Study On Simultaneous Antibacterial/Anti-inflammatory Therapy Based On Up-conversion Photodynamics

Infection diseases induced by bacteria are a serious threat to human health with approximately 700,000 deaths worldwide every year.Antibiotics have been widely used for bacterial infections as the most accepted way of therapeutics.As a promising and practical antibacterial treatment approach,antibacterial photodynamic therapy(aPDT)explores new routes to resolve the problem posed by major invasion of surgery and antibiotic resistance.Especially near infrared(NIR)light triggered aPDT has attracted more and more attention.NIR light has longer penetration depth and better biosafety with minimal background interference,hence NIR-responsive PSs are more promising,such as typical NIR PS indocyanine green(ICG),which can produce substantial ROS upon 808 nm light irradiation,becoming an important candidate for NIR based antibacterial treatments.aPDT still two difficulties that need to be addressed before moving to clinical applications: First,the bacterial infections in deep sites possessed a hypoxic microenvironment,imposing restrictions on the oxygen-dependent aPDT;Second,aPDT only kills bacteria,but does not eliminate bacteria induced inflammation.Therefore,how to alleviate the hypoxic environment and eliminate the inflammation caused by bacteria is of great significance for aPDT in the treatment of bacterial infections.To address the key scientific issues of simultaneously addressing deep tissue hypoxia and alleviating inflammation,we developed an NIR-mediated O2/CO self-supplied aPDT nanoplatform,which consists of two-dimensional(2D)partially oxidized tin disulfide(Sn S2)nanosheets(POS NSs)upconversion nanoparticles(UCNPs)and ICG molecules(POS-UCNPS /ICG).The platform realizes the simultaneous generation of CO and O2 through up-conversion fluorescence,enhances aPDT performance with O2,and alleviates inflammation with CO gas molecules,thus solving the problem of hypoxia and inflammation caused by bacteria at the infected site simultaneously,and clarifying the therapeutic mechanism,providing a new idea for the treatment of bacterial infection diseases.In chapter 1,we first introduce the harm of bacteria and the current conventional antibacterial methods,then introduce the development tendency of aPDT in antibacterial and the challenges it faces,and then introduce the application of gas therapy in inflammation,and finally introduce the research significance and content of this paper.In chapter two,we synthesized POS-UCNPs NSs with different proportions by hydrothermal method,compared the amount of O2 and CO produced by POS-UCNPs NSs with different proportions,and screened out that POS-UCNPs NSs with the best proportions corresponding CO formation rate was 0.06 ?M/min.Then POS-UCNPs/ICG in different proportions were prepared.The optimal combination of POS-UCNPs/ICG was determined by comparing the absorption value at 780 nm and ROS production of POS-UCNPs/ICG in different proportions.In chapter three,the appearance,performance and biosafety of POS-UCNPs/ICG were characterized and evaluated.The experimental results showed that POS-UCNPs/ICG taked POS-UCNPS NSs as the skeleton,and ICG sticked to its surface through electrostatic adsorption.POS-UCNPs/ICG could not only produce ROS efficiently under 808 nm light,but also produce O2 and CO simultaneously.Cytotoxicity and animal metabolism experiments showed that POS-UCNPS /ICG had high biosafety.In chapter four,the antibacterial and anti-inflammatory activities of POS-UCNPs/ICG in vitro were evaluated.The results showed that POS-UCNPs/ICG had good antibacterial effect on bacterial biofilms.CO produced by POS-UCNPs/ICG could not only inhibit LPS-induced M1-type transformation of macrophages,but also promote the polarization of M2-type macrophages,and achieve anti-inflammatory effect by inhibiting PI3K/NF-?B signaling pathway.In chapter five,the antibacterial and anti-inflammatory activities of POS-UCNPs/ICG in vivo were evaluated by establishing the mouse abscess model.The results showed that POS-UCNPs/ICG with both antibacterial and anti-inflammatory activity significantly increased the rate of abscess scab and healing.In conclusion,a NIR light responsive nanoplatform(POS-UCNPs/ICG)was designed for CO/enhanced aPDT synergistic treatment of bacteria-induced infection diseases,realizing the NIR-mediated collaborative treatment of bacterial infectious diseases.With 808 nm light only,ICG can produce large amounts of ROS with the O2 supplication.Simultaneously,the produced CO can efficiently inhibit the inflammatory responses through adjusting the PI3K/NF-?B signal pathway.In animal models,this anti-inflammatory and enhanced antimicrobial activity lead to faster recovery of abscess sites.This nanoplatform provides a promising approach to solving hypoxia and the following inflammation treatment issues in aPDT.