Polymeric antibacterial systems based on passive targeting and synergistic effect

• Main Author: Ma, Jielin
• Other Authors: Duan Hongwei
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Engineering::Chemical engineering::Biochemical engineering; Engineering::Chemical engineering::Polymers and polymer manufacture
• Online Access: https://hdl.handle.net/10356/144899
• Institution: Nanyang Technological University

Bacterial infection is one of the most challenging problems in the biomedical field. A long list of antibiotics has been developed to fight bacterial infections since 1928. However, the overuse and misuse of antibiotics have led to the emergence of multidrug resistance of pathogenic bacteria and adverse events to patients. Methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa) are serious threats to public health that cause high rates of mortality and morbidity. This thesis aims to develop antibacterial systems to address the MRSA and multidrug-resistant P. aeruginosa infections. In the first project, PEG blocked degradable anionic polymer was coated on nano rods grafted with cationic polymer to achieve passive targeting, selective antibacterial and low cytotoxicity. Cationic quaternized poly(2-dimethylaminoethyl methacrylate) (PDM) and anionic methoxy poly(ethylene glycol)-block-poly(ε-caprolactone-co-methacrylic acid) co-polymer (PCM) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and hybrid co-polymerization. The antimicrobial cationic polymers were grafted to gold nano rods by ligand exchange. The lipase-degradable anionic polymers were coated on the antimicrobial cationic polymers modified gold nano rods via electrostatic interaction, yielding hybrid nano structures NR@PDM-PCM. This design led to both the selectivity between bacteria and mammalian cells and the selectivity between lipase-producing bacteria and non-lipase-producing bacteria. The strategy also showed excellent synergic antibacterial activity based on cationic polymer brushes and photo-thermal therapy of the gold nano rods at near-infrared spectral range. In the second project, the anionic polymer poly{{2-[(2-methylprop-2-enoyl)oxy]ethyl}phosphonic acid} (PDMPOH) was developed to bind with zinc ions to form ZnPD complexes. While PDMPOH polymer itself is not effective against bacteria, the ZnPD complexes showed better antibacterial effects than that of free zinc ions, indicating that the anionic polymer PDMPOH in ZnPD acts as a carrier for zinc ions and improves the availability of zinc ions. Importantly, ZnPD showed good synergistic antibacterial effect in combination with disulfiram (DSF) against Gram-positive and Gram-negative multi-drug resistant bacteria: Methicillin-resistant Staphylococcus aureus MRSA BAA40 and Escherichia coli EC 958. Three key factors collectively contributed to the antibacterial action of ZnPD+DSF: (1) the anionic polymer PDMPOH in ZnPD acts as a carrier of zinc ions and improves the availability of zinc ions; (2) the synergy of zinc ions and DSF significantly increases the uptake of Zn and DSF in bacteria; (3) the high uptake of DSF and Zn destroys bacterial proteins by interfering with thiol-disulfide homeostasis. In the third project, I investigated the interactions between gallium (III) and 21 antibiotics against P. aeruginosa PAO1 and found that there was a synergistic antibacterial effect between gallium (III) and rifampicin (RMP). Further, I synthesized gallium-anionic polymer PDMPOH complex nano-gel (GaPD) by using PDMPOH to complex with gallium (III). The GaPD+RMP pair was able to eradicate the biofilm of P. aeruginosa PAO1. The data obtained support the excellent anti-biofilm properties from three aspects: (1) the nano gel form of GaPD enhanced the biofilm dispersal ability resulting from the amphiphilicity of PDMPOH with both hydrophilic (anions + Ga III) and hydrophobic alkyl domains; (2) the lipase-degradation of GaPD caused the release of Ga ions; (3) the synergistic antibacterial effect between gallium (III) and RMP against PAO1. The system of GaPD combining with RMP was non-toxic towards 3T3 and MCF-7 cells. Overall, this thesis presented three systems for addressing antibiotic resistance based on passive targeting, the synergistic effect of cationic polymers and photo-thermal effect, and the synergistic effect of metal-ions complexes and antibiotics. It not only offers the possibility of reducing the uses of antibiotics but also provides insights of new designing strategies of alternative antibacterials.