Design,Synthesis,and Diagnosis And Treatment Applications Of Water-soluble Conjugated Polymers Based On Diketopyrrolopyrrole

Water-soluble conjugated polymers(WSCPs)are a type of conjugated polymers(CPs)which have hydrophilic side chains.They have been widely used in biomedical fields such as fluorescence/photoacoustic imaging and phototherapy.Fluorescence imaging has the characteristics of high sensitivity and rapid response,which can realize real-time imaging in clinical surgery.Photoacoustic imaging has high selectivity and high penetration,and can obtain high-resolution,highcontrast tissue images.As an emerging method for the treatment of malignant tumors,phototherapy has unique advantages such as high selectivity and good biological safety.Among them,photothermal/photodynamic synergistic therapy is an innovative strategy to obtain ideal therapeutic effects.At present,most of the materials that have been developed absorb or emit mainly in the first nearinfrared region(NIR-Ⅰ,700～1000 nm),and the penetration depth of NIR-Ⅰlight into tissues is limited.Studies have shown that the penetration depth of NIR-Ⅱ(NIR-Ⅱ,1000～1700 nm)light is much greater than that of NIR-Ⅰ light,so it shows much greater advantages in the diagnosis and treatment of deep tumors.In order to treat deeper tumors,reduce tissue scattering,and improve imaging accuracy,it is urgent to develop NIR-Ⅱ fluorescent materials with the same NIR excitation light source,so that it can simultaneously have fluorescence/photoacoustic imaging,photothermal/photodynamic synergistic treatment effects.The diketopyrrolopyrrole(DPP)molecule is a planar conjugated structure with a broad absorption peak in the NIR region,high photothermal conversion capacity and a certain amount of active oxygen generation capacity.Therefore,we have designed and developed a series of new WSCPs based on DPP:(1)DPP derivatives,fluorene derivatives and dithiophenes were copolymerized through Heck reaction to obtain WSCPs with ethylene bonds as π-conjugated bridges;(2)DPP derivatives covalently grafted with PEG chains are used for direct(hetero)arylation(DHAP)polymerization with two other monomers to expand the conjugated system to obtain two WSCPs.The main research work is as follows:1.Heck coupling reaction has the advantages of high catalytic activity and short catalytic induction period.The hydrophilic chain-modified fluorene derivative,DPP derivative,and dithiophene are coupled through Heck reaction to obtain a CP(P1),and then quaternized to obtain WSCP(P1’).By introducing PEG segments into DPP to improve its water solubility and keeping other monomers unchanged,another kingd of WSCP(P2)is obtained,and then P1’ and P2 are prepared into nanoparticles(NPs)for better application in vivo.The water solubility of P2 is significantly better than that of P1’,and the singlet oxygen yields of the two are 56.1% and 47.44%,respectively,indicating that the introduction of PEG side chains can not only improve the water solubility,but also increase the singlet oxygen generation capacity.In addition,the NIR-Ⅱfluorescence emission peak of P2 reaches about 1000 nm,and the photoacoustic signal intensity of P1’ NPs is nearly twice that of P2 NPs.In vitro He La cell experiments confirm that both P1’ NPs and P2 NPs show excellent biocompatibility and excellent photothermal/photodynamic synergistic therapy effects.2.DHAP is a novel method for preparing conjugated polymers developed in recent years.It has the advantages of environmental friendliness,convenience,and low cost.The PEG chain-modified DPP derivative is respectively polymerized with thiophene or another carbon chain-substituted DPP derivative through DHAP reaction to obtain two WSCPs P3 and P4,which are prepared into nanoparticles respectively.Both P3 and P4 emit NIR-Ⅱ fluorescence in the range of 700～1200 nm and 950～1400 nm,respectively.P3 and P4 NPs also show excellent photoacoustic signal intensity and photothermal/photodynamic therapy effects,and P4 NPs perform well in the in vivo NIR-Ⅱimaging,which can be used for clear imaging of blood vessels in the mouse brain and legs.It is expected to become a NIR-Ⅱdiagnostic and therapeutic agent integrating fluorescence/photoacoustic imaging and photothermal/photodynamic therapy.