| Background : Targeted antibiotic delivery nanomaterials have emerged as a new therapeutic approach to overcome the barriers to treatment of methicillin-resistant Staphylococcus aureus(MRSA)infection.However,traditional nanomaterials have certain defects,including lack of targeting,poor dispersion and short circulation time in vivo,etc.,so the development of a new multifunctional nanomaterial delivery system is a key breakthrough for MRSA treatment.The combination of silver nanoparticles with antibiotics can enhance the overall antibacterial activity,reduce the dose of antibiotics and reduce side effects,which is an important strategy to overcome multiple drug resistance.Platelets,as components of autologous blood,have incomparable biocompatibility in the synthesis of allogeneic carriers.Meanwhile,platelets are the most abundant cellular components which was first gathered in the blood vessels of infection site,and have the function of recognizing inflammatory cells.Nanoparticles disguised by platelet membrane enhanced biocompatibility and targeted drug delivery,not only could solve the exogenous nanoparticles in circulation system the problem of short half-life and is expected to pass the platelet surface protein in combination with endothelial cells and staphylococcus aureus infection,targeting the antibacterial drugs carried in the nanomaterials to the MRSA infection site,thus effectively inhibiting MRSA.Objective: To synthesize a novel silver-metal-organic framework(MOF)with good antibacterial activity,and load vancomycin on this MOF to form Ag-MOF-Vanc.To solve the problem that nanomaterials are easy to be phagocytic and cleared and to target the nanomaterials to MRSA infection site by platelet camouflage technology,forming PLT@Ag-MOF-Vanc.To detect the characterization of PLT@Ag-MOF-Vanc,to evaluate the toxicity and antibacterial action of PLT@Ag-MOF-Vanc in vitro and in vivo,and to discuss its antibacterial mechanism.Methods:The characterization of PLT@Ag-MOF-Vanc was detected by transmission electron microscope,energy dispersive spectrometer,dynamic light scattering,UV-visible absorption spectrometer and infrared spectrometer,and the drug loading and release ability were discussed.The effects of PLT@Ag-MOF-Vanc on cell viability,production of reactive oxygen species,blood compatibility and apoptosis were detected in vitro.In vivo through the tail vein injection,detection of PLT@Ag-MOF-Vanc on the main tissues and organs,blood and blood biochemistry;The antibacterial effect of PLT@Ag-MOF-Vanc on MRSA was detected by disk diffusion method and dilution method,and the targeting effect of PLT@Ag-MOF-Vanc on MRSA was observed by scanning electron microscopy and laser confocal scanning microscopy.By detecting the effects of PLT@Ag-MOF-Vanc on MRSA metabolism,oxidative stress and biofilm production,the antibacterial mechanism was discussed.The feasibility of PLT@Ag-MOF-Vanc in MRSA pneumonia infection was discussed by constructing a mouse MRSA pulmonary infection model and injecting different drugs into the tail vein.Results : PLT@Ag-MOF-Vanc showed excellent drug loading capacity and p H responsive drug release.The platelet membrane on PLT@Ag-MOF-Vanc effectively covered the internal Ag-MOF and reduced the recognition and clearance of macrophages in the reticuloendothelial system.PLT@Ag-MOF-Vanc has good blood compatibility,no significant effect on cell activity,apoptosis and oxidative stress,and no obvious visceral toxicity.Ag-MOF showed good antibacterial performance against Escherichia coli,Pseudomonas aeruginosa and Staphylococcus aureus.Ag-MOF and vancomycin had synergistic antibacterial effect on MRSA,and the inhibitory effect of PLT@Ag-MOF-Vanc on MRSA was significantly better than that of free vancomycin,which could reduce the dosage of vancomycin.The antibacterial effect of PLT@Ag-MOF-Vanc was time-dependent and concentration-dependent.PLT@Ag-MOF-Vanc can kill MRSA by a combination of physical,biological and chemical mechanisms: 1)targeting MRSA through platelet membranes;2)interfere with bacterial intracellular metabolism;3)inducing bacteria to produce ROS;4)destroy the integrity of bacterial cell membrane;5)inhibit the formation of biofilm.PLT@Ag-MOF-Vanc has a good targeting effect on MRSA infection site in pneumonia model mice,and has a good anti-infection effect on MRSA pneumonia model mice,which is significantly better than free vancomycin,Ag-MOF or uncoated Ag-MOF-Vanc,and can effectively reduce the dose of vancomycin and improve the survival rate of the MRSA lung infection model mice.Conclusion : The bionic targeted nano drug delivery system PLT@Ag-MOF-Vanc has good antibacterial activity and biocompatibility,and is expected to be safely used in the treatment of anti-MRSA infection.There are 25 figures,6 tables and 97 references. |
