Antibacterial Polymer Vesicles

Inflammation caused by bacterial infections is a serious threat to human health.Although antibiotics are very effective in preventing or curing bacterial infections,the misuse or overuse of antibiotics has induced more and more drug-resistant bacteria.In addition,a single chemotherapy method based on antibiotics cannot achieve the expected therapeutic effect on many diseases caused by pathogenic bacteria,typically diabetic infected wounds,which are prone to repeated infections and extremely hard to be cured.Therefore,it is urgent to develop new non-antibiotic antibacterial agents and establish new methods for treating complex bacterial infections.Polymer vesicles self-assembled from macromolecules are a new type of non-antibiotic antibacterial agent,whose antibacterial activity is usually 1-3 orders of magnitude higher than that of single-chain polymers.Polymer vesicle-based antibacterial agent is a frontier research direction in the field of antibacterial materials.However,there are still some important scientific problems,for example:1.Is it possible to treat diabetic infected wounds with lower antibiotic doses through in situ removal of reactive oxygen species by polymer vesicles?2.Is it possible to construct non-antibiotic antibacterial/antioxidant polymer vesicles to treat diabetic infected wounds?3.Is it possible to construct low-temperature photothermal synergistic antibacterial polymer vesicles to treat infected wounds?To solve the above problems,we designed and synthesized a series of multifunctional antibacterial polymer vesicles,with the original goals of reducing the dose of antibiotics as well as developing new treatment approaches for infected wound healing.The main research contents include the following three aspects:1.A therapeutic method combined antibacterial/antioxidant components was proposed to reduce the dose of antibiotics in treating hard-healing diabetic infected wounds.The drug-loaded and Ce O₂-decorated polymer vesicles with both antibacterial and antioxidant properties were designed and prepared.The vesicles were assembled from the block copolymer PCL₄₀-b-PGA₂₀,and the antibiotic ciprofloxacin was loaded during the assembly process.The carboxyl groups on the PGA segment were used for electrostatically adsorbing cerium ions to in situ deposit Ce O₂ nanoparticles,which could function as superoxide dismutase mimics.The final vesicles could release antibiotics for lasting sterilization,and also scavenge superoxide free radicals to reduce oxidative stress in diabetic wounds.In vitro antibacterial tests showed that the vesicles exhibited enhanced antibacterial effect.The MIC values of antibiotics against E.coli and S.aureus in pure polymer vesicles were 0.05 and 0.20μg/m L,which decreased to0.0375μg/m L and 0.10μg/m L in ceria-decorated polymer vesicles.The dosage of antibiotics was reduced by 50%.The results of animal tests confirmed that the diabetic infected wounds administered with the drug-loaded and Ce O₂-decorated polymer vesicles healed within two weeks without obvious side effects,while the untreated wounds remained at 73%of the initial area.2.A silver/Ce O₂-loaded polymer vesicle with both antibacterial and antioxidant functions was prepared for the rapid healing of diabetic infected wounds.We first synthesized a triblock copolymer PCL₄₆-b-PGA₆-b-P(Lys₁₂-stat-Phe₈)that could be assembled into polymer vesicles.The P(Lys₁₂-stat-Phe₈)block was a randomly copolymerized segment of lysine and phenylalanine,which showed intrinsic antibacterial properties;the PGA segment had carboxyl groups,which were used to deposit silver and Ce O₂ nanoparticles.Nano-silver could continuously release silver ions and realize long-lasting sterilization.Ce O₂ could simulate superoxide dismutase to scavenge superoxide free radicals.The in vitro antibacterial tests showed that the silver/Ce O₂ polymer vesicles exhibited excellent antibacterial effect because of the synergy of antibacterial peptides and silver.MIC values of silver against E.coli and S.aureus were 4.0μg/m L and 8.0μg/m L,which reached the order of magnitude of MICs for many antibiotics.The results of animal tests showed that silver/Ce O₂ polymer vesicles significantly accelerated the healing speed of the diabetic infected wounds.3.A bismuth sulfide-loaded antibacterial polymer vesicle was prepared,which had good antibacterial effect because of the synergy of low-temperature photothermal therapy and antibacterial polypeptide.The triblock copolymer PCL₅₄-b-PGA₆-b-P(Lys₁₅-stat-Phe₉)was first synthesized and assembled into polymer vesicles.Among them,P(Lys₁₅-stat-Phe₉)was an antibacterial polypeptide,and PGA was used to adsorb bismuth ions and in situ deposit bismuth sulfide nanoparticles.The finally obtained bismuth sulfide-loaded polymer vesicles showed high photothermal conversion efficiency,which could effectively convert the light energy from 808 nm laser into heat energy.When the bismuth sulfide concentration was 200μg/m L,the temperature of the solution could be photothermally increased to 50°C.The bismuth sulfide-loaded polymer vesicles showed intrinsic antibacterial ability,with an MIC value of 400μg/m L for polymer concentration（the corresponding bismuth sulfide concentration was 40μg/m L）.However,after 10 min of 808 nm laser irradiation,the MIC value was reduced to 200μg/m L（the corresponding bismuth sulfide concentration was 20μg/m L）.The low-temperature photothermal therapy could minimize damage to normal cells,and at the same time synergize with antibacterial peptides to achieve better bactericidal effect.Animal tests showed that bismuth sulfide-loaded polymer vesicles could significantly promote the healing rate of bacterial infected wound under 808 nm laser irradiation.In summary,we have carried out a series of research work aiming at enhancing the antibacterial effect of antibiotics,reducing the dosage of antibiotics,and developing a new integrated antibacterial and antioxidant treatment platform for infected wound healing.We proposed a dual-pronged strategy of antibacterial and antioxidant treatment for fast curing diabetic infected wounds.We have also constructed integrated platforms of multi-means antibacterial therapy based on polymer vesicles.These materials and strategies have solved a series of scientific problems in the therapeutic methods of bacterial infected wounds and may be extended for many bacterial-and oxidative stress-related disease.