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Dendrimers for Cancer Therapy and Diagnostic Imaging
Get PDFTitle: Dendrimers for Cancer Therapy and Diagnostic Imaging, Author: Matthew C. Parrott, Location: ThodeThe 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. 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. 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. 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.ThesisDoctor of Philosophy (PhD
EXPLORING THE REACTIVITY AND INTERACTIONS OF A POLY(FLUORENE-CO-TETRAZINE)-CONJUGATED POLYMER WITH SWNTS
Get PDFConjugated tetrazine-containing polymers that undergo Inverse Electron Demand Diels-Alder (IEDDA) reactions with trans-cyclooctenes are interesting not only for their intrinsic optoelectronic properties, but also their interactions with π-conjugated surfaces. Here, we prepared a series of poly(fluorene-co-tetrazine) polymers and carried out IEDDA reactions to decorate them with hydroxyl, hexadecyl, or triethylene glycol side chains. The polymers were investigated pre- and post-IEDDA coupling in terms of their ability to disperse single-walled carbon nanotubes (SWNTs) in organic solvent. It was found that polymer molecular weight, side chain structure, and degree of conjugation all impacted the quality of SWNT dispersions. While the starting poly(fluorene-co-tetrazine) polymer produced concentrated dispersions, the post-IEDDA polymer containing dihydropyridazine groups did not produce dispersions of equal concentration. However, upon oxidation to the fully aromatic pyridazines, the polymers regained their ability to form concentrated dispersions. Furthermore, the post-IEDDA polymers exhibited increased selectivity toward metallic SWNTs relative to the starting polymer. In addition, due to the efficiency of the IEDDA reaction, it was possible to perform modification of the polymer-SWNT dispersion formed with poly(fluorene-co-tetrazine) to modify the polymer structure while on the SWNT surface. Overall, this work demonstrates the first use of reactive polytetrazines to disperse SWNTs and to rapidly modify the solubility of polymer-nanotube complexes.ThesisMaster of Science (MSc
Poly(ethylene glycol) Hydrogels Crosslinked via the Strain-Promoted Alkyne-Azide Cycloaddition
No full textHydrogels are promising materials for a number of biomedical applications, including tissue engineering, controlled drug delivery, and wound healing. Due to the semi-permeable nature of the water-swollen crosslinked polymer network, hydrogels have the unique ability to encapsulate materials, while allowing passage of any necessary resources, such as the import of oxygen or nutrients and the export of waste or therapeutic agents. Hydrogel properties vary greatly depending on the polymer material and crosslinking chemistry chosen, all of which can be tuned for a particular application. Current hydrogel systems typically involve either natural or synthetic polymers. Synthetic polymers afford more structural control to the resulting hydrogel, however the employed crosslinking chemistry is often non-ideal, due to the high temperatures required or the presence of cytotoxic catalysts. Click chemistry, particularly the strain-promoted alkyne-azide cycloaddition (SPAAC), is ideal for hydrogel crosslinking as it is fast at physiological temperatures, bio-orthogonal, doesn’t produce any byproducts, and doesn’t require a catalyst or external stimuli. For the hydrogel material, synthetic poly(ethylene glycol) (PEG) is most appealing since it is non-toxic, easy to functionalize, and physiologically stable. At the time of this thesis, there were few examples of PEG hydrogels prepared via SPAAC, with limited characterization of the physical properties of these gels and the parameters that dictate their gelation behavior.
The work presented in this thesis involved the optimized synthesis of a cyclooctyne derivative, aza-dibenzocyclooctyne (DIBAC), which was subsequently used for the preparation and characterization of a series of PEG hydrogels crosslinked via SPAAC. We showed that the PEG chain length and number of crosslinking groups had a significant effect on the swelling, degradation time and stiffness of the resulting hydrogels. Additionally, there was very little protein adsorption on the surface of the hydrogels, and the polymer components proved non-cytotoxic.
