Macromolecular engineering for modulating the response of oxidation-sensitive polymers

  • Richard D'Arcy

    Student thesis: Unknown


    In this thesis the primary focus is on polysulfides, a class of oxidation-responsive polymers with potential biomedical applications as 1) polymeric anti-inflammatory/anti-oxidant agents and/or 2) drug delivery vehicles, specifically for inflammation and cancer. Within the Tirelli lab, polysulfides for inflammation targeting drug delivery are a key area of research and as such a comprehensive review of this topic is covered in Chapter 1. Polysulfides are able to target inflammation (and cancer) due to their inherent ability to react with reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) and hypochlorite (ClO-) which are markedly upregulated in inflamed and cancerous milieu; in Chapter 2 we demonstrate the different effects of these two oxidants on poly(propylene sulfide) (PPS) nanoparticles. Using diffusion-ordered NMR spectroscopy (DOSY), both size and spatial characteristics of the oxidation products were probed; specifically, the size of the oxidation products and the spatial location of Pluronic i.e. physically entrapped within the polysulfide core or 'free' Pluronic micelles. We additionally showed that these nanoparticles displayed a protective effect on both L929 fibroblasts and J774.2 macrophages when challenged with ClO-. In Chapter 3, micellar PEG-PPS composed of linear- (2-arm) or star-(4, 6 and 8 arm)shaped polymers were synthesised; we found micelles formed of the linear PEG-PPS reacted with H2O2 at a quicker rate than the star PEG-PPS, however, the critical micelle concentration of the stars was significantly lower indicating a marked increase in stability to dilution. Chapter 5 aimed to assess new monomer ethylene sulfide (ES), which was copolymerised with propylene sulfide (PS) and end-capped with PEG vinyl sulfone; the resulting PEG-P(PS-ES) copolymers were found to have a gradient composition due to the greater reactivity of ES. The rate of oxidation with the PEG-P(PS-ES) micelles (1:1 monomer composition) was ~2x faster with respect to PEG-PPS. The effect of primary structure on oxidation and gelation was evaluated using copolymers with various ES/PS gradients; there was little effect on oxidation kinetics, however, high ES gradients displayed significantly lower gel points; we ascribe this to the higher ES-ES association in polymers with longer ES sequences. Chapter 4 investigated the Mitsunobu reaction as a means to functionalize PEG-OH with a variety of commonly used (bio)conjugation groups (thiol, maleimide, azide and amine). This project arose when synthesising PEG-thioacetate as a potential macroinitiator for the polymerisation of PS/ES. Currently, the Mitsunobu reaction is scarcely used for the functionalization of PEG-OH but here we demonstrate its benefits over other commonly used functionalization methods; namely, it being a quantitative and high-yielding one-pot synthesis reaction.
    Date of Award1 Aug 2016
    Original languageEnglish
    Awarding Institution
    • The University of Manchester
    SupervisorNicola Tirelli (Supervisor) & Neil Hanley (Supervisor)


    • Polysulfides

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