Synthesis Of Microwave Responsive Antibacterial Materials And Treatment Of Deep Tissue Bacterial Infections

Clinically,deep tissue infection is mainly treated by systemic injection of a large number of antibiotics with a long treatment cycle.Long-term and transitional use of antibiotics can not only lead to bacterial resistance,but also damage the immune system and cause serious adverse effects.In order to tackle the crisis of antibiotic resistance,both antibiotic-strengthening and antibiotic-free treatment strategies are being developed,such as phototherapy and photo-assisted antibiotics therapy.However,light therapy remains ineffective in treating deep tissue infections due to the poor penetration depth of light.Microwaves can penetrate several centimeters of biological tissue and can overcome the limitation of poor light penetration.To this end,this thesis uses microwave as an exogenous means to design a variety of microwave-responsive antibacterial materials,and explore the interaction between microwave and bacteria,which provides a new idea for the clinical treatment of deep tissue infections.Specifically reflected in the following aspects:Firstly,the precise delivery and treatment of antibiotics can be achieved through the synergy of microwave heat of microwave responsive materials and the in-situ drug release strategy of thermal control,which plays a role in reducing the amount of antibiotics.The system is composed of mesoporous ferric oxide（Fe₃O₄）and multi-walled carbon nanotubes（CNT）to form a microwave sensitizer Fe₃O₄/CNT,then loaded with gentamicin（Gent）,and then sealed with a phase change material 1-tetradecanol to obtain Fe₃O₄/CNT/Gent.Specifically,the network-like heterostructure of Fe₃O₄/CNT can produce microwave thermal effects through multiple scattering,interface polarization,dipole polarization,dielectric loss and ferromagnetic resonance loss.Moreover,CNT with carboxyl and hydroxyl groups can bind to amino groups in the peptidoglycan layer of bacterial membranes to capture and target bacteria.At the same time,the high temperature generated by microwave heat can change 1-tetradecanol（melting point 40℃）from solid to liquid,thereby in situ releasing the Gent.The experimental results show that the capture rate of Fe₃O₄/CNT/Gent on methicillin-resistant Staphylococcus aureus（MRSA）is as high as 95.32%.Fe₃O₄/CNT/Gent can be heated to 52.8℃ within five minutes under microwave irradiation,and release 85%of Gent within 20 minutes,killing 99.56%MRSA and98.53%Escherichia coli,and can effectively cure MRSA-infected rabbit tibial osteomyelitis.Meanwhile,Fe₃O₄/CNT/Gent has good biocompatibility and blood compatibility,Secondly,enhancing the microwave kinetic effect of materials by constructing surface states and synergizing with the microwave thermal effect for antibiotic-free treatment of deep tissue infectious diseases.We composite CNTs and two-dimensional conductive metal-organic frameworks with copper ions as nodes（CNT-CuHHTP）to construct heterostructured materials.CNT-CuHHTP can not only efficiently absorb microwaves and convert them into high heat by enhancing the heterointerface polarization,which can be used for microwave hyperthermia,and the generation of excited electrons through surface states under microwave irradiation can be used for microwave kinetic therapy.Meanwhile,the built-in electric field self-driven charge transfer at the interface increases the transport of excited electrons and prevents the recombination of electron-hole pairs,thereby enhancing the microwave dynamics effect.Cellular and antibacterial experiments demonstrated that this well-biocompatible CNT-CuHHTP exhibited potent broad-spectrum antibacterial activity against six pathogens,including Gram-negative and Gram-positive pathogens,under 7-minute microwave irradiation.And,it can effectively eradicate tibia osteomyelitis in rabbits infected by Staphylococcus aureus.Lastly,the interaction between microwave thermal and non-thermal effects and bacterial outer membrane assists the narrow-spectrum traditional Chinese medicine nanoparticles that are only sensitive to Gram-positive bacteria to kill Gram-negative bacteria,providing a new strategy for the treatment of deep tissue bacterial infections.Due to the dense outer membrane structure of Gram-negative bacteria,most antibacterial agents cannot enter the cells to exert antibacterial effects.To this end,we propose to use microwave thermal and non-thermal effects to induce transient nanopores in the bacterial outer membrane to facilitate the rapid penetration of small drug molecules into the bacterial interior.The verification was carried out by taking Garcinia cambogia nanoparticles（GNs）extracted from herbal medicines as an example.GNs are a kind of narrow-spectrum traditional Chinese medicine antibacterial agent which is only sensitive to Gram-positive bacteria,and kill bacteria by creating nanopores in the peptidoglycan layer of Gram-positive bacteria and depolarizing the inner membrane.After synergistic microwave（15 minutes）,the antibacterial efficiency of GNs against Escherichia coli（Gram-negative bacteria）can be increased from 6.73%to 99.48%.Combined with the molecular dynamics simulation and experimental results of GNs under microwave,the nanopores generated in the outer membrane after application of microwave,and GNs were induced to enter bacterial cells to exert antibacterial effect,which eventually led to the death of Gram-negative bacteria.The mouse pneumonia model experiment confirmed that this method can effectively cure pneumonia mice co-infected with Staphylococcus aureus and Escherichia coli.The above three aspects are interrelated and progressive,from the microwave thermal effect of materials to assist small doses of antibiotics in the treatment of osteomyelitis,to the antibiotic-free treatment of osteomyelitis through the microwave thermal and microwave kinetic effects of the material,to the new strategy of assisting narrow-spectrum Chinese herbal medicines with broad-spectrum antibacterial properties through microwave thermal and non-thermal effects.The novel microwave-responsive antibacterial materials and the new antibacterial strategies designed in this thesis have the advantages of rapidity,high efficiency and safety,which provide an experimental basis and theoretical basis for the treatment of deep tissue infections.