Synthesis and characterisation of the bis-MPA based branched materials was performed. Thymine derivative was incorporated into the polymer structure as a core moiety and an active centre for H-bonding. The formation of assemblies was investigated. / Im Rammen der Doktorarbeit wurden bis-MPA basierter dendrititsche und hochverzweigte Polymeren synthetisiert. Sie haben Thymin Derivat als Kernmolecule. Die H-Brücken zwischen Polymeren und DAPy Derivate wurden untersucht.

Synthesis and characterisation of the bis-MPA based branched materials was performed. Thymine derivative was incorporated into the polymer structure as a core moiety and an active centre for H-bonding. The formation of assemblies was investigated. / Im Rammen der Doktorarbeit wurden bis-MPA basierter dendrititsche und hochverzweigte Polymeren synthetisiert. Sie haben Thymin Derivat als Kernmolecule. Die H-Brücken zwischen Polymeren und DAPy Derivate wurden untersucht.

This study investigated a CNF/dendrimer hydrogel and how different concentrations of the carboxylated CNF and bis-MPA ammonium dendrimer affected the hydrogels’ rheological properties. A third generation bis-MPA ammonium dendrimer was diffused into a dispersion of carboxylated cellulose nanofibrils. The CNF was carboxylated by TEMPO-oxidation and phosphate buffer deprotonating the carboxylic group. The ammonium dendrimers are cationic and, when added to the dispersion, act as a salt together with the CNF-carboxy anion creating a cationic dendrimer salt bridge. These will serve as physical crosslinks, and a CNF/dendrimer network is formed; the structure and the absorbed water make a hydrogel. Amplitude strain sweeps were performed with a rheometer to determine the gels' elastic capabilities in terms of storage modulus, G’ and loss modulus, G” as the function of the shear stress. The result shows that a higher concentration of both CNF dispersion and dendrimer yielded a higher value of the storage modulus and a lower critical strain, meaning that the hydrogel becomes firmer and less elastic. / I denna studie undersöktes en CNF/dendrimer hydrogel och hur olika koncentrationer av den karboxylerade CNF och bis-MPA ammonium dendrimer påverkar hydrogelens reologiska egenskaper. En tredje generations bis-MPA ammonium dendrimer läts diffusera i en dispersion av karboxylerade cellulosa nanofibriller (CNF). CNF karboxylerades via TEMPO-oxidation, varefter en fosfatbuffer adderades för att skapa en anjon. Dendrimerens ammoniumgrupper är katjoner och då den adderas till dispersionen kommer den agera som ett salt tillsammans med CNF-karboxyanjonen vilket skapar en katjonisk dendrimersaltbrygga. Denna agerar som en fysisk tvärbindning och skapar ett nätverk av CNF och dendrimer. Nätverket skapar tillsammans med det absorberade vattnet en hydrogel.  En amplitude strain sweep utfördes för att bestämma gelernas viskoelastiska förmåga, från mätningarna fås elasticitetsmodulen, G’ och den viskösa modulen, G’’ som funktioner av skjuvningen. Resultatet visar att en högre koncentration av CNF-dispersionen och dendrimeren leder till ett högre värde på elasticitetsmodulen samt ett lägre värde för den kritiska skjuvningen. Detta innebär att hydrogelen blir hårdare och mindre elastisk.

The objective of this research was to develop and validate new macromolecular imaging agents to detect and characterize malignant tumours. Using well-defined, highly branched macromolecules called dendrimers as the structural scaffold, efficient functionalization of the periphery was demonstrated using “click” chemistry in order to prepare multivalent imaging probes. Furthermore, a transmetalation was demonstrated to displace chelated copper with technetium, enabling “click” reactions to be performed in the presence of the dipicolylamine (DPA), a ligand known to chelate many metals. The dendritic scaffold was functionalized with either hydrophobic or hydrophilic targeting vectors. The hydrophobic ligand, an acyloxymethyl ketone targeting the overexpression of cathepsin B exhibited poor in vitro affinity when coupled to either G1 or G2 dendrimers, despite the use of various linkers. A glu-urea-lys dipeptide, representing a hydrophilic prostate specific membrane antigen targeting vector, demonstrated excellent affinity in vitro. The lead compound, a G2 dendrimer bearing four PSMA targeting vectors attached via an alkyl spacer was further investigated in vitro and in vivo. Unfortunately, poor tumor uptake was observed and the compound was hypothesized to hydrolyze readily (<15min), based on the in vitro plasma stability data. To rectify the aforementioned problem, non neo-pentyl esters were replaced with either carbamate or ether linkages. In vitro plasma stability analysis of the analogous compounds demonstrated increased stability. In particular, the ether analogue was found to be most stable, with minimal degradation observed after 4 hours. / Thesis / Doctor of Philosophy (PhD)

The Enhanced Permeability and Retention (EPR) effect has seen considerable exploration by many researchers since it’s discovery by Maeda et al in 1985. Polymers and nanoparticles with a long blood residence half-life can accumulate in some tumour tissues, allowing for the delivery of either diagnostic or therapeutic payloads. We have contributed to this field by the development of methodology to prepare radiolabeled dendrimers which are suitable for EPR effect accumulation with a variety of peripheral functionalities. The first of these was a 99mTc-labeled fifth generation dendron which was peripherally functionalized with low molecular weight poly(ethylene glycol) chains, which was observed to accumulate in xenograft mouse tumours over the course of 6 hours. This work led to the development of improved synthetic means for the preparation of high generation dendrimers with complex peripheral functionality, which hinged on the use of the Strain Promoted Alkyne-Azide Cycloaddition reaction to give high generation dendrimers by a convergent approach. This resulted in the facile preparation of dendrimers with challenging peripheral functionality in reaction times as short as 5 minutes. This SPAAC based convergent synthesis approach was used to prepare 99mTc labeled sulfobetaine and carboxybetaine dendrons of the sixth generation, and these compounds were found to have a size greater than the renal clearance threshold of ~ 5 nm, though it was found that labeling with [99mTc(CO)3]+ was not possible without extensive degradation of the zwitterionic dendrimers. Finally, the dendritic architecture explored for imaging was adapted for use in shielding an enzyme from macromolecules while retaining activity against the native small molecule substrate, and we found that conjugation of high-generation bis-MPA dendrons to α-chymotrypsin was an effective way to eliminate enzyme activity against macromolecules while preserving efficacy against small substrates, indicating this approach may be an effective way to shield proteins from the immune system without interfering with their desired function. This work illustrates the ability to radiolabel polyester dendrimers for tumour imaging through the EPR effect. In addition, it has demonstrated that polymer architecture has a large impact on the properties of polymer-protein conjugates and gives evidence of unique properties that are imparted by the conjugation of high-generation dendrimers onto a protein. / Thesis / Doctor of Science (PhD)