Design Of Near-Infrared-Ⅱ Organic Semiconducting Polymers For The Combination Therapy Against Cancer

Optical technology has been widely used in modern medicine,and has played an important role in the diagnosis and treatment of many diseases.Phototheranostics can be divided into two parts: optical diagnosis and optical treatment.It is a minimally invasive and efficient diagnosis and treatment method that uses specific light to image or eliminate tumors.Fluorescence imaging(FI)is a technology in which fluorescent substances are injected into the living body and photoexcited.The fluorescence signals emitted by the fluorescent substances after being excited will be captured by the machine to achieve high-precision imaging of the tumor.Due to the limited tissue penetration of fluorescence imaging in the conventional wavelength range(400-950nm),researchers have developed a method for fluorescence imaging in the NIR-Ⅱ region(1000-1700 nm)in recent years.NIR-Ⅱ fluorescence imaging has the advantages of low light scattering,low self-absorption of biological tissues and high signal-to-noise ratio,which can carry out high penetration depth and high resolution imaging of biological tissues,and further promote the application of fluorescence imaging in biomedicine.Nowadays,the representative fluorescent dyes are: gold nanoparticles,single-walled carbon nanotubes(SWCNTs),quantum dots(QD),rare earth doped nanoparticles(RENPs),semiconductor polymer nanoparticles(SPNs),small molecule dyes(SMD),and so on.SPNs have good biocompatibility and high photostability,and have been successfully applied in fluorescence imaging,photoacoustic imaging,chemiluminescence imaging and so on.Phototherapy has the advantages of high efficiency,minimal invasiveness,high penetration depth and few side effects.Among them,photothermal therapy(PTT)is a therapeutic method in which nano-agents can kill tumors by inducing photothermal conversion through non-radiative decay under photoexcitation.PTT has the advantages of strong operability,high specificity and remarkable therapeutic effect.In addition,photodynamic therapy(PDT)is also an effective method to treat cancer and other diseases.The principle is that photosensitizer induces the transfer of photon energy to the surrounding oxygen to produce reactive oxygen species(ROS)to kill the lesion site.Single phototherapy effect is limited,often lead to incomplete tumor elimination,easy to relapse and metastasis and other problems.Therefore,combining phototherapy with chemotherapy,immunotherapy,gene therapy and other means to develop combination therapy is a feasible method to improve the efficacy of optical therapy,which is also the focus of current research in this field.Based on optical diagnosis and treatment,two different nano-diagnosis and treatment systems are constructed in this thesis,and different diagnosis and treatment platforms combining imaging and treatment methods are studied.Specific research contents are as follows:(1)Conjugated polymer nanoparticles loaded with DOX were used in the combination chemotherapy/photothermal therapy mediated by NIR-Ⅱ fluorescence imaging.In this chapter,we designed a multifunctional phototheranostic system(SPN@DOX)that can be used in the combination of NIR-Ⅱ fluorescence imaging,photothermal therapy and chemotherapy.Firstly,the nanoparticle SPN was prepared by nanoprecipitation method using amphiphilic polymer HA-DSPE-PEG and SP,which was adsorbed by DOX to yield the SPN@DOX.Due to the presence of HA on the surface,the SPN@DOX can specifically bind to cancer cells to deliver drugs targeted to the tumor site.SPN@DOX provides efficient NIR-Ⅱ fluorescence imaging of tumor sites under 808 nm laser irradiation.At the same time,under 1064 nm laser irradiation,SPN@DOX can produce photothermal effect along with the drug DOX to kill tumor cells.Therefore,we developed a nanoplatform for photodiagnosis and treatment based on the combination of chemotherapy/photothermal therapy mediated by NIR-Ⅱfluorescence imaging.(2)Conjugated polymer nanoparticles doped with naphthalimide were used in NIRⅡ fluorescence imaging-mediated photodynamic/photothermal combination therapy.In this chapter,we designed and synthesized a water-soluble conjugated polymer(NDI-Se-DPP-PEG)doped with naphthalimide.Firstly,NDI and DPP was polymerized with three different link monomers respectively at the ratio of 1:1:2,and three materials(NDI-O-DPP-PEG,NDI-S-DPP-PEG,NDI-Se-DPP-PEG)were prepared by subsequent PEG modification.Then,by comparing the photodynamic properties of the three materials,NDI-Se-DPP-PEG with the best performance was selected for biological experiments.It is found that the doping of naphthalimide can improve the photodynamic and photothermal properties of the materials to a certain extent,and the NDI doping showed the ability to produce superoxide anion which was not found before.Through experiments,we found that NDI-Se-DPP-PEG can efficiently generate reactive oxygen species under 808 nm laser excitation,and has high photothermal efficiency.In vitro studies have shown that NDI-Se-DPP-PEG can be effectively taken up by cancer cells and can kill cancer cells with high efficiency under near-infrared laser irradiation(killing rate: 77%).Therefore,we developed a single-component nanotheranostic system that induces photothermal and photodynamic therapy through a single light excitation.