Visible Light-Mediated Polymerization for Protein-Polymer Conjugation: A Biocompatible Tool for Therapeutic Applications

Proteins are natural biopolymers composed of amino acids, holding significant roles in both industry and medicine towing to their high efficiency and selectivity. Conjugating synthetic polymers to proteins results in novel hybrid macromolecular structures, which synergistically combine the benefits of each component. Consequently, these novel conjugates often display enhanced solubility, stability, in vivo half-life, and reduced immunogenicity, thereby expanding the application scope for proteins. In the late 1970s, Davis’s pioneering work on the PEGylation of proteins marked the beginning of an era of protein-polymer conjugation for the preparation of therapeutic agents. However, early methods for protein-polymer conjugation often involved complex polymer modifications, leading to low yields and posing purification challenges. The development of controlled/living radical polymerization (CLRP) techniques (or also known as reversible-deactivation radical polymerization, RDRP) has been emerging since 1990’s to address these issues and refine the process. Notably, the recent advancements in photochemistry, such as photo-RDRP or photo-CLRP, has revolutionized the protein-polymer conjugation process. These developments enable the establishment of robust and biocompatible reaction conditions, including ambient temperature and aqueous systems, when employing photo-mediated CLRP for bioconjugation. The successful integration of Photo-initiated Reversible Addition-Fragmentation Chain-Transfer Polymerization (Photo-RAFT) and Photo-induced Atom Transfer Radical Polymerization (Photo-ATRP) into the protein-polymer conjugation process, allows for the synthesis of bioconjugates with exceptional performance characteristics, including well-defined polymers and enhanced enzymatic activity. Herein, taking advantage of these properties of Photo-CLRP, this thesis focuses on developing novel visible light mediated CLRP, enabling the synthesis of protein-polymer conjugates for therapeutics application. In the first part, this thesis describes a biocompatible vitamin-based photo initiating system for conducting aqueous Photo-RAFT polymerization under mild, presenting great promise for biological application. In a following chapter, an EY/TEOA-initiated Photo-RAFT system is introduced with excellent oxygen tolerance, allowing high-bioactivity protein-polymer conjugates to be synthesized under mild, aerobic conditions while maintaining protein structure and function. The synthesized protein-polymer conjugates were employed as antimicrobial agents that exhibit enhanced antimicrobial activity against both Gram-positive and Gram-negative bacteria. By introducing an N-terminus modified Lysozyme-Polycation conjugate via Photo-ATRP, a new protein-conjugation method is reported, which results in the production of protein-polymer conjugates with enhanced proteolytic and thermal stability as well as superior therapeutic efficacy compared to the native protein.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2023

Author dc:creator

• Zhang, Tong

• anzsrc-for: 4004 Chemical engineering
• anzsrc-for: 3403 Macromolecular and materials chemistry
• anzsrc-for: 340606 Photochemistry

Statement dc:rights

• open access
• CC BY 4.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by/4.0/

Identifier

https://doi.org/10.26190/unsworks/25397

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/101690