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      • HARVEST
      • Electronic Theses and Dissertations
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      RGDSK-FUNCTIONALIZED HELICAL ROSETTE NANOTUBE INTERACTIONS WITH INTEGRIN αvβ3-EXPRESSING BIOLOGICAL MILIEUS

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      HOUSE-DISSERTATION-2016.pdf (689.0Mb)
      Date
      2016-07-26
      Author
      House, Nicole 1987-
      Type
      Thesis
      Degree Level
      Doctoral
      Metadata
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      Abstract
      The development of nanomaterials (NMs) for drug delivery vehicles is a rapidly growing field. One NM of interest are helical rosette nanotubes (RNT). Soluble, metal-free, and highly tunable RNTs have strong potential for targeted therapeutic applications. Recently RNTs have been functionalized with the RGDSK motif to target integrins — cell surface receptors with key roles in physiology and pathology. Integrin αvβ3, highly expressed in tumours, upon recognition of the RGD sequence can initiate apoptosis and attenuate angiogenesis and metastasis. This novel work presents an interconnected picture of how RGDSK-RNTs interact in three integrin αvβ3-expressing physiological and pathological milieus to assess their feasibility for therapeutic use. Specifically in regard to, RGDSK-RNT interactions in healthy, non-target tissue (lung), target tissue (melanoma tumour), and immune cells (dendritic cells). In an isolated perfused lung model, a real-time effects assessment on the non-target pulmonary vasculature was carried out. Results demonstrated that RGDSK-RNTs are acutely well tolerated in healthy blood vessels as only mild inflammation and minimal ROS production were observed. Increased endothelial [Ca2+]i and apoptosis were also noted and should be further investigated. Additionally, RGDSK-RNTs were able to translocate across both the endothelium and epithelium following pulmonary instillation. The direct effects of RGDSK-RNTs in a target tissue were assessed with a subcutaneous melanoma model to account for tumour microenvironment complexity. This preliminary study suggested, based on numerous endpoints, that RGDSK-RNTs could attenuate cell proliferation and modestly increase angiogenesis in melanoma tumours. Finally, as dendritic cells (DC) are found throughout the body and tumours the immunological potential of RGDSK-RNTs needed to be determined. As a starting point, the uptake and trafficking of RGDSK-RNTs was characterized. RGDSK-RNTs used, in part, receptor-mediated endocytosis followed by transport through the endosomal-lysosomal pathway. As such they could potentially stimulate antigen presentation. In all three milieus there is evidence indicating RNTs act as a scaffold for multimeric ligation of RGDSK peptides to integrins. Collectively, the results presented in this dissertation support further research into the potential therapeutic application of RGDSK-RNTs.
      Degree
      Doctor of Philosophy (Ph.D.)
      Department
      Toxicology Centre
      Program
      Toxicology
      Supervisor
      Singh, Baljit
      Committee
      Mutwiri, George; Fenniri, Hicham; Blakley, Barry; Janz, David; Kuebler, Wolfgang; Lessard, Carl
      Copyright Date
      July 2016
      URI
      http://hdl.handle.net/10388/7375
      Subject
      nanotechnology
      rosette nanotube
      RGD peptide
      self-assembly
      drug delivery
      melanoma
      isolated perfused lung
      dendritic cell
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