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DC Field | Value | Language |
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dc.contributor.advisor | Adronov, Alex | - |
dc.contributor.author | Parrott, Matthew C. | - |
dc.date.accessioned | 2016-07-21T14:33:12Z | - |
dc.date.available | 2016-07-21T14:33:12Z | - |
dc.date.issued | 2009-01 | - |
dc.identifier.uri | http://hdl.handle.net/11375/19875 | - |
dc.description | Title: Dendrimers for Cancer Therapy and Diagnostic Imaging, Author: Matthew C. Parrott, Location: Thode | en_US |
dc.description.abstract | <p>The enhanced permeation and retention (EPR) effect is a phenomenon that allows macromolecular (or polymeric) structures to passively concentrate in tumour tissue. The large size and high molecular weight of macromolecular-drug conjugates increase their blood circulation time, which allows for significant accumulation in tumor tissue over an extended period of time. Linking chemotherapeutic agents to the backbone of water-soluble polymers has resulted in a number of polymer therapeutics currently in clinical trials.</p> <p>A growing number of researchers are utilizing the EPR effect to develop new macromolecular-drug conjugates for the treatment and/or diagnostic imaging of diseased tissue. We have added to this research by constructing three novel carborane containing dendrimers for drug delivery. We were able to synthesize these materials using a bifunctional carborane synthon bearing a carboxylic acid and protected alcohol functionality. This bifunctional synthon could be integrated into an aliphatic polyester dendrimer using esterification conditions followed by further dendronization. This approach led to three water soluble dendrimers that contain 4, 8, and 16 hydrophobic carborane cages within their interior. The sensitive balance between the hydrophobic nature of the carborane cages and hydrophilic nature of the dendrimer scaffolds led to materials that had a lower critical solution temperature (LCST), a phenomenon where material precipitates from solution at high temperatures. The final dendrimers had a high molecular weight, were water soluble, and had a large concentration of boron encapsulated within the dendritic interior. These characteristics are ideal for potential agents for Boron Neutron Capture Therapy (BNCT), a well known treatment for cancer and rheumatoid arthritis. However, the inability to track each dendrimer in vivo and determine its biodistribution was a major drawback.</p> <p>To overcome this limitation we synthesized three additional dendrimers. These dendrimers were synthesized to a high molecular weight using a unique orthogonal protecting group strategy. Following the removal of a toluene sulfonyl ethanol protecting group located at the core of the dendrimer, we were able to introduce a metal chelating ligand using standard amidation chemistry. This ligand was comprised of a tri-nitrogen bis-pyridyl moiety known to chelate an atom of radioactive technetium-99m with high affinity. Technetium-99m is the most widely used radionuclide in diagnostic nuclear medicine due to its ideal nuclear properties, low cost, widespread availability, and its ability to be tracked in vivo using Single Photon Emission Computed Tomography (SPECT). By placing the radioactive nuclide at the core of the dendrimer we were able to provide a unique environment that maintained overall dendrimer solubility characteristics, provided protection from the external environment, and minimized the interaction between the metal/ligand complex and biological tissues. These were the first dendritic compounds to utilize the core functionality for radioactive labeling, and the first dendritic compounds to chelate radioactive technetium-99m. Real-time dynamic SPECT and three dimensional SPECT-CT were performed on all three radioactive dendrimers, and an in depth biodistribution study was performed on the largest macromolecule.</p> <p>This work opens the possibility for combining carborane-containing dendrimers with the 99mTc-label, allowing the potential development of a dendrimer that can 1) passively target diseased tissue via the EPR effect, 2) be tracked and imaged in vivo by SPECT, and finally 3) be used to treat diseased tissue by way of BNCT.</p> | en_US |
dc.language.iso | en | en_US |
dc.title | Dendrimers for Cancer Therapy and Diagnostic Imaging | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Chemistry | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Doctor of Philosophy (PhD) | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Parrott_Matthew_C_2009_01_phd.pdf | Title: Dendrimers for Cancer Therapy and Diagnostic Imaging, Author: Matthew C. Parrott, Location: Thode | 10.17 MB | Adobe PDF | View/Open |
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