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Enzyme Mimics for Nitric Oxide Delivery

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Enzyme Mimics for Nitric Oxide Delivery Enzyme Mimics for Nitric Oxide Delivery Tao Yang A thesis submitted to the University of New South Wales in fulfilment of the requirements for the degree of Doctor of Philosophy School of Chemical Engineering Faculty of Engineering September 2020 Thesis/Dissertation Sheet Surname/Family Name : Yang Given Name/s : Tao Abbreviation for degree as give in the University calendar : PhD in Engineering Faculty : Faculty of Engineering School : School of Chemical Engineering Thesis Title : Enzyme Mimics for Nitric Oxide Delivery Abstract 350 words maximum: (PLEASE TYPE) Nitric oxide (NO) is a multifunctional molecule that contributes to a broad range of physiological activities. However, the therapeutic potential of NO has been severely impaired by its short half-life (less than 5 seconds) and limited diffusion distance (20-160 µm) in human tissues. In addition, NO activity is strongly dependent on its concentrations and locations. Therefore, there is a need to develop NO delivery technologies that enable controllable and tunable NO administration. Current NO delivery systems include encapsulation of NO donors into prefabricated scaffolds or enzyme-prodrug therapy approach. However, the former is limited by the finite deliverable NO while the latter is challenged by the intrinsic low stability of natural enzymes. A crafty design to circumvent these limitations is to develop enzyme mimics that can catalyze endogenous NO prodrugs to produce NO. This thesis focuses on the design, synthesis, and applications of a new class of zinc-based enzyme mimics that enables sustained NO delivery. I synthesized ZnO particles using a chemical precipitation method and provided the first report documenting that ZnO mimics the activities of glutathione peroxidase and galactosidase to catalyze endogenous S-nitrosoglutathione (GSNO) and exogenous β-gal-NONOate to produce NO. Physiologically relevant NO levels were achieved by adjusting the concentrations of ZnO and NO prodrugs. ZnO enabled NO generation in human serum and preserved its catalytic efficacy for at least 6 months, which is highly beneficial for long-term biomedical applications. I further investigated the influence of morphology and surface modification on the catalytic activity of ZnO towards NO generation and found that: 1) the NO-generating activity of ZnO is morphology-dependent due to the different crystal growth directions of the particles and 2) ZnO retained 60 % of its NO-generating activity after modifying its surface with zeolitic imidazolate framework (ZIF-8). ZnO/ZIF-8 enabled NO generation from GSNO, S-Nitroso-N-Acetyl-D,L-Penicillamine (SNAP), and β-gal-NONOate. I also developed a multifunctional enzyme mimic by encapsulating superoxidase dismutase, a natural enzyme with free radical scavenging ability, into ZnO/ZIF-8, which holds potential for cancer therapy. The findings presented in this thesis open new routes to the next generation of NO-releasing biomaterials and devices in diverse biomedical applications. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents a non-exclusive licence to archive and to make available (including to members of the public) my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known. I acknowledge that I retain all intellectual property rights which subsist in my thesis or dissertation, such as copyright and patent rights, subject to applicable law. I also retain the right to use all or part of my thesis or dissertation in future works (such as articles or books). …………………………………………………………… ……….……………………...…….… Signature Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years can be made when submitting the final copies of your thesis to the UNSW Library. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents a non-exclusive licence to archive and to make available (including to members of the public) my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known. I acknowledge that I retain all intellectual property rights which subsist in my thesis or dissertation, such as copyright and patent rights, subject to applicable law. I also retain the right to use all or part of my thesis or dissertation in future works (such as articles or books).’ ‘For any substantial portions of copyright material used in this thesis, written permission for use has been obtained, or the copyright material is removed from the final public version of the thesis.’ Signed ……………………………………………........................... Date …………………………………………….............................. AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis.’ Signed ……………………………………………........................... Date …………………………………………….............................. ORIGINALITY STATEMENT I hereby declare that this submission is my own work and to the best of my knowledge it contains no material previously published or written by another person, or substantial portions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institute, except where due acknowledgment is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project’s design and conception or in style, presentation and linguistic expression is acknowledged. Signed ……………………………………………........................... Date …………………………………………….............................. INCLUSION OF PUBLICATIONS STATEMENT UNSW is supportive of candidates publishing their research results during their candidature as detailed in the UNSW Thesis Examination Procedure. Publications can be used in their thesis in lieu of a Chapter if: • The candidate contributed greater than 50% of the content in the publication and is the “primary author”, ie. the candidate was responsible primarily for the planning, execution and preparation of the work for publication • The candidate has approval to include the publication in their thesis in lieu of a Chapter from their supervisor and Postgraduate Coordinator. • The publication is not subject to any obligations or contractual agreements with a third party that would constrain its inclusion in the thesis Please indicate whether this thesis contains published material or not: This thesis contains no publications, either published or submitted for publication ☐ (if this box is checked, you may delete all the material on page 2) Some of the work described in this thesis has been published and it has been documented in the relevant Chapters with acknowledgement ☐ (if this box is checked, you may delete all the material on page 2) This thesis has publications (either published or submitted for publication) ☒ incorporated into it in lieu of a chapter and the details are presented below CANDIDATE’S DECLARATION I declare that: • I have complied with the UNSW Thesis Examination Procedure • where I have used a publication in lieu of a Chapter, the listed publication(s) below meet(s) the requirements to be included in the thesis. Candidate’s Name Signature Date (dd/mm/yy) POSTGRADUATE COORDINATOR’S DECLARATION To only be filled in where publications are used in lieu of Chapters I declare that: • the information below is accurate • where listed publication(s) have been used in lieu of Chapter(s), their use complies with the UNSW Thesis Examination Procedure • the minimum requirements for the format of the thesis have been met. PGC’s Name PGC’s Signature Date (dd/mm/yy) For each publication incorporated into the thesis in lieu of a Chapter, provide all of the requested details and signatures required Details of publication #1: Full title: Progress and Promise of Nitric Oxide-Releasing Platforms Authors: Tao Yang, Alexander N. Zelikin, Rona Chandrawati Journal or book name: Advanced Science Volume/page numbers: 5/1701043 Date accepted/ published: 23 April 2018 Status Published Accepted and In In progress press (submitted) The Candidate’s Contribution to the Work I am the first author of this publication. My contribution includes proposing the review sections, literature investigation, and manuscript writing (original draft, review, and editing). Location of the work in the thesis and/or how the work is incorporated in the thesis: Chapter 2 PRIMARY SUPERVISOR’S DECLARATION I declare that: • the information above is accurate • this has been discussed with the PGC and it is agreed that this publication can be included in this thesis in lieu of a Chapter • All of the co-authors of the publication have reviewed the above information and have agreed to its veracity by signing a ‘Co-Author Authorisation’ form. Primary Supervisor’s name Primary Supervisor’s signature Date (dd/mm/yy) Details of publication #2: Full title: Enzyme Mimics for the Catalytic Generation of Nitric Oxide from Endogenous Prodrugs Authors: Tao Yang, Alexander N. Zelikin, Rona Chandrawati Journal
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