title: Mechanochemical stimulation of MCF7 cells with rod-shaped Fe-Au Janus particles induces cell death through paradoxical hyperactivation of ERK.
abstract: Multifunctional nanoparticles that actively target-specific tissues are studied for cancer diagnosis and treatment. Magnetically and optically active particles are of particular interest because they enable multiple imaging modalities and physically modulated therapies, such as magnetic hyperthermia. Fe-Au nanorods are synthesized that have a long iron segment, coated with polyethylene glycol, and a short gold tip functionalized with heregulin (HRG), a known ligand of ErbB family of receptors. HRG-nanorods preferentially target MCF7 cells relative to MDA-MB-231 cells, as demonstrated in a novel microfluidics device. Targeting rates of these classical breast cancer cells correlate with their differential expression of ErbB2/3 receptors. HRG-nanorod binding stimulates the extracellular signal-regulated kinase 1/2 (ERK) phosphorylation in MCF7 cells. The increase in ERK phosphorylation is linked to "active zones," dynamic regions in the cell periphery, which exhibit higher rates of particle binding than the rest of the cell. Periodically stretching cells using magnetic tweezers further activates ERK, which leads to cell death in cells co-treated with B-Raf inhibitors, through ERK hyperactivation. Although to a lesser extent, cell death is also achieved through magnetic hyperthermia. These results demonstrate nanoscale targeting and localized mechanochemical treatment of specific cancer cell lines based on their receptor expression using multifunctional nanoparticles.
authors.affiliation: UCD Nanomedicine Centre, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Devrim
authors.initials: D
authors.lastname: Kilinc
authors.forename: Anna
authors.initials: A
authors.lastname: Lesniak
authors.forename: Suad A
authors.initials: SA
authors.lastname: Rashdan
authors.forename: Dhruv
authors.initials: D
authors.lastname: Gandhi
authors.forename: Agata
authors.initials: A
authors.lastname: Blasiak
authors.forename: Paul C
authors.initials: PC
authors.lastname: Fannin
authors.forename: Alex
authors.initials: A
authors.lastname: von Kriegsheim
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.forename: Gil U
authors.initials: GU
authors.lastname: Lee
mesh_terms: D016923:Cell Death / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006046:Gold / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods; D007211:Indoles / Q000494:pharmacology; D007501:Iron / Q000737:chemistry* / Q000494:pharmacology; D061986:MCF-7 Cells / Q000187:drug effects* / Q000378:metabolism; D060526:Magnetic Fields; D046210:Microfluidic Analytical Techniques; D058990:Molecular Targeted Therapy / Q000379:methods; D036103:Nanotechnology / Q000379:methods; D043942:Nanotubes / Q000737:chemistry*; D020890:Neuregulin-1 / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D010812:Physical Stimulation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D006046:Gold; D007211:Indoles; D007501:Iron; D020890:Neuregulin-1; D048493:Proto-Oncogene Proteins B-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D013449:Sulfonamides; D000077484:Vemurafenib; C508053:ERBB2 protein, human; C482119:BRAF protein, human
keywords: ErbB receptors; active targeting; cancer; heregulin; magnetic hyperthermia