox-responsive nanohybrids were further loaded with camptothecin and the intensified synergistic therapeutic effects were observed associated with combined chemotherapy and oxidative stress strategy. The results clearly demonstrate that such unique nanohybrids hold great promise for selective and effective cancer treatments.
authors.affiliation: Department of Chemistry, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu 30013, Taiwan; BioAnalytical Chemistry and Nanobiomedicine Laboratory, Department of Biochemical Science and Technology, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Lu
authors.affiliation: BioAnalytical Chemistry and Nanobiomedicine Laboratory, Department of Biochemical Science and Technology, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.
authors.forename: Ya-Ju
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: BioAnalytical Chemistry and Nanobiomedicine Laboratory, Department of Biochemical Science and Technology, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.
authors.forename: Nien-Chu
authors.initials: NC
authors.lastname: Fan
authors.affiliation: BioAnalytical Chemistry and Nanobiomedicine Laboratory, Department of Biochemical Science and Technology, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Department of Chemistry, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Nien-Chu
authors.initials: NC
authors.lastname: Lai
authors.affiliation: Department of Chemistry, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu 30013, Taiwan. Electronic address: cmyang@mx.nthu.edu.tw.
authors.forename: Chia-Min
authors.initials: CM
authors.lastname: Yang
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, No. 1, University Road, Puli, Nantou 54561, Taiwan. Electronic address: lw25@ncnu.edu.tw.
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Department of Chemistry, National Tsing Hua University, No. 101, Sec. 2, Kuang-Fu Road, Hsinchu 30013, Taiwan; BioAnalytical Chemistry and Nanobiomedicine Laboratory, Department of Biochemical Science and Technology, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan. Electronic address: jaho@ntu.edu.tw.
authors.forename: Ja-an Annie
authors.initials: JA
authors.lastname: Ho
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D016062:Porosity; D012822:Silicon Dioxide / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D008315:Malondialdehyde; D012822:Silicon Dioxide; D005978:Glutathione; D002166:Camptothecin
keywords: Autophagy; Chemotherapy; Glutathione-mediated intracellular release; Gold nanoparticles capping; Mesoporous silica nanohybrid; Oxidative stress strategy