Construction And Combined Therapy Application Of Diketopyrrolopyrrole Derivatives / MnO₂ Composite Nanodiagnostic Agents And Therapeutic Agents

Cancer has been raging around the world for a long time and countless patients are facing great suffering.As an effective way to fight cancer,phototherapy is characterized by low tissue resistance,low invasiveness and good spatiotemporal controllability.In recent years,photothermal therapy(PTT)and photodynamic therapy(PDT)have made great progress and shown broad application prospect in the field of cancer treatment.In addition,bioimaging technology based on organic semiconductor materials has also made great contributions to the diagnosis and treatment of cancer.,and resolution of metabolic fluorescence imaging(FLI),has the characteristics of high sensitivity and fast response speed,which can be used for real-time monitoring of clinical surgeries.Photoacoustic imaging(PAI)is an emerging imaging method with the advantages of selectivity,penetration,and high resolution,enabling ultra-deep imaging of biological tissues.Organic semiconductor small molecules have good light absorption performance,are easy to regulate optical properties through structural design,and have low biotoxicity and cost.Therefore,it is of profound significance to create an integrated platform of phototherapy and bioimaging based on organic semiconductor small molecules for the diagnosis and treatment of cancer.TDPP not only exhibits excellent photothermal effects due to its large π-conjugated structure,but also exhibits strong intramolecular charge transfer(ICT)effect,making it an ideal electron acceptor unit.However,poor water solubility and short absorption wavelength limit the medicinal value of TDPP.On the other hand,manganese dioxide nanoparticles(Mn O2 NPs)have a large specific surface area,can catalyze the endogenous H2O2 generated by tumors to generate O2,generating additional heat,thereby alleviating tumor hypoxia and enhancing PDT and PTT effects.They are widely used in drug delivery and release,chemodynamic therapy(CDT),PDT and PTT.Based on the advantages of TDPP,we designed and prepared two kinds of organic conjugated small molecules with extended near-infrared absorption wavelengths.Two composite nano diagnostic and therapeutic agents were obtained by encapsulating two small molecules with hydrophilic poly(ethylene glycol)-block poly(propylene glycol)-block poly(ethylene glycol)(Pluronic F-127)and then combining them with Mn O2 NPs.Both nanoparticles have been used to guide the combination of PTT and PDT in cancer treatment under photoacoustic imaging and fluorescence imaging.The specific research contents are as follows:1.Near-infrared absorptionorganic conjugated small molecule(FVD)with D-π-A structure was synthesized from fluorene derivatives,vinylbenzene and TDPP derivatives.Then,it was coated with Pluronic F-127 to form FVD@F127 NPs to improve the water solubility of FVD.Finally,Mn O2 NPs was loaded onto the surface of FVD@F127 NPs by electrostatic action to improve its singlet oxygen yield and enhance the effect of PDT and PTT.The photothermal conversion efficiency of FVD@F127 NPs is 39.4%,and the singlet oxygen yield is 33.83%.The photothermal conversion efficiency and singlet oxygen yield of FVD@F127@Mn O2 NPs increased to 43% and 38.48%,respectively.In vitro cell experiments show that the biocompatibility of these two nanoparticles is very good.When the concentration of the two nanoparticles was 200 μg/m L,both of them can effectively inhibit the growth of 4T1 cells by PTT/PDT combination therapy.In vivo experiments have shown that,FVD@F127@Mn O2 NPs can perform clear photoacoustic and fluorescence imaging of tumor in mice under 660 nm laser irradiation.2.On the basis of molecular structure of FVD,the unmodified Br atom at the end of TDDP unit was used to further design and synthesize near-infrared absorption organic conjugated small molecule FVDVF.It has a D-π-A-π-D molecular structure,which not only extends the emission spectrum to the second region of near infrared but also obtain stronger molecular rigidity,which is conducive to the non-radiative transition of excited molecules,and emit more heat to enhance the photothermal conversion efficiency.At the same time,FVDVF@F127 NPs and FVDVF@F127@Mn O2 NPs were prepared by the same procedure as 1,and their photothermal conversion efficiencies were 65.9% and 68.48%,respectively,and singlet oxygen yields were 24.39% and 38.95%,respectively.In vitro experiments show that the two nanoparticles can effectively kill tumor cells under 730 nm laser irradiation.In particular,FVDVF@F127@Mn O2 NPs can not only perform clear photoacoustic imaging of tumor in mice under 730 nm laser irradiation,but also can image tumors by emitting NIR-II fluorescence under 808 nm laser irradiation.