Nanoparticle-based drug delivery systems (NDDS) have emerged as a promising strategy for formulation of anticancer drugs due to their ability to passively target solid tumors via exploitation of the enhanced permeation and retention effect. In particular, nano-sized block copolymer micelles (BCMs) have proven to be a viable delivery vehicle for hydrophobic anticancer drugs. To further enhance the specificity of BCMs towards cancer cells, extensive research has been focused on the formulation of actively targeted BCMs with tumor cell binding antigens conjugated to their surface. However, the in vivo transport of passively and actively targeted BCMs has only been studied to a limited extent.
This thesis explores the potential and limitations of passively and actively targeted BCMs, as NDDS for delivery to solid tumors. The in vivo transport of BCMs at the whole body, tumor, and cellular levels is investigated in human breast cancer xenografts. Overall, active targeting of BCMs with epidermal growth factor (EGF) as the tumor cell binding antigen was not found to alter the whole body clearance of the vehicles; however, particle size had a profound effect on their pharmacokinetics and biodistribution profiles. Both passively and actively targeted BCMs exhibited heterogeneous distribution throughout solid tumors, with preferential localization in the tumor periphery and/or highly vascularized regions. In addition, the BCMs were found to exhibit impaired tumor penetration due to limited mobility and/or the binding site barrier. Although active targeting increases the in vivo BCM cellular uptake, the BCMs largely remained in the extracellular compartment, indicating that incomplete BCM delivery to all tumor cells remains as a major biological barrier. Interestingly, EGF-conjugated BCMs induced a potent bystander effect in vitro as a result of the paradoxical apoptotic effect of EGF, which has the potential to treat nearby tumor cells that do not respond directly to BCM treatment in vivo. In this way, EGF-BCMs may be beneficial for rendering the aforementioned in vivo barriers such as limited tumor penetration, as well as heterogeneity in tumor vascularization and receptor expression.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/26365 |
| Date | 23 February 2011 |
| Creators | Lee, Helen Hoi Ning |
| Contributors | Allen, Christine |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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