Synthesis And Study Of Photothermal Properties Of Organic Nanomaterials With "D-A" Structure

Cancer has plagued human lives for centuries,causing millions of deaths annually.Compared with traditional cancer therapies,phototherapy is a means of damaging cancer cells by singlet oxygen or thermal effect with near-infrared light.The minimally invasive treatment has gained great interest owing to its controllability,high efficiency and safety.Therefore,the development of near-infrared absorption phototherapy agents provides a novelty means for tumor treatment.AD is a progressive neurodegenerative disease in which the aggregation or misfolding of amyloid-βin vivo is the critical step in the pathogenesis.Because amyloid formation is highly dependent on temperature,the change of localized temperature can affect Aβaggregation.However,current photothermal materials has limited by poor solubility in humoral environment,inadequate selectivity,uncontrollable photoactivity and non-specific activation.To overcome these limitations,it is urgent to develop a switchable photothermal agent that can be selectively activated at particular condition beside light.The dissertation work includes the following four parts:（1）Preparation of porphyrin monomer nanomaterials and study on photothermal therapy for tumors.In this chapter,hydrophilic porphyrin and diketopyrrolopyrrole were linked to donor-acceptor（D-A）structure through alkyne bond,and then self-assembled into organic nanoparticles Pdpp NPs（～119 nm）.The nano-frame enhanced system"D-A"structure,the ultraviolet maximum absorption of Pdpp NPs red-shifted from 661 nm to 705 nm.Subsequently,the binding mode and constant of Pdpp NPs to ct-DNA,photodynamic performance,photothermal effect,cytotoxicity and 4T1 tumor-bearing mice model experiments had been studied.Pdpp NPs bound to ct-DNA through external mode.The photothermal conversion efficiency（PCE）of the Pdpp NPs was calculated to be 53.61%under the continuous laser irradiation（680 nm,1 W/cm²）.Cellular experiments demonstrated that Pdpp NPs showed highly phototoxic to 4T1 cells with irradiation.The photothermal imaging signal intensity was maximum after 7-8 hours of drug intravenous injection.Within21 days after administration and photothermal therapy,the tumor volume was reduced from303.35 mm³to 81.59 mm³,with an average mass of 0.69 g.No pathological changes were observed in vital organs under H&E staining,and TUNEL-stained tumor sections showed partial necrosis in the photothermal group,indicating that Pdpp NPs could inhibit tumor growth under 680 nm laser irradiation.Considering the advantages of facile fabrication,good biocompatibility and high photothermal therapeutic performance and photothermal stability,Pdpp NPs are expected to be potential photothermal reagents for the photothermal treatment of tumors.（2）Preparation of porphyrin dimer nanomaterials and study on photothermal therapy for tumors.The organic small molecule nanomaterials Pdpp NPs prepared in the previous chapter had problems such as weak near-infrared absorption,poor tissue penetration ability and therapeutic effect of 680 nm irradiation.To solve these issues,in this chapter,the polymeric organic nanomaterials Ppordpp NPs were synthesized by modifying the diketopyrrolopyrrole compounds.The donor-acceptor（D-A）porphyrin dimer molecule Ppordpp was synthesized by Sonogashira coupling reaction,which UV absorption maximum absorption and fluorescence emission reached to 885 nm and 1034 nm,and the UV absorption wavelength red-shifted to 943 nm after self-assembly with the fluorescence completely quenched.TEM confirmed the morphology of Ppordpp NPs as spherical particles of ca 190 nm with good dispersion.After a series of tests of oxygen species generation ability,photothermal effect,cytotoxicity and 4T1 tumor-bearing mice model experiments showed the photothermal conversion efficiency of Ppordpp NPs was as high as 86.21%under low-density laser irradiation（940 nm,0.75 W/cm²）.And Ppordpp NPs could passively target the tumor sites owing to the EPR effect.The tumor volume decreased from 362.71 mm³to 0.65 mm³within21 days after administration and photothermal therapy,with an average mass of 0.04 g that could ignored.It was indicated that Ppordpp NPs showed high anti-tumor efficacy at 940 nm irradiation,where the tumor sites experienced cell necrosis,crusting and shedding until spontaneous healing.Moreover,Significant changes without any observed in heart,liver,spleen,lung,and kidney these organs under H&E staining and tumor sections stained showed obvious necrosis of tumors in irradiation group.In conclusion,Ppordpp NPs had good photothermal stability,biocompatibility,at the same time,tiny biologic toxic and high antitumor efficacy made it great application prospects in photothermal therapy.（3）Preparation of fluoroboron dipyrrole organic nanomaterials and study on photothermal therapy for tumors,In this chapter,fluoroborodipyrrole was introduced with a triethylene glycol chain to enhance its hydrophilicity and then conjugated with N,N-dimethylstyrene to extend theπ-conjugation system,increasing the absorbance in the near-infrared region.The BDP-PEG NPs with D-A hydrophobic twisted structures stacked on top of each other and wrapped by hydrophilic triethylene glycol chains externally were self-assembled,leading ultraviolet maximum absorption red-shifted from 689 nm to 770 nm.In-depth bioactivity experiments of binding mode of BDP-PEG NPs to ct-DNA,photodynamic properties,photothermal properties,cytotoxicity and 4T1 tumor-bearing mice model experiments were carried out.The results showed that BDP-PEG NPs interacted with ct-DNA via an external binding mode with a binding constant of 2.49×10⁵,and the photothermal conversion efficiency was calculated to be 61.42%with laser irradiation（808 nm,1 W/cm²）.Cellular experiments demonstrated that BDP-PEG NPs showed highly phototoxic to 4T1 cells.The tumor volume decreased from370.55 mm³to 5.13 mm³,with an average mass of 0.35 g which was 6 times smaller than that of the control group within 21 days after administration and photothermal therapy.Moreover,important organs were no observed under H&E staining for the occurrence of obvious lesions,and TUNEL staining showed significant tumor necrosis with 808 nm irradiation.The above results indicated that that BDP-PEG NPs was a potential NIR photothermal agent with effectively inhibit tumor growth and ablate tumors with 808 nm laser irradiation（4）Preparation of polymer thermosensitive nanomaterials and their photothermal therapy for AD.In this chapter,we explored a smart platform based on a boron dipyrrolidone scaffold based photothermal agent（BDP）was integrated with a temperature-responsive polymer backbone of hydroxypropyl cellulose（HPC）for the photothermal dissociation of Aβprotein aggregates.The resultant polymeric nanomaterial BDP-HPC exhibits an ultra-high photothermal conversion efficiency of 78.1%along with prominent cyclic stability of phase-transition behavior under NIR irradiation（680 nm,1 W/cm²）in the light of the lower critical solution temperature（LCST at 42.5℃）.A series of characterization results including CD,TEM,DLS analysis,confocal fluorescence microscopy images and PC12 cell viability suggested that thermo-switchable BDP-HPC with excellent reversible phase transition behavior could be used as inhibitor for prolonging the Aβ₄₂fibril process and decreasing the aggregation,which are capable of not just quenching but actually temporarily reversing the fibrillation of Aβ₄₂protein.The survival rate of PC12 cells was sharply increased from 48%to 94.4%with 2.0 h irradiation,The results demonstrated that the NIR irradiation could manipulate the reversible phase transition behavior of BDP-HPC provided a new strategy for the treatment of AD.