Tumor Hypoxia Imaging And Photodynamic Therapy Based On Phosphorescence Photosensitizers

Hypoxia is one of the most important features of solid tumor,which has been served as a tumor marker for cancer diagnosis.However,the hypoxic microenvironment can facilitate the drug resistance of the cancer cells and reduce the therapeutic effectiveness.Therefore,the development of cancer diagnosis and therapy methods against tumor hypoxia is significant in clinical medicine.Phosphorescent photosensitizers exhibit the long-lived triplet excited state,which could result in the generation of oxygen-sensitive phosphorescence and toxic reactive oxygen species(ROS),and thus were widely applied in hypoxia imaging and photodynamic therapy(PDT)of tumor.However,most commonly used photosensitizers require ultraviolet or visible light excitation,which will seriously decrease the tissue penetration depth and generate the background autofluorescence interference,limiting their applications in tumor hypoxia imaging and PDT.Moreover,the hypoxic environment in tumor will also suppresse the PDT effect of the photosensitizers,because the generation of singlet oxygen needs the participation of oxygen molecules.To solve the above problems,the oxygen sensors with high signal-to-noise ratio(SNR)and deep tissue penetration and photosensitizers with improved PDT effect under hypoxia conditions were designed and synthesized based on iridium(?)complexes to realize more efficient hypoxic tumor diagnosis and therapy.Finally,the performance of the oxygen sensors and photosensitizers was evaluated and discussed in detail.The research contents of this thesis include the following parts: 1.A phosphorescent iridium(?)complex-modified nanoprobe for hypoxia bioimaging via time-resolved luminescence microscopyA NIR light excitable oxygen nanoprobe was designed and synthesized base on the energy transfer process between the upconversion nanoparticles(UCNPs)and the oxygen-sensitive Ir(?)complex to increase the tissue penetration.Besides,the long-lived phosphorescence of Ir(?)complex could also be distinguished from the short-lived autofluorescence via time-resolved luminescence imaging technology(TRLI)to improve the signal-to-noise ratio during the hypoxia detection and imaging.With the high oxygen sensitivity and SNR,the oxygen nanoprobe will be very promising for application in biomedical fields.2.A mitochondria-targeted photosensitizer showing improved photodynamic therapy effects under hypoxiaTwo photosensitizers which specifically target the mitochondria and lysosomes were designed and synthesized to evaluate the PDT effect of living cells,especially under hypoxia conditions.Results showed that when the cells were cultured under hypoxia conditions(2% oxygen atmosphere),the oxygen contents in the mitochondria and lysosomes were calculated to be 11% and 3%,respectively.The higher oxygen content in mitochondria resulted from the respiration inhibition induced by the mitochondria-targeted complex,and thus led to improved PDT effect of the complex under hypoxia conditions,which is more practicable in cancer therapy and meaningful for designing and developing high effective PDT agents for hypoxic tumors.3.A novel singlet oxygen carrier for hypoxic tumor therapyAlthough the above work provided an alternative solution for improving PDT effect under hypoxia environment,the therapy effect was still limited by the fact that the generation of 1O2 needs the participation of oxygen molecules.To address this problem,we developed a novel self-sensitizable and water-soluble singlet oxygen carrier,which was composed of photosensitizers,single oxygen carrier,hydrophilic part and modifiable groups.The singlet oxygen carrier could release singlet oxygen thermally without the participation of oxygen molecules,which is more suitable for therapy of hypoxic tumors.