Synthesis Of Water-soluble Functional Theranostic Agent For Combined Therapy Based On Diketopyrrolopyrrole

Nowadays,as a highly concerned cancer treatment method,combination therapy solves the problem that a single treatment method can not completely eliminate tumors in clinical practice and exploratory research,which is also ineffective in preventing metastasis of tumors.For example,long-term use of anticancer drugs often leads to multidrug resistance?MDR?in tumors,which is the cause of the gradual failure of chemotherapy;because hypoxic cancer cells are insensitive to ionizing radiation,radiotherapy?RT?also loses its original therapeutic effect in hypoxic environment.Therefore,in order to overcome the obstacles of single treatment,the combination of two or more forms of treatment is proposed as an alternative treatment.Nowadays,light therapy has been widely used in clinical practice,which is little harmful for human body.Also,it is efficient,accurate and is easy to adjust.As a typical non-invasive photodynamic therapy mode,photodynamic therapy?PDT?has been applied in clinic and has been successfully used in the treatment of cancer.Photosensitizers can be selectively activated to produce cytotoxic reactive oxygen species?ROS?at a specified wavelength of light,which can induce cancer cell death.Because of the air-conditioning time of light transmission,the production of reactive oxygen species can be accurately controlled in tumour tissues rather than in normal tissues,thus realizing tumor-specific PDT and achieving the goal of minimal side effects.Photothermal therapy?PTT?is another phototherapy mode that uses photothermal conversion agents?PTCA?to generate heat for thermal ablation of cancer cells,compared with PDT in which photosensitizer induces ROS-induced cancer cell death.In this paper,two new ideas of photothermal and photodynamic therapy are proposed.The specific research contents are as follows:?1?Multifunctional supramolecular vesicles are used in combination therapy for photothermal/photodynamic/photoinduced hypoxia-activated chemotherapy:Multifunctional supramolecular vesicles based on recognition of water-soluble pillar[5]arene?WP5?and G were fabricated.It can exist stably in aqueous solution when[WP5]/[G]=1/3 and its?-potential reaches-30.99 mV.As a photothermal conversion agents?PTCA?for photothermal therapy,the temperature of vesicles?[G]=300?g/mL?rises rapidly to 53?within 7 minutes under the irradiation of 660 nm.The photothermal conversion efficiency of WP5?G is 52.56%.At the same time,G is also used as photosensitizer?PS?in photodynamic therapy,and the singlet oxygen yield reaches 59%.With good hydrophilicity of vesicles and high hypoxic-activated prodrug tirapazamine?TPZ?,TPZ could be released rapidly in acidic microenvironment of tumor site.About 64.6%and 81.7%TPZ could be released within 24 hours at pH=6.0 and 4.5.The loaded prodrug TPZ could be reduced to cytotoxic oxidizing radicals under a PDT-induced hypoxic environment for synergistic enhancemen of cancer therapy.Under laser irradiation?660 nm?,the survival rate of MCF-7 cells treated with TPZ-loaded vesicles?[G]=30?g/mL?was only 18%,which achieved good therapeutic effect.TPZ-loaded vesicles can effectively enter MCF-7 cancer cells,and accurately locate the lysosomes of cancer cells.And the vesicles can achieve significant drug accumulation in the tumor site,which further proves the good biocompatibility of drug-loaded vesicles.?2?Water-soluble organic semiconducting oligomer nanoparticles are used in combination therapy for photothermal/photodynamic/NIR-II imaging:DPP-BT-PEG nanoparticles have good absorption in the near infrared region of 550⁸00 nm,and the calculated molar extinction coefficient is 3.8×10⁴ M^-11 cm^-1.It also has good NIR-II fluorescence imaging.The maximum fluorescence wavelength of DPP-BT-PEG nanoparticles is 1000 nm when stimulated by 808 nm laser.Under the irradiation of 660 nm laser,DPP-BT-PEG?200?g/mL?,as a photothermal conversion agents,rapidly rises to 61?within 4 minutes,and the photothermal conversion efficiency is calculated to be 56.71%.Meanwhile,as a photosensitizer,the singlet oxygen yield is61.23%.Under laser irradiation,with the increase of material concentration,the therapeutic effect is continuously enhanced.When the concentration reaches 30?g/mL,the survival rate of cells is less than 20%.It can effectively kill cancer cells and achieve the effect of inhibiting the growth of tumors.