Multifunctional Synergistic Phototherapeutic Agents: Design,synthesis And Applications In Hypoxic Tumor Treatment

Photodynamic therapy（PDT）,as an emerging phototherapy modality with broad applicability,minimal invasiveness,high accuracy and low side effect,has become a promising way for clinical cancer therapy.In PDT process,the excited state of photosensitizers can transform their energy to O₂ to produce cytotoxic singlet oxygen（¹O₂）upon irradiation with a certain wavelength of light,causing the apoptosis or necrosis of tumor cells,microvascular injury and immune response,achieving noninvasive tumor therapy.However,the therapeutic efficacy of PDT has been badly affected by the hypoxic tumor microenvironment because the poor blood flow in a solid tumor cannot provide a sufficient supply of O₂ for photosensitization during the PDT process,causing a severe decline of PDT effect.Besides,the rapid O₂ consumption during the PDT process will aggravate the hypoxic degree in tumor tissues,which not only restrains the PDT effect,but also increases the treatment resistance and metastatic potential.Hence,tumor hypoxic microenvironment is the most important problem for restricting PDT efficacy.In recent years,various strategies have been developed for efficient treatment of hypoxic tumors,mainly including O₂ delivery systems,in situ O₂ generation strategies,¹O₂ carriers,and type I PDT.Although significant progress has been made,these single-mode strategies still face several obstacles,including insufficient therapeutic effect,limited function,and complicated operation.In addition,the penetration depth of PDT effect mainly depends on the tissue penetration depth of the excitation light.Long-wavelength laser permits phototherapeutic effects to reach deep tissues to improve tumor inhibitory performance.Consequently,developing long-wavelength absorbing photothermal agents and photosensitizer,and exploiting novel less O₂-dependent or O₂-independent therapeutic strategy which can overcome tumor hypoxia through multiple pathways,are highly demanded to further improve tumor clearance efficiency.To solve the above problems,we propose a multifunctional therapeutic strategy based on aza-dipyrromethene（Aza-DP）to realize the synergistic therapeutic effect for deep hypoxic tumors.The structure of Aza-DP is easy to modify,and its property is easy to regulate.Based on the advantages of Aza-DP,the small-molecule and polymeric phototherapy agents were designed.The main research contents of the thesis are described as follows.（1）A series of Zn（II）-coordinated Aza-DP（Zn DPX,X=1,2,3）were designed and synthesized to explore the effect of electron-donating ability of different substituents on their photophysical and photoconversion properties,so as to obtain high-performance PDT and PTT（Photothermal Therapy）synergistic phototherapy reagents based on low-cost transition metal complexes.Their good photothermal conversion performance was adopted to provide photoacoustic imaging guidance and O₂-independent PTT damage for hypoxic tumor treatment.The limitation of the hypoxic microenvironment on the therapeutic effect of PDT was alleviated.Finally,an accurate PTT/PDT synergistic treatment of hypoxic tumors was realized.（2）Based on the advantages of controllable photoconversion behavior,adjustable excitation wavelength,and easy modification of polymer,the heat-responsive singlet oxygen carrier（1,4-dimethylnaphthalene）was introduced into the polymer.Both the photothermal/photosensitizing unit（iodinated Aza-BODIPY derivative）and the hypoxia-responsive prodrug unit（Azobenzene derivative）were employed to construct a multifunctional integrated NIR polymeric singlet oxygen carrier as phototherapy system to achieve PDT,PTT,and CT（Chemotherapy）synergistic therapy.Moreover,the process of ¹O₂ capture and release was regulated in this study by adjusting the power of a single laser alone,without the need for additional light sources,photosensitizers,or photothermal reagents to control ¹O₂ capture and release.This method is easier to operate and more practical,with a significant advance.In the treatment of hypoxic tumors,multiple therapeutic approaches simultaneously take effect to overcome the complication that the hypoxic microenvironment restricts cancer treatment.（3）A novel NIR polymer synergistic therapeutic system was constructed by introducing a heat-responsive nitric oxide（NO）donor（Captopril derivative）and a photothermal unit（Aza-BODIPY derivative）into the polymer.The photothermal unit was used to provide not only PTT action for tumor cells but also sufficient thermal stimulation for NO donors to achieve the combined treatment of PTT and NO gas therapy.The PTT and NO gas therapy contained in this polymer phototherapy reagent were both O₂-independent treatments.The treatment process is not limited by the low oxygen content in the tumor tissue,nor does it aggravate the degree of hypoxia inside the tumor,enabling it to effectively overcome the therapeutic obstacles caused by the hypoxic microenvironment.