Design,preparation,and Diagnosis And Therapy Applications Of Diketopyrrolopyrrole-Based Near-Inrared Absorption Water-Soluble Conjugated Polymers And Composite Nanomaterials

Recently,water-soluble conjugated polymers have been used in fluorescence/photoacoustic imaging guided tumor therapy research due to their good water solubility,excellent photoelectric properties,and low biological toxicity.Photoacoustic imaging（PAI）is the reconstruction of images of biological tissues by detecting ultrasound signals converted from the absorbed of light energy by photoacoustic contrast agents.It has the advantages of high contrast,high penetration,and high resolution.Fluorescence imaging（FLI）forms images by detecting the intensity of fluorescence signals emitted by fluorescent contrast agents after excitation,and has the advantages of high sensitivity and fast response.The combination of two imaging methods visualizes the tumor situation in the body,playing a huge role in real-time guidance and dynamic monitoring of tumor treatment.At present,photodynamic therapy（PDT:photosensitizers produce reactive oxygen species under laser irradiation to ablate tumors）,photothermal therapy（PTT:transform light energy into heat energy to kill tumor cells through photothermal agents）and chemical dynamic therapy（CDT:ablate tumors through hydroxyl radical generated by Fenton or Fenton like reactions）have aroused extensive research interest in recent years.They all have the advantages of low side effects and low invasiveness,and high specificity,and research has shown that the combination of PTT and PDT can promote each other,and the combination of PTT and CDT can enhance the efficacy of CDT.Currently,the absorption and emission of most developed diagnostic and therapeutic agents are in the first near-infrared region（NIR-I,700-1000 nm）.However,excitation in the near-infrared second region（NIR-II,1000-1700 nm）can more effectively reduce tissue light scattering,light absorption,and endogenous fluorescence,making excitation light more effective in penetrating biological tissues for imaging and treatment.Therefore,there is an urgent need to develop diagnostic and therapeutic agents with NIR-II absorption.Manganese dioxide（Mn O₂）nanomaterials are transition metal oxide nanomaterials with redox properties,possessing unique composition,structure,and physicochemical properties.Mn O₂ can react with H₂O₂ in weakly acidic tumor environments to generate Mn²⁺and O₂,and Mn²⁺and H₂O₂undergo Fenton like reactions to produce·OH,which can enhance PDT and CDT,respectively.Therefore,Mn O₂ nanomaterials provide a new pathway for enhancing therapeutic efficacy.Diketopyrrolopyrrole（DPP）derivatives are prone to absorb strongly in the NIR region,exhibiting high planarity,strong electron absorption ability,good photothermal conversion ability,and certain singlet oxygen generation ability.Therefore,we have designed and developed a series of DPP based NIR absorption water-soluble conjugated polymers in this paper,and prepared composite nanomaterials based on Mn O₂ for PTT/PDT/CDT synergistic tumor therapy guided by FLI/PAI.The main research work is as follows:1.Using DPP derivatives and 4,9-bis（5-bromothiophenyl）-6,7-bis（4-hexoxyphenyl）-[1,2,5]thiadiazo[3,4-g]quinoxaline（TQ）as electron acceptor（A）,doped with fluorene derivatives in different proportions（0,10%,20%）as electron donor（D）,three water-soluble conjugated polymers P1,P2 and P3 were obtained by direct（hetero）aromatization polymerization（DHAP）.Polyethylene glycol（PEG）is introduced into the side chains of DPP and fluorene derivatives.As the proportion of fluorene derivatives in the system increases,the absorption of the polymer undergoes a red shift,and the absorption gradually increases at 808 nm and 1064 nm.The singlet oxygen yields of P1,P2,and P3 are 25.20%,22.35%,and 56.07%,respectively.The photothermal conversion efficiency is31.92%,45.02%,30.89%（excited at 808 nm）,and 38.76%,59.17%,and 41.17%（excited at 1064nm）,respectively.P2 has the best photothermal effect,while P3 has the highest singlet oxygen yield and fluorescence quantum yield.The mouse breast cancer cell（4T1）experiment show that the three polymers can inhibit the proliferation of cancer cells through PDT/PTT synergistic treatment,and the effects of P2 and P3 are better than P1.2.The conjugated polymer DPP-PEG previously prepared by our research group has strong NIR-I absorption peak（812 nm）and NIR-II fluorescence emission（950-1400 nm）,as well as good photothermal conversion performance and certain photodynamic property.However,its water solubility still needs improvement.Based on the excellent properties of Mn O₂,bovine serum albumin BSA-Mn O₂（B-M）complex is prepared by biomineralization method in this chapter,and DPP-PEG is further loaded to obtain DPP-PEG/BSA-Mn O₂（DPP-PEG/B-M）composite nanomaterials.At the same time,DPP-PEG/BSA（DPP-PEG/B）is prepared as a control.The water solubility and singlet oxygen generation ability of DPP-PEG/B-M are significantly improved as compared with DPP-PEG,and the addition of Mn O₂ can produce·OH in the tumor microenvironment,and also enhance the CDT effect.The 4T1 cell experiments also demonstrated that DPP-PEG/B-M is more effective in inhibiting the proliferation of cancer cells than DPP-PEG/B.Meanwhile,the experiments on 4T1 tumor bearing mice have shown that DPP-PEG/B-M can generate FL/PA signals in vivo,possessing the potential for FLI/PAI guided PDT/PTT/CDT synergistic therapy.