Preparation And Property Evaluation Of Inhalable Infection-responsive Polysaccharide-based Drug-loaded Nanoparticles To Overcome Drug-resistant Bacteria

Bacteria-related infections have become the second leading cause of mortality in the world,dealing a heavy blow to patients and society alike.Lower respiratory tract infections caused by bacteria are a serious threat to people’s life and health.Since the discovery and use of antibiotics,some bacterial infections have been treated effectively and lower respiratory tract infections have been controlled clinically.However,in the process of treatment,antibiotics also have many problems,such as low delivery efficiency,poor penetration effect and the tendency to cause the emergence of drug-resistant bacteria,all of which greatly reduce the therapeutic effect of antibiotics.Therefore,in this thesis,based on a series of current problems of antibiotic therapy,we designed carrier nanomaterials for delivery of antibiotics and applied them to the treatment related to severe lower respiratory tract infections.In this thesis,we successfully prepared and synthesized responsive drug-loaded anti-drug-resistant bacterial nanoparticles against severe lower respiratory tract infections.The quaternary ammonium salt QPEI-C₆ and sodium alginate were assembled into nanomaterials by electrostatic interactions and successfully loaded with antibiotics.The optimal group of material STQ₁₂was successfully prepared through a series of screening and optimization.Firstly,the physicochemical properties of the material were characterized by particle size potentiometry,infrared spectroscopy,transmission electron microscopy.The results showed that the materials were formed into nanomaterials by electrostatic assembly and successfully loaded with the antibiotic aztreonam.Due to the protonation of the carboxylate of sodium alginate in the micro-acidic environment of the material,the p H-responsive release of the antibiotic occurred by the weakened electrostatic interaction with QPEI-C₆.Thus,the material released antibiotics at p H=5.5 at a significantly better release rate and amount than that at p H=7,thus achieving responsive on-demand release.At the same time,the material had a significant killing effect on drug-resistant bacteria,with an effective killing concentration of 16μg/m L for multidrug-resistant P.aeruginosa（MDR-PA）.Because of the combined bactericidal effects of QPEI-C₆ and antibiotics,the material reduced the effective bactericidal concentration of antibiotics by a factor of 12.The material was able to penetrate quickly and efficiently in the mucus layer due to its particle size of about 200 nm and near-neutral potential of about 11.03 m V.Compared to antibiotics,it could effectively kill the bacteria inside biofilms under the mucus layer.In addition,the material had good biocompatibility,and the cell survival rate can reach more than 80%at the effective bactericidal concentration.Finally,through in vivo experiments in mice,it was successfully demonstrated that the material had a significant reduction in the validation effect in mice by two doses,and was significantly better than the antibiotic group with the same concentration.This thesis developed a kind of novel antibacterial nanoparticles with the ability to eliminate multi-drug resistant bacteria,which will provide new concept for treatment of serious infections of lower respiratory tract.