New polymers for bio-imaging applications

The thesis begins with an introduction and background of Magnetic resonance imaging (MRI) and contrast agents (CAs). MRI is now a widely applied, indispensable and powerful tool for diagnosis in modern clinical medicine. Contrast agents are used to shorten the relaxation time of water protons to give a better contrast of MRI. Different Gadolinium (Gd(III)) based contrast agents were summarized and reviewed. Such low molecular contrast agents have their own positive and negative attributes. To limit their risks and side effects, the use of bio-compatible macromolecular contrast agents were proposed. To build the nano-carriers, firstly, by analysing different monomers, the backbone of nano-carriers and functional monomers for attachment of targeting moieties or chelating agents were chosen. Secondly, reversible addition fragmentation transfer (RAFT) polymerization was selected among different controlled radical polymerization (CRP) techniques. Thirdly, different complex polymer architectures were designed to encapsulate Gd(III). Finally, different techniques used to investigate Gd(III)-polymer CAs were discussed.Chapter 2 investigated macromolecular ligands for Gadolinium CAs which were prepared via a grafting to" strategy. This work has been published in Macromolecules in 2012. Copolymers of poly(ethylene glycol) methyl ether acrylate (PEGA) and an activated ester monomer, pentafluorophenyl acrylate (PFPA), were synthesized and modified with a 1-(5-amino-3-aza-2-oxypentyl)-4,7,10-tris(t-butoxycarbonylmethyl)-1,4,7,10-tetraaza-cyclododecane (DO3A-tBu-NH2) chelate for the complexation of Gd(III). The relaxivity properties of the ligated Gd(III) agents were then studied to evaluate the effect of macromolecular architecture on their behaviour as MRI CAs. Ligands made from linear polymer and hyperbranched polymer (HBP) showed a substantially increased relaxivity in comparison to existing commercial Gd(III) MRI contrast agents. In contrast, core cross-linked star polymers (CCS) exhibited a slightly lower relaxivity per Gd(III) ion (but still substantially higher relaxivity than existing low molecular weight commercial CAs). This work shows that macromolecular ligands have the potential to serve as components of Gd(III) MRI agents as there are enhanced effects on relaxivity, allowing for lower Gd(III) concentrations to be used to achieve contrast, whilst potentially imparting control over pharmacokinetics.Macromolecular contrast agent (Gd(III)-HBP and Gd(III)-CCS) were demonstrated as potential contrast agent and have better performance compared to low molecular contrast agent (Gd(III)-DOTA) in chapter 2. In this work, PEGA was used as the backbone of nano-structure, and PFPA as an activated ester was used as the functional monomer to introduce DOTA chelating agent into the nano-structure. However, the sequence of these two monomers in the nano-structure was not well studied. The investigation of the kinetics of polymerization of these two monomers and the activity of PFPA-amine reaction would help to understand better the nano-structure and the influence of the structure to the relaxivity. Therefore, in chapter 3, copolymerization reactions involving poly(ethylene glycol) methyl ether acrylate (PEGA) or diethylene glycol acrylate (DEGA) with pentafluorophenyl acrylate (PFPA) have been studied. The effect of the reaction conditions on the nucleophilic acyl substitution reactions of PFPA was studied using a model amine (furfuryl amine). The resulting PEGA/PFPA functional copolymers were then used as scaffolds to produce a library of polymers by reaction with a range of amines. This work was collaborated with Dr. Mariana Beija and published in European Polymer Journal in 2013. Chapter 4 continues the work from Chapter 2 and Chapter 3 and has been published in Polymer Chemistry in 2014. Using the experience to build HBP and CCS structure from Chapter 2 and the kinetic study from Chapter 3, the influence of the structure of macromolecular ligands on the relaxivity of gadolinium contrast agents constructed as nanoparticle systems were studied in Chapter 4. Macromolecular ligands were assembled as single-molecule nanoparticles in the form of either discrete CCS or HBP structure. 1-(5-Amino-3-aza-2-oxypentyl)-4,7,10-tris(t-butoxycarbonylmethyl)-1,4,7,10-tetraaza-cyclododecane (DO3A-tBu-NH2) chelate was incorporated into different parts (arms, cores, end-groups) of the polymeric structures using activated ester / amine nucleophilic substitutions, followed by deprotection and complexation with Gd(III). The relaxivity properties of the ligated Gd(III) agents were then studied to evaluate the effect of macromolecular architecture and Gd(III) placement on their behaviour as discrete nanoparticle magnetic resonance imaging (MRI) contrast agents. The precise placement of Gd(III) in the polymeric structures (and therefore in the nanoparticles) proved critical in optimizing the performance of the nanoparticles as MRI contrast agents. The relaxivity was measured to vary from 11 to 22 mM-1s-1.

Medienart:	E-Book

Erscheinungsjahr:	2014
Erschienen:	Erscheinungsort nicht ermittelbar: University of New South Wales. Centre for Advanced Macromolecular Design ; 2014

Sprache:	Englisch

Beteiligte Personen:	Li, Yang [VerfasserIn]
Hochschulschrift:	Dissertation, University of New South Wales. Centre for Advanced Macromolecular Design, 2014

Links:	handle.unsw.edu.au [kostenfrei]

Förderinstitution / Projekttitel:

PPN (Katalog-ID):	1803284315