Functional Polymers Based On Ring Opening Reactions For Bacterial Infection

Since the introduction of penicillin in the 1940s,antibiotic-resistant bacteria have become increasingly serious.As WHO reported,nearly 700,000people worldwide die of"multidrug-resistance"infections each year due to the overuse of antibiotics.In addition,80%of bacterial infections are associated with the formation of bacterial biofilms,which further increases bacterial resistance to drugs.However,the development of new antibiotics now requires longer time,higher cost,and more resources since the golden age of antibiotic research occurred around 1940 to 1960.As a result,it is of great importance to explore new antimicrobial materials to address the problem of drug-resistant bacteria.Antibacterial photodynamic therapy（a PDT）has been proposed as an ideal bactericidal method to combat drug-resistant bacteria.Most photosensitizers kill Gram-positive bacteria and Gram-negative bacteria by using cationic a PDT polymers.Unfortunately,broad-spectrum a PDT agents that kill bacteria indiscriminately may lead to an imbalance in microbiota.Moreover,the positive charges of cationic a PDT show serious side effects on normal mammalian cells due to the lack of selectivity for bacteria.Therefore,it is highly desirable to develop antibacterial photodynamic agents that can specifically kill specific pathogenic bacteria without causing bacterial mutations or damaging normal host mammalian cells.Deep infections in vivo are often hypoxic and outside the penetration depth of visible light,which limits the use of a PDT.In the meantime,deep infections are generally accompanied by the formation of biofilms,which protect the bacteria within the biofilm from the a PDT.Therefore,it is of great need to further develop a PDT for deep biofilm killing in vivo.Available antimicrobial polymers often require time-consuming synthetic procedures and are non-degradable and easily accumulate in the body,which may affect the biological activities and biosafety of biomolecules.Thus,it remains to be very important to develop a simple and mild synthetic procedure that can produce degradable antimicrobial polymers.Based on the above problems,high-performance polymers that can be used in the treatment of bacterial infections were obtained by introducing functional molecules through ring-opening reactions to achieve bacterial selectivity,singlet oxygen delivery,and polymer degradability.The specific researchs are as follows:P.aeruginosa often exhibits various drug resistances and is associated with many diseases,becoming a big threat for immunocompromised patients.Additionally,biofilm formation by P.aeruginosa is a leading cause of bacterial keratitis due to the presence of EPS and heightened virulence.Thus,it is important to develop novel treatments for biofilms formed by MDR-P.aeruginosa.Firstly,a series of block ratio diblock copolymers PαGal₅₀-b-PGRB_nwere obtained via reversible addition-fragmentation chain transfer（RAFT）polymerization and ring-opening reaction.PαGal₅₀-b-PGRB_nspecifically kills P.aeruginosa forα-D-galactose species can specifically bind to Lec A of P.aeruginosa and generates reactive oxygen species(ROS:¹O₂,H₂O₂,·OH and·O^2-)by RB under light.In addition,the in vivo experiments in MDR-PA biofilm infected rabbit keratitis further proved the antibacterial activities and biosafety of PαGal₅₀-b-PGRB_n.This part designed and synthesized safe and effective antibacterial materials to fight MDR-P.aeruginosa biofilm infection.Secondly,Dex-PGMA was obtained via initiating atom transfer radical polymerization（ATRP）of glycidyl methacrylate（GMA）by using brominated dextran as an initiator,followed by a ring-opening reaction of amino-2-Hydroxypyridine with Dex-PGMA to obtain Dex-PGP.Dex-PGP can load with ¹O₂to generate peroxide Dex-PGP-EPO in the presence of photosensitizers and light.When biofilm is formed in deep oral periodontitis,Dex-p GP-EPO can penetrate the biofilm and release ¹O₂at a higher oral temperature to achieve biofilm dissolution and bacterial killing.We have successfully overcome the limitation of a PDT brought by the deep infection and anoxia,and thus extended the bioapplication of ROS therapy,providing a new therapeutic strategy for the subsequent treatment of anaerobic bacteria and deep infections in vivo.Lastly,a simple,an efficient,and safe disulfide exchange ring-opening polymerization for bioreducible disulfide polymers was established to obtain low-toxicity and efficient bioreducible polyguanidines possessed degradable S-S main chain(mPEG₂₂₅-b-PSS_n,n=26,75)to avoide polymer accumulating by regulating the solvent and reaction time under mild reaction conditions.Guanidinium groups can efficiently deliver p EGF in infected environments and provide broad-spectrum antibacterial ability,which confirms a variety of biological applications.In summary,we firstly obtained specific P.aeruginosa targeting photodynamic antimicrobial materials via RAFT polymerization and ring-opening reaction;secondly,to solve the illumination depth and anoxia problem in vivo which may influence the treatment efficiency of a PDT,pyridone polymers which can dynamically store and release ¹O₂were obtained by ATRP polymerization and ring-opening reaction;finally,to further avoiding potential toxicity and improving biosafety,degradable polyguanidine were synthesised via disulfide exchange ring-opening polymerization.The above three antibacterial polymers obtained by ring-opening reaction have been applied to different infections and provide attractive strategy for the construction of degradable antibacterial polymers.