A second objective of this work was to investigate reproducible hydrogels. We created novel, SPAAC crosslinked PEG hydrogels that contained well-defined dendritic crosslinking groups, making them more reproducible than the previous linear analogs. These hydrogels have short gelation times at low polymer concentration, minimal swelling at physiological temperatures, and kept human mesenchymal stem cells (hMSCs) viable for over 15 days.ThesisDoctor of Philosophy (PhD
Dendronized Polymers and Surfaces: Strategies Toward Novel Therapeutics and Biomaterials
No full textCombining linear polymers and dendrimers provides numerous advantages such as increased solubility, biodegradability and a large number of functionalizable peripheral moieties. In this work, novel carborane-containing dendronized polymers were designed as potential candidates for Boron Neutron Capture Therapy (BNCT). These polymers were successfully synthesized using two different approaches. The resulting carborane-functionalized polymers were dendronized using a divergent approach to introduce aliphatic polyester dendrons of generation 1-4 grafted from the polymer backbone. Both approaches produced water-soluble dendronized polymers with high molecular weights. The synthetic approach developed in the first part of this work was also applied in the functionalization of poly(ethylene glycol) (PEG)-grafted gold surfaces with hydrophilic dendrons. In this project, the effect of surface dendronization on protein adsorption was investigated. Contrary to our expectation, protein resistance was found to decrease when the surfaces were covalently functionalized with the hydrophilic dendrons despite their improved hydrophilicity. It was postulated that several factors could be responsible for the increased protein adsorption to the dendronized surfaces, including increased surface area, the introduction of hydrogen-bond donor groups, and a decrease in the mobility of the surface-grafted polymers as a result of inter- and intra-molecular hydrogen bonding between the dendrons. To circumvent these confounding phenomena, while maintaining surface hydrophilicity, we have chosen to covalently attach PEG mono-methyl ether (PEG-OMe) chains of various molecular weight to the peripheral hydroxyl groups of first to fourth generation dendronized surfaces. Results showed that protein adsorption was reduced when dendronized surfaces were grafted with PEG-OMe chains. The hydroxyl-terminated G l-G4 dendronized surfaces and PEG-grafted dendronized surfaces were also investigated for cell adhesion and proliferation. These studies showed that little or no cell adhesion occurred on PEG-grafted gold surfaces. However, greater cell affinity for the dendronized surfaces was observed. When dendronized surfaces were coupled with PEG-OMe chains, cell adhesion was significantly diminished.ThesisDoctor of Philosophy (PhD
Polymer Functionalization of Single-Walled Carbon Nanotubes through Covalent Methods
Get PDFThe discovery of nanotubes with unique mechanical, electrical, and
thermal properties has led to their use in the development of the next generation
of composite materials. However, their poor solubility and dispersion properties
in any organic and aqueous solvents limits their potential applications.
In order to improve their solubility, single-walled carbon nanotubes
(SWNTs) were functionalized along their sidewalls with phenol groups using a
1,3-di^polar cycloaddition reaction. These phenols could be further derivatized
with 2-bromoisobutyryl bromide, resulting in the attachment of atom transfer
radical polymerization initiators to the sidewalls of the nanotubes. These
initiators were found to be active in the polymerization of methyl methacrylate
and t-butyl acrylate from the surface of the nanotubes. However, the
polymerizations were not controlled, leading to the production of high molecular
weight polymeric grafts with relatively large polydispersities. The resulting
polymer carrying nanotubes were analyzed by IR, Raman spectroscopy, solid-state NMR, DSC, TEM, and AFM. The nanotubes functionalized with
poly(methyl methacrylate) were found to be insoluble in organic solvents, such as
THF and CH2CI2. However, the dispersion property of SWNTs in the polymer matrix
was improved dramatically.
Another monomer t-butyl acrylate (t-BuA) was also polymerized using
the same macroinitiators. It was found that the SWNTs functionalized with t-BuA
iii were soluble in a variety of organic solvents. The t-butyl groups of these
appended polymers could also be removed to produce nanotubes functionalized
with poly (acrylic acid), resulting in nanocomposites that are soluble in aqueous
solutions.
In addition, polystyrene (PS) which was prepared by stable free radical
polymerization, was used to functionalize SWNTs through the radical coupling
reaction. IR, NMR, TEM, and AFM confirmed that this polystyrene was
covalently bonded to the SWNTs. It was also found that the resulting PS-SWNTs
composites were quite soluble in organic solvents, such as THF and CH2C12.ThesisMaster of Science (MSc
Interactions of Well-Defined, Pyrene-Functionalized Diblock Copolymers with Single-Walled Carbon Nanotubes
Get PDFSince their discovery in 1991, carbon nanotubes, and especially single walled carbon nanotubes (SWNTs), have attracted significant attention due to their unique structural, mechanical, and electronic characteristics. Although many potential applications for carbon nanotubes have been suggested, several key obstacles currently preclude their practical commercial applications. One of these is their lack of solubility and processability. In order to address this issue, a number of covalent and non-covalent nanotube functionalization techniques have recently been reported in the literature. These methods allow for the manipulation of nanotube properties, such as their solubility, through the attachment of various chemical moieties. Although most of these methods involve covalent attachment of structures to either the ends or sidewalls of SWNTs, several examples of non- covalent functionalization have also been reported. Pyrene, with its flat and
aromatic structure, has been shown to form strong pi-pi stacking interactions with the surface of SWNTs. With this in mind, we explored several methods towards SWNT solubilization with diblock copolymers through non-covalent polymer- nanotube interactions. Living free radical polymerizations (SFRP, ATRP) were employed to produce diblock copolymers with narrow polydispersity. Commercial and synthetic monomers with different functionalities could be utilized to produce polymers with varying properties. Specifically, we used polymers such as polystyrene, poly(methyl methacrylate), poly(t-butyl acrylate) and poly(acrylic acid) as one block of our diblock copolymers. The second block was composed of synthetic pyrene-functionalized monomers mixed with different amounts of monomers that match the composition of the first block. It was found that, upon mixing these diblock copolymers with insoluble nanotubes in various solvents, the nanotubes were partially solubilized through pi-pi stacking with the pyrene- containing blocks.ThesisMaster of Science (MS
Carbon Nanotube Thin Films as Flexible Substrates for the Support of Inorganic Nanostructures
No full textCarbon nanotubes (CNTs) are arguably the most widely studied material within the field of nanotechnology. The impressive physical and electronic properties of these materials have led to their investigation in a diverse range of applications. In recent years, the deposition of inorganic nanoparticles upon the surface of CNTs has received much attention. Research within this field has been driven by the desire to develop new composite materials exhibiting novel electronic, optical, and catalytic properties. In addition to the decoration of individual nanotubes, several groups have also investigated the use of CNT thin films as scaffolds for the assembly of inorganic nanostructures as well as other secondary components, including polymers and biomaterials. Nanotube films exhibit a number of physical properties that make them suitable for such
applications, displaying impressive electrical conductivity, flexibility, and thermal stability while also possessing a high surface area upon which chemical modification can be conducted.This thesis presents work that demonstrates the potential of CNT thin films as flexible conductive scaffolds for the support of a variety of inorganic nanostructures. Procedures are described for the preparation of SWNT -Au nanoparticle composite films that, as subsequently demonstrated, are suitable substrates for the growth of III-V semiconductor nanowires using gas-source molecular beam epitaxy. At the time of writing, the majority of published research within this field focused upon the preparation of SWNT composite films containing spherical metallic or semiconductor nanoparticles. In contrast, the growth of semiconductor nanowires upon nanotube thin films had not been explored. The work described in this thesis therefore represents the development of a novel composite material that combines the flexibility of CNT films with the unique optoeletronic properties exhibited by semiconductor nanowires. The development of functional electronic devices incorporating these materials is also discussed, as is the extension of the methods developed to investigate novel composite materials that combine other inorganic nanostructures with carbon based substrates.ThesisDoctor of Philosophy (PhD
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Reversible Functionalization of Single-Walled Carbon Nanotubes by Switchable Conjugated Polymers
Get PDFSingle-walled carbon nanotubes (SWNTs), since their first discovery in early 1990s, have drawn enormous research attention owing to their extraordinary properties. These excellent optical, electrical, thermal and mechanical properties have enabled SWNTs to make profound impacts in the field of nanotechnology, which includes nanoscale nanoelectronics, chemo-/biosensors, photovoltaics, drug delivery, and advanced nanocomposite materials. However, the as-produced SWNT samples contain a mixture of metallic and semiconducting SWNTs, amorphous carbon, and metal catalyst particles. Also, due to π-π stacking and van der Waals forces, pristine SWNTs tend to form bundles, making them insoluble in most of organic solvents. The poor processibility and purity hinder the direct use of as-produced SWNTs as the material for fabrication of SWNT-based devices. Therefore, the post-synthesis purification is highly required. Conjugated polymers have proven to be efficient SWNT dispersants, but after solution processing, conjugated polymers adhered to the sidewall of SWNTs can not be easily removed and thus negatively affect the performance of the resulting SWNT-based electronic devices. Therefore, polymers that can dissociate from the surface of SWNTs after solution processing is highly desirable.
Apart from the introduction to several other efficient purification methods of SWNTs, Chapter 1 also gives a brief review on reversible functionalization of SWNTs by polymers. The work reported in the literature categorized by the different external stimuli used to reverse the polymer-SWNT association. Chapter 2 describes the design and synthesis of a vinylogous tetrathiafulvalene (TTFV)-based conjugated polymer, which is responsive to pH changes and thus realized reversible functionalization of SWNTs. Chapter 3 describes the design and synthesis of dithiafulvenyl-grafted phenylene ethynylene polymers, which can reversibly interact with SWNTs by changing solvents. Chapter 4 describes the design and synthesis of dithiafulvene (DTF)-based electron-rich conjugated polymers, which can selectively bind with semiconducting SWNTs. In addition, Chapter 5 describes the use of SEC to achieve high-resolution separation, and isolation of surfactant-free metallic and semiconducting SWNTs. This allowed us to study the competition behavior when different ratios of metallic and semiconducting nanotubes are used as the starting material for polymer dispersions. Finally, Chapter 6 describes a side project that involves covalent functionalization of GO using Piers-Rubinsztajn reaction. The functionalized GO is loaded into silicone elastomer to reduce the air permeability and enhance the mechanical strength of the resulting silicone elastomer.ThesisDoctor of Philosophy (PhD
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