A novel, lipid-based platform nanotechnology has been designed to overcome limitations of in vivo fluorescent imaging, multidrug resistance (MDR) phenotypes hindering breast cancer chemotherapy, and shortcomings of magnetic resonance imaging (MRI) thermometry. Using this platform, three nanoparticle systems have been developed: QD-SLN (quantum dot-loaded solid lipid nanoparticles), DMsPLN (doxorubicin and mitomycin C co-loaded polymer-lipid hybrid nanoparticles), and HLN (hydrogel-lipid hybrid nanoparticles). Stealth, near-infrared emitting QD-SLN were developed for deep tissue fluorescence imaging, which were capable of extending the depth of penetration beyond 2 cm, with near complete probe clearance and good tolerability in vivo. The QD-SLN was used to evaluate the biodistribution of non-targeted SLN and actively targeted RGD-conjugated SLN. Non-targeted SLN accumulated in breast tumors and evaded liver uptake. The RGD-SLN showed prolonged retention in breast tumor neovasculature at the cost of lesser tumor accumulation due to enhanced liver uptake. With this information, a long circulating, non-targeted DMsPLN with a synergistic cancer chemotherapeutic combination of doxorubicin and mitomycin C was formulated to overcome MDR, enhancing breast cancer chemotherapy. Extensive tumor cell uptake and perinuclear trafficking of DMsPLN overcame the MDR phenotype of breast tumor cells in vitro. The DMsPLN provided the most efficacious chemotherapy reported in literature against aggressive mouse mammary tumors in vivo with significant reduction in whole animal and cardiotoxicity as compared to clinically applied liposomal doxorubicin. In establishing our tumor models, the impact of Matrigel™ on the tumor microenvironment was investigated, demonstrating altered tumor vascular and lymphatic anatomy and physiology, and significantly impacting nanomedicines assessment in mouse models of cancer. In all in vivo studies, tumors were established without use of Matrigel™. To guide thermotherapy of solid tumors, a novel HLN was formulated for use in MRI thermometry, presenting the first contrast agent capable of indicating a tunable, absolute two-point temperature window. In using specific limitations of therapeutic and imaging modalities to inform rational nanoparticle design, this lipid-based platform nanotechnology has extended the application of fluorescence imaging in vivo, enhanced the utility of nanoparticulate chemotherapeutics against breast cancer independent of MDR status, and provided novel functionality for MRI thermometry.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/36253 |
| Date | 15 August 2013 |
| Creators | Shuhendler, Adam Jason |
| Contributors | Wu, Xiao Yu |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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