RGDSK-FUNCTIONALIZED HELICAL ROSETTE NANOTUBE INTERACTIONS WITH INTEGRIN αvβ3-EXPRESSING BIOLOGICAL MILIEUS
House, Nicole 1987-
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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.
DegreeDoctor of Philosophy (Ph.D.)
CommitteeMutwiri, George; Fenniri, Hicham; Blakley, Barry; Janz, David; Kuebler, Wolfgang; Lessard, Carl
Copyright DateJuly 2016
isolated perfused lung