Construction Of Novel Organic Nanoparticles And Their Application In Tumor Diagnosis And Treatment Guided By Optical Imaging

Cancer is one of the biggest killers threatening global human life and health in the 21st century.Due to the high risk and mortality rate of cancer,researchers have been working hard to develop more accurate and efficient integrated diagnosis and treatment platforms.Optical imaging has the advantages of high sensitivity,strong real-time detection,and simple operation,and has been widely used in biological imaging and disease diagnosis.At present,NIR-II fluorescence imaging with low tissue spontaneous fluorescence interference and deep penetration depth,as well as photoacoustic imaging with medium sensitivity and deep tissue penetration,have attracted sufficient attention.At present,NIR-II fluorescence imaging and photoacoustic imaging have been widely used in various aspects of in vivo diagnosis and treatment,such as imaging atherosclerotic plaque,tumors in situ,lymph nodes,surgical navigation,etc.Living tumors have unique characteristics such as microacidity,hypoxia,and high expression of reactive oxygen species（ROS）.Therefore,constructing optical imaging probes based on tumor characteristics for tumor diagnosis and treatment related research remains crucial.Photodynamic therapy（PDT）,as a minimally invasive therapy,has broad application prospects in the treatment of diseases such as tumors.Compared with chemotherapy,radiotherapy and other treatment methods,PDT has advantages such as low drug resistance,non-invasive,good spatiotemporal selectivity,repeatable operation,and minimal side effects.Various ROS produced by photosensitizers under light has been widely used in the treatment of many tumors,such as oral cancer,skin cancer,head and neck cancer,bladder cancer cancer,etc.At present,a large number of photosensitizers have been reported.However,due to the contradiction between the tumor hypoxia microenvironment and the high oxygen dependence of PDT,the effect of some photosensitizers in tumor photodynamic therapy is inhibited.In addition,PDT is difficult to determine issues such as illumination time,photosensitizer dosage,laser irradiation time,and laser intensity.Therefore,auxiliary imaging methods are needed to guide and monitor PDT,achieving efficient PDT while avoiding interference from other factors.Based on the above problems to be solved,this paper synthesizing a series of organic small molecular dyes,through self-assembly into a variety of nanoparticles with excellent performance,and they are used in the diagnosis and treatment of tumor-related diseases,as well as the detection of tumor-related targets.Specific research contents are as follows:（1）In Chapter 2,in order to improve the imaging effect of photoacoustic contrast,we synthesized a new type of photoacoustic contrast agent Nano（O-Nonacene）PEG.Its photothermal conversion efficiency is 1.5 times that of semiconductor polymer nanoparticles（Nano（PCPDTBT）-PEG）and 2.8 times that of Au nanorods.Moreover,Nano（O-Nonacene）PEG exhibits high stability of photoacoustic signals and can be used for long-term photoacoustic imaging.In addition,when magnetic Zn_0.4Fe_2.6O₄ nanoparticles are doped into Nano（O-Nonacene）PEG,the magnetic resonance signal is generated and the photoacoustic imaging effect is greatly enhanced.Therefore,Nano（O-Nonacene）PEG has excellent performance:（i）enhanced photoacoustic effect enables high-resolution photoacoustic imaging in vivo,（ii）small size（10 nm in diameter）is conducive to efficient tumor targeted enrichment,and（iii）efficient photothermal tumor treatment effect in mice.（2）In Chapter 3,aiming at the problems of excitation wavelength length and low imaging resolution,we synthesized a ratio NIR-II fluorescence nanoprobe BTz-IC-H@IR1061.The system consists of small molecules BTz-IC-H and IR1061.There is a fluorescence resonance energy transfer（FRET）between the two molecules,and the fluorescence of BTz-IC-H is quenched by IR1061.In the presence of HCl O,the structure of IR1061 is destroyed,FRET disappears,and the fluorescence of BTz-IC-H molecules is restored,achieving a ratiometric fluorescence signal change.At the same time as fluorescence quenching is turned on,the PDT of BTz-IC-H molecules is also turned off and on,achieving the goal of monitoring the PDT through changes in ratiometric fluorescence signals.In addition,this probe can guide the controllable treatment of subcutaneous tumors in mice through changes in the ratiometric NIR-II region fluorescence signal.（3）In Chapter 4,based on the limited light penetration depth,we developed a series of small molecule organic sound sensitizer BTz-IC-X（X=H,F,Cl,Br）,which was assembled into nanoparticles BTz-IC-X@F127（X=H,F,Cl,Br）by surfactant Pluronic F127.The effect of ultrasound on ROS production was verified in solution and cells.In combination with acetaldehyde dehydrogenase inhibitor KS100,the acid-responsive polymer PEG-PDA and DSPE-m PEG co-doped was used as a surfactant to form BTz-IC-H@KS100@PEG-PDA nanoparticles.Under acidic conditions,KS100 was released and inhibited the activity of acetaldehyde dehydrogenase.Promote the accumulation of toxic aldehydes（such as acetaldehyde,malondialdehyde,etc.）,enhance the activity of ROS and lead to lipid peroxidation process,and finally achieve the effect of amplifying dynamic therapy.（4）In Chapter 5,the ratio NIR-II imaging nanoprobe BTz-IC-H@FD1080@Mn Ox is synthesized by taking advantage of long wavelength and deep penetration in the second region of near-infrared fluorescence imaging.Under acidic conditions,Mn³⁺is released,and the released Mn³⁺reacts with water to produce ROS and converts to Mn²⁺.On the one hand,the ROS produced destroys FD1080,causing the fluorescence resonance energy transfer（FRET）between BTz-IC-H and FD1080 to disappear,thus achieving the ratio type fluorescence signal change in the second region of near infrared.On the other hand,it can make tumor cells die and release ds DNA to activate STING immune pathway.In addition,the generated Mn²⁺can further enhance STING immune pathway.Therefore,the release of ROS and Mn²⁺is monitored through changes in ratiometric fluorescence signals,thereby visualizing the activation of STING immunotherapy.