title: Uptake and fate of surface modified silica nanoparticles in head and neck squamous cell carcinoma.
abstract: BACKGROUND
  Head and neck squamous cell carcinoma (HNSCC) is currently the eighth leading cause of cancer death worldwide. The often severe side effects, functional impairments and unfavorable cosmetic outcome of conventional therapies for HNSCC have prompted the quest for novel treatment strategies, including the evaluation of nanotechnology to improve e.g. drug delivery and cancer imaging. Although silica nanoparticles hold great promise for biomedical applications, they have not yet been investigated in the context of HNSCC. In the present in-vitro study we thus analyzed the cytotoxicity, uptake and intracellular fate of 200-300 nm core-shell silica nanoparticles encapsulating fluorescent dye tris(bipyridine)ruthenium(II) dichloride with hydroxyl-, aminopropyl- or PEGylated surface modifications (Ru@SiO2-OH, Ru@SiO2-NH2, Ru@SiO2-PEG) in the human HNSCC cell line UMB-SCC 745.
  
  
  RESULTS
  We found that at concentrations of 0.125 mg/ml, none of the nanoparticles used had a statistically significant effect on proliferation rates of UMB-SCC 745. Confocal and transmission electron microscopy showed an intracellular appearance of Ru@SiO2-OH and Ru@SiO2-NH2 within 30 min. They were internalized both as single nanoparticles (presumably via clathrin-coated pits) or in clusters and always localized to cytoplasmic membrane-bounded vesicles. Immunocytochemical co-localization studies indicated that only a fraction of these nanoparticles were transferred to early endosomes, while the majority accumulated in large organelles. Ru@SiO2-OH and Ru@SiO2-NH2 nanoparticles had never been observed to traffic to the lysosomal compartment and were rather propagated at cell division. Intracellular persistence of Ru@SiO2-OH and Ru@SiO2-NH2 was thus traceable over 5 cell passages, but did not result in apparent changes in cell morphology and vitality. In contrast to Ru@SiO2-OH and Ru@SiO2-NH2 uptake of Ru@SiO2-PEG was minimal even after 24 h.
  
  
  CONCLUSIONS
  Our study is the first to provide evidence that silica-based nanoparticles may serve as useful tools for the development of novel treatment options in HNSCC. Their long intracellular persistence could be of advantage for e.g. chronic therapeutic modalities. However, their complex endocytotic pathways require further investigations.
authors.affiliation: Institute of Anatomy, University of Zürich, and Clinic for Cranio-Maxillofacial Surgery, University Hospital of Zürich, Winterthurerstr, 190, 8057 Zürich, Switzerland. emina.besicgyenge@uzh.ch
authors.forename: Emina
authors.initials: E
authors.lastname: Besic Gyenge
authors.forename: Xenia
authors.initials: X
authors.lastname: Darphin
authors.forename: Amina
authors.initials: A
authors.lastname: Wirth
authors.forename: Uwe
authors.initials: U
authors.lastname: Pieles
authors.forename: Heinrich
authors.initials: H
authors.lastname: Walt
authors.forename: Marius
authors.initials: M
authors.lastname: Bredell
authors.forename: Caroline
authors.initials: C
authors.lastname: Maake
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes; D005456:Fluorescent Dyes / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D053758:Nanoparticles; D012822:Silicon Dioxide / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013499:Surface Properties; D017975:Ruthenium Compounds
chemical_list: D015082:2,2'-Dipyridyl; D056831:Coordination Complexes; D005456:Fluorescent Dyes; D012822:Silicon Dioxide; C547232:tris(2,2-bipyridine)-ruthenium(II); D017975:Ruthenium Compounds