Design And Synthesis Of Stimuli-Responsive Organic Photosensitizers For Tumor Imaging And Photodynamic Therapy

Photodynamic therapy?PDT?has served as an emerging cancer therapeutic modality that employs cytotoxic reactive oxygen species to kill cancers generated from photosensitizers by light activation.Compared to the traditional treatments of cancer,such as radiotherapy,chemotherapy and surgery,PDT has the advantages of minimal invasiveness and specific spatiotemporal selectivity,and does not cause toxicity that is ascribed to dose accumulation after treatments for many times,reducing the risk of recurrence.Up to now,PDT has been used for atherosclerosis,viral infection,wet age-related macular degeneration psoriasis and malignant cancers.Several photosensitizers have been approved by the U.S.Food and Drug Administration?FDA?.However,most photosensitizers are unable to recognize normal cells and cancer cells due to their low selectivity for cancer cells,leading to irreversible oxidative damage and uncontrollable side effects for normal tissues during the PDT treatments.Moreover,intratumoral hypoxia seriously limits the applications of PDT in clinic owing to insufficient generation of reactive oxygen species.The consumption of oxygen in PDT process aggravates the hypoxic environment,further restricting the therapeutic effect.To overcome the above problems,we focus on the design and development of cancer-related stimuli-responsive photosensitizers to realize imaging of cancer cells via monitoring cancer-related agents and conduct a selective PDT in cancer cells.Furthermore,a smart PDT platform has been applied for in vivo hypoxic tumor treatments.The research content of the thesis includes the following parts:1.Design and synthesis of oxygen-responsive iridophosphors for hypoxia imaging of cancer cellsFour novel Ir???complexes?Ir1-Ir4?with different oxygen sensitivity have been designed and prepared with two N^N ligands bearing carbazolyl or 1,2,3-trifluorobenzene.The different oxygen sensitivity of the complexes was ascribed to the lifetimes of triplet excited state.According to the results of experiments and theoretical calculations,the complexes with the triplet excited state dominated by ³ILCT transition have a longer lifetime than those dominated by ³MLCT transition,resulting in a better oxygen sensitivity.Furthermore,Ir1 has been used to detect the intracellular oxygen level under complicated conditions via time-resolved luminescence imaging?TRLI?.Importantly,TRLI can minimize the short-lived fluorescence interference and improve the signal-to-noise ratio,increasing the accuracy of O₂ sensing in cancer cells.2.Design and synthesis of glutathione-reponsive photosensitizers based on phosphorescent iridium???complexes for photodynamic therapyA series of phosphorescent Ir???complexes with benzyl pyridinium have been designed and employed as the glutathione?GSH?activated photosensitizers.The electron-withdrawing pyridinium was sensitive to GSH,resulting in the enhancement of the emission intensity,lifetimes and the quantum yields of singlet oxygen?¹O₂?generation of the photosensitizers.According to the higher GSH concentration of cancer cells than that of normal cells,these photosensitizers can differentiate cancer cells from normal cells through monitoring of the intracellular GSH levels by using luminescence and lifetime imaging measurements.Additionally,the intracellular GSH will trigger the increased ¹O₂ sensitization upon irradiation,selectively improving the PDT effects in cancer cells and effectively avoiding the side effects and nonspecific damages for normal cells.3.Design and synthesis of photothermal-responsive polymeric carrier of singlet oxygen for hypoxic photodynamic therapyA novel ¹O₂ polymer carrier,which is composed of 1,4-dimethylnaphthalene?DMN?,aza-BODIPY?B1?and hydrophilic polyethylene glycol?PEG?,has been designed and prepared.DMN is employed to deliver ¹O₂ into tumors,owing to the excellent ability of ¹O₂ capture.¹O₂ release can be triggered easily under thermal stimuli.B1 was selected as the photothermal agent and near-infrared?NIR?imaging dye in vivo because of its strong NIR absorption and emission and good physiological stability.PEG improves the water solubility and the enhanced permeation and retention effect of the polymer carrier.The ¹O₂ polymers carrier not only effectively enhances the production of ¹O₂ in vitro in hypoxic condition,but also accumulates into tumor through intravenous injection and releases ¹O₂upon irradiation,which has good inhibitory effect on tumor growth.The realization of this strategy provides a huge boost to develop the photothermal-triggered oxygen-independent PDT platform.