Study On The Design Of Antimicrobial Polymer With Tunable Amphiphilic Balance And Its Application

Antimicrobial polymers(APs)with cationically amphiphilic structures have shown great promise in combating drug-resistance bacteria.However,the amphiphilic structure not only contributes to high antimicrobial activity of APs,but also is the prime culprit for their high toxicity.In this thesis,we developed a class of pH-sensitive amphiphilic balanced-tunable antimicrobial polymers(pATAPs)inspired by the acidic characteristics of infectious microenvironment.At normal physiological sites,the pATAPs exhibited a hydrophobic structure with low toxicity but a cationically amphiphilic structure with potent antibacterial activities in the acidic bacterial infectious sites.The main research contents and conclusions are divided into three parts as follows:(1)The pATAP,C628Bu9,was prepared by Reversible Addition Fragmentation Chain Transfer(RAFT)copolymerization of methacrylate monomers with ionizable 1-Ethylpiperidine(C6)and hydrophobic residues(butyl,Bu).At physiological pH(～7.40),C628Bu9,with most C6 deprotonated and hydrophobic,exhibited a neutrally hydrophobic conformation and low toxicity.At infectious acidity,the protonated of C6 converted C628Bu9 into a cationically amphiphilic structure,resulting in potent antibacterial activity.(2)A series of pATAPs were prepared by the copolymerization of the methacrylate monomers with different hydrophobic residues and ionizable tertiary amine pendants.The acidity-sensitive selectivity of the pATAPs can be regulated by the hydrophobicity of the polymer chain,including the molar fractions of monomers with hydrophobic alkyl residues,the hydrophobicity of alkyl residues and tertiary amine side groups.The biological properties of the pATAPs are dependent on their protonation degree(PD),exhibiting low toxicity towards red blood cells at low PD.The pATAPs showed high antibacterial activity when the PD was 50～95%,especially when the PD was 85±3%.The optimized C628Bu9 in vitro was subcutaneously injected into mice.The histological analysis results implied that C628Bu9 showed low toxicity to the surrounding tissue.The results of in situ treatment of subcutaneous abscess model confirmed that the C628Bu9 showed good antibacterial activity and could effectively kill Escherichia coli(E.coli)at the infectious sites.(3)The C628Bu9 can be conveniently coated on the surface of titanium-based implants.At physiological pH(～7.40),the C628Bu9 coating exhibited hydrophobic conformation,which could be stably attached on the surface of the titanium-based implants,and showed little effect on the proliferation of mouse embryonic fibroblasts(NIH3T3).The C628Bu9 coating displayed acidity sensitive antibacterial activities,which could effectively kill the E.coli on the surface of subcutaneously implanted titanium sheet and showed low toxicity to the surrounding normal tissues.In this thesis,the pH-sensitive amphiphilic balanced-tunable antibacterial polymers were successfully designed and applied to the surface coating of implant materials,which provided a new idea for the design of antibacterial polymers and a new strategy for the anti-infective therapy of titanium-based implants.