Photothermal Responsive Drug-loaded Nanosystem For Treatment Of The Drug-resistant Bacterial Infections

Multi-drug resistant bacterial infections seriously threaten human physical and psychological health and have caused serious financial losses to countries all over the world.How to eliminate the multi-drug resistant bacterial infections is a major challenge facing in all countries.The failure of traditional methods has prompted the development of new strategies to fight drug-resistant bacteria.Herein,we prepared a smart triple-function nanostructure through nanoprecipitation,namely TRIDENT(Thermo-Responsive-Inspired Drug-dElivery Nano-Transporter),for reliable bacterial eradication.The robust antibacterial effectiveness was attributed to integrated fluorescence monitoring and synergistic chemo-photothermal killing.A thermo-responsive nanostructure was formulated by lauric acid and stearic acid with a tunable melting point around 43 °C.Both imipenem and IR780 were incorporated into the thermo-responsive nanostructure for preventing premature drug release and then wrapped by the phospholipid that made of lecithin and DSPE-PEG2000 for increasing the biocompatibility of the resultant TRIDENT.TEM image showed that our TRIDENTs were spherical in shape with a particle size of about 40 nm and a narrow size distribution within 50 ~ 80 nm was measured by DLS.TRIDENT also had a good colloidal stability and could be stable in a variety of solution media.The results of photothermal responsive properties of the TRIDENT system indicated that the temperature increment of the suspension of TRIDENT depended on both the IR780 concentration and the duration of NIR exposure.And the rapid release of imipenem from TRIDENT would be activated once the temperature upon the phase change temperature of the photothermal responsive nanotransporter under NIR irradiation.These results confirmed that our TRIDENT had good photothermal responsive properties.We noticed that temperature risen generated by near-infrared irradiation not only melt the nanotransporter and promoted drug release via phase change mechanism,but also irreversibly damaged bacterial membrane to facilitate imipenem permeation to interfere the biosynthesis of cell wall,eventually leading to rapid bacterial death.In addition,the biodistribution of TRIDENT around the infected site could be monitored through fluorescence imaging to guide further therapeutic interventions.And the results demonstrated that the TRIDENT could be effectively remained around the infected areas.Results from in vitro antibacterial assays illustrated that antibiotic-sensitive and clinical multidrug-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus could be effectively eradicated by our TRIDENT under NIR irradiation.And the mice infected by these bacteria were also regained health after the same treatment in vivo,which was better than other groups.Both in vitro and in vivo evidences demonstrated that even low dose of imipenem-encapsulated TRIDENT could eradicate methicillin-resistant Staphylococcus aureus,which is natural resistance to imipenem.The satisfactory rehabilitation of infected sites and well biosafety of TRIDENT in vivo indicated that the use of TRIDENT could effectively prevent local bacterial infection of mice from worsening into sepsis,and could also reduce the side effects caused by high doses of antibiotics.The remarkable antibacterial activity means that the TRIDENT system can be developed as a universal antimicrobial platform to fight against multidrug-resistant or extremely drug-resistant bacteria.