Design And Synthesis Of Efficient Photosensitizers For Hypoxic Tumor Photodynamic Therapy

Photodynamic therapy?PDT?holds great promise for the treatment of cancer.Increasing attentions have been drawn to PDT because of high regional specificity and non-invasiveness.PDT usually works by the combination of nontoxic photosensitizers?PSs?,light irradiation of appropriate wavelength and substrates?O₂,lipids,etc.?.Thus it can be supposed that PSs are crucial elements in PDT protocol.The PDT efficiency is usually dominated by the nature of the PSs.In general,the mechanism of PDT includes type I and type II according to the different photochemical processes.Energy?type II?or electron?type I?transfer from the excited PSs to substrates results in the generation of reactive oxygen species?ROS?,which can instantaneously damage biomolecules to induce cell death.Type II PDT is largely dependent on molecular oxygen,while type I is not.Thus compared to type II PDT,type I PDT is more suitable for the utilization under hypoxic conditions.Hypoxia is a common feature in solid tumors due to rapid tumor growth and insufficient oxygen supply.Moreover,fast oxygen consumption during PDT further aggravates the hypoxic condition and restricts the therapeutic effect,which has become a major obstacle for PDT.Furthermore,hypoxia in tumor is closely associated with its increased aggressiveness and strong resistance to therapy,leading to the poor prognosis.In addition,tumor hypoxia may further increase the risk of angiogenesis,mutation,invasiveness,metastasis,and altered metabolism.Hence,it is very important to design and prepare excellent PSs which can maintain good PDT effect under hypoxia or real-time monitor the hypoxia environment in tumors with high accuracy for cancer diagnosis and therapy.In this thesis,we focus on the design of PSs with excellent therapeutic effects under hypoxia.1.Phosphorescent Starburst Pt?II?Porphyrins as Bifunctional Therapeutic Agents for Tumor Hypoxia Imaging and Photodynamic TherapyA series of hydrophilic phosphorescent starburst Pt?II?porphyrins have been rationally designed and synthesized as bifunctional therapeutic agents for simultaneous tumor hypoxia imaging and highly efficient PDT.They have been obtained by using Pt?II?porphyrins as the functional core and cationic oligofluorenes as the arms.The three-dimensional structural feature ensures good hydrophilicity,ultra-sensitive oxygen-sensing performance and high ¹O₂ quantum yields.Furthermore,the O₂-sensitive phosphorescence lifetimes of starburst Pt?II?porphyrins can eliminate the interference from background fluorescence remarkably and enhance the signal-to-noise ratio of hypoxia imaging by phosphorescence lifetime imaging microscopy.Additionally,their PDT effects were also evaluated both in vitro?under both hypoxia and normoxia?and in vivo.All of these results demonstrate that starburst Pt?II?porphyrins could be used as the promising bifunctional therapeutic agents for early diagnosis and treatment of cancer.2.Cyclometalated Ru?II?complex as type I photosensitizer for achieving efficient photodynamic therapy under both normoxia and hypoxiaA coumarin-functionalized cyclometalated Ru?II?photosensitizer?Ru2?was designed and synthesized.Ru2 exhibits the lower oxidation potential and stronger absorption in the visible region than the coumarin-free counterpart.The evaluation of PDT effect was performed under both normoxia and hypoxia.The results showed that Ru2 has a better therapeutic effect than coumarin-free counterpart in in-vitro experiments.Especially under hypoxia,Ru2 still remained excellent PDT effect,which can be attributed to the direct charge transfer between the excited PS and an adjacent substrate through type I photochemical process,forming highly-oxidative hydroxyl radicals to damage tumor cells.Anti-tumor activity of Ru2 was further proved to be effective in tumor-bearing mice,and the tumor growth was inhibited remarkably after PDT treatment.3.HA-conjugated polymer hybrid as multiple-targeting photosensitizer for highly efficient imaging guided photodynamic therapyThe HA-conjugated polymer hybrid nanoparticles?HA-PFP-NPs?were designed and synthesized for highly efficient imaging guided photodynamic therapy.The HA-PFP-NPs were prepared through electrostatic interactions between the positive conjugated polymer and negative hyaluronic acid?HA?.The HA-PFP-NPs exhibited nearly no dark toxicity to cancer cells in wide range of concentration.The cells imaging experiments demonstrated that the HA-PFP-NPs could selectively be internalized into the CD44 over-expressed cancer cells?A549?over normal cells?NIH-3T3?,confirming the specific binding of the HA-PFP-NPs to cancer cells.The results of the live/dead assay of HA-PFP-NPs showed significantly enhanced cytotoxicity after light irradiation.Furthermore,the stronger fluorescence of HA-PFP-NPs in tumor site indicated that HA-PFP-NPs can serve as an imaging reagent of tumor.The in vivo PDT experiments fully demonstