Fabrication Of Novel High-performance Cationic Antibacterial Polymers Based On Ring-opening Reactions

As we are living in a post-antibiotic era,the emergence of drug-resistant bacteria is increasingly threatening public health.Meanwhile,the draining of first-line antibiotics in clinic is making the situation more daunting.Therefore,it is in urgent demand to develop new antibacterial strategies to cope with this situation.Currently,cationic antibacterial polymers have attracted much attention from researchers because of their excellent antibacterial potency,flexibility in synthesis and functionalization,low cost and good stability.Cationic antibacterial polymers are mainly composed of a hydrophilic positively charged cationic part and a hydrophobic part,and the hydrophilic/hydrophobic balance is a key factor affecting the antibacterial activity and biocompatibility of the materials.In this thesis,the effects of hydrophobic alkyl chain length,polymer molecular weight and alkyl chain type on the performance and antibacterial mechanism of cationic antibacterial polymer materials were investigated respectively.Meanwhile,a series of high performance cationic antibacterial polymer materials were fabricated based on the ring opening reaction and applied to the antibacterial modification of medical materials such as gelatin sponge and Vaseline.The main research contents are as follows:How to balance the antimicrobial potency and biocompatibility of cationic antibacterial polymers is an important challenge for implantable medical materials.In Chapter 2,poly(N,N-dimethylaminoethylmethacrylate)b-polycaprolactone-b-poly(N,N-dimethylaminoethyl methacrylate)(PDMAEMA-b-PCL-b-PDMAEMA)triblock copolymers were built based on ring-opening reactions and atom transfer radical polymerization(ATRP),which were then modified by iodomethane(Cl),bromohexane(C6)and bromodecane(C10),respectively.A series of quaternized triblock copolymers,namely QP-b-PCL-b-QPs,were obtained and self-assembled into reverse micelles(RM)in tetrahydrofuran(THF).The RM contains biocompatible poly(?-caprolactone)(PCL)blocks in the shell and biocidal quaternary blocks in the core,which made the RM coatings good cytocompatible compared to the positive micelle and can also be hydrolyzed by lipase to release quaternary ammonium agents(QBAs)to kill bacteria.Compared to C1 and C10,the RM coatings of C6-modified cationic copolymers possessed both good antibacterial properties and biocompatibility.The research in this chapter lays the foundation for the design and study of bacterial lipase responsive self-bactericidal RM coatings.In Chapter 3,a series of QP-b-PCL-b-QPs triblock copolymers with different molecular weights were constructed by adjusting the degree of polymerization of PDMAEMA based on the ring-opening reaction,ATRP and quaternization reaction.Only when the molecular weight of QP-b-PCL-b-QP is 39.2 kDa,can RM2 own both lipase responsiveness and good antibacterial properties.In contrast,RM coating may be unstable as the polymer molecular weight was 88.4 kDa or had poor antibacterial efficiency as the polymer molecular weight was 26.6 kDa.The RM can be facilely impregnated into commercial gelatin sponge to fabricate RM2-coated GS,which impose potent antibacterial activity in the presence of lipase.Compared to low lipase producing strains(For example,Escherichia coli(E.coli)),RM2-coated GS showed higher antibacterial performance against high lipase producing strains such as Staphylococcus aureus(S.aureus)and Bacillus subtilis(B.subtilis).RM2-coated GS exerted excellent antibacterial properties against S.aureus in bacterial-infected environment in vivo,and hematoxylin and eosin(H&E)staining results showed that RM2-coated GS was able to mitigate tissue inflammation caused by bacterial infection.This work provides a valuable approach for the design of self-sterilizing implantable healthcare dressings.In Chapter 4,fluoroalkyl chain-modified branched polyethyleneimine(PEI-PFO)and alkyl chain-modified PEI(PEI-HPO)with different grafting ratios were synthesized separately based on the ring-opening reaction,and the effects of fluoroalkyl and alkyl chains on the antibacterial properties of PEI were compared.PEI-PFO exhibited stronger antibacterial efficiency than PEI-HPO with similar grafting ratios.The larger the grafting ratio were,the stronger the antibacterial ability of both PEI-PFO and PEI-HPO owned.The study investigated the differences between the antibacterial mechanisms of PEI-PFO and PEI-HPO in four aspects:bacterial outer membrane(OM)integrity,cytoplasmic membrane(CM)depolarization,CM integrity and bacterial internal ROS production.The results showed that PEI-PFO has a stronger disruptive effect on the CM of bacteria than PEI-HPO,thus PEI-PFO possessed a superior antibacterial performance.Bactericidal kinetic tests also shown that PEI-PFO had higher bactericidal efficiency than PEI-HPO again.PEI-PFO3.0 can be blended with commercial Vaseline(VL)to obtain antibacterial VL,namely PEI-PFO3.0/VL,which can promote wound healing at methicillin-resistant Staphylococcus aureus(MRSA)infection site.This work provides an important reference value for the design of fluorine-containing high-performance cationic antibacterial polymers.In summary,the design principles of cationic antibacterial polymers in terms of the length of hydrophobic alkyl chains,the molecular weight of the polymer and the type of alkyl chains were explored,respectively.A series of novel high-performance cationic antibacterial polymers are synthesized and the underlying antibacterial mechanisms were investigated.The results of this thesis preliminarily reveal the relationship between the structure and performance of antimicrobial polymer materials,and provide new ideas and strategies for the fabrication of new antibacterial medical materials and the reduction of nosocomial infections.