| In recent years,organic conjugated materials,which are easily to be designed and synthesized through chemical methods to achieve the adjustable photophysical properties and low biological toxicity,have been widely studied in the field of biomedical research including fluorescence,photoacoustic imaging and phototherapy to deal with the diagnosis and treatment of major diseases(such as tumors).As an emerging imaging technology,fluorescence and photoacoustic imaging can realize real-time dynamic monitoring with high sensitivity,resolution and contrast without using radioactive materials.Moreover,photoacoustic imaging combines the high penetration characteristics of ultrasound imaging.Phototherapy mainly includes photodynamic therapy(PDT)and photothermal therapy(PTT).It is a non-invasive cancer therapy,with the characteristics of high selectivity,good treatment effects and low side effects.Compared with traditional surgical treatment combined with chemotherapy,it shows unique advantages.The strong adaptability and stubborn vitality of tumor cells is also one of the reasons for the recurrence of cancer treatment.Research shows that the synergistic treatment of photodynamic and photothermal therapy is an innovative strategy to obtain ideal therapeutic effect.In order to treat the deeper diseased tissues,reduce tissue scattering,and improve imaging accuracy,it is urgent to develop new materials with the same photodynamics and photothermal near infrared(NIR)excitation light source to avoid tissue injury caused by laser and reduce side effects and psychological pressure on patients produced by multiple laser irradiations.Furthermore,in oeder to significantly improve the tumor cure rate and survival rate,the realization of phototherapy under the guidance of accurate tumor imaging has become a leading international research topic.Hyaluronic acid(HA)characterized with good biocompatibility and easily chemical modification is a natural biological macromolecular polysaccharide,and it can achieve active tumor targeting based on the specific combination of HA and CD44 receptor.Therefore,in this thesis,we designed and developed a diketopyrrolopyrrole(DPP)-based near-infrared conjugated material(TTDTT),which integrated imaging and phototherapy,and combined with hyaluronic acid and chlorin e6(Ce6)to prepare composite nano meterials,which realized the excitation of a single near-infrared light source.Under the guidance of fluorescence / photoacoustic dual-modal target imaging,we performed photodynamic and photothermal cooperative treatment,so as to achieve better diagnosis and treatment.In the TTDTT molecule,DPP with high photothermal conversion efficiency,photoacoustic characteristics,and certain singlet oxygen generation capacity,is regarded as an electron-withdrawing group(A),and the electron-rich thiophene group acts as a ?-conjugated bridge,to increase the excitonic intersystem crossing ability by the heavy atom effect,which is conducive to improving the photodynamic effect.In addition,triphenyla mine(TPA)has been widely used in biological materials as an electron donating group(D)for its unique propeller structure and strong electron donating ability to effectively trigger cell death.TTDTT with the structure of D-?-A-?-D is expected to achieve good near infrared absorption to increase the migration speed of charges in the molecule and help to improve the light-to-heat conversion efficiency.The specific research contents are as follows:1.TTDTT with D-?-A-?-D structure was synthesized from TPA,thiophene and DPP derivatives by using suzuki reaction.HA was coupled with TTDTT through disulfide bond,which endowed TTDTT with biocompatibility,water solubility and targeting,and formed amphiphilic material.HATTDTT nanoparticles were self-assembled by the dialysis method.HA-TTDTT NPs exhibit broad absorption ranging from 500 to 750 nm with the near infrared absorption characteristic peak at 650 nm in water,which display good phototherapy effect with singlet oxygen yield of 29.6% and photothermal conversion efficiency up to 43.9%.The photoacoustic imaging ability and photodynamic / photothermal combined treatment effects of HA-TTDTT NPs were confirmed by the solution and in vitro He La cell experiments.2.In order to further optimize the diagnosis and treatment capabilities,a porphyrin photosensitizer Ce6 with a near-infrared absorption wavelength similar to TTDTT was introduced into the composite nanomaterial.Ce6 has been proven to have high singlet oxygen production capacity,and is widely used in the treatment of various malignant tumors such as lung cancer,breast cancer,and ovarian cancer.Ce6 was encapsulated inside nanoparticles through weak molecular interactions such as hydrophobicity,hydrogen bonding,and ?-? stacking,to construct a composite nano diagnostic and therapeutic agent Ce6@HA-TTDTT NPs.The singlet oxygen yield in aqueous solution was as high as 52.9%,and the photothermal conversion efficiency was 37.7%.The experiment in solution and in vitro He La cell experiment confirmed that Ce6@HA-TTDTT NPs excited at a single near infrared wavelength(635 nm)have achieved the photodynamic/photothermal synergistic treatment under the guidance of fluorescence/photoacoustic dual-modality targeted imaging.In the in vivo mouse experiment,a good diagnosis and treatment effect was achieved,and the tumor inhibition rate of a single light(10 min)was as high as 86.36%. |
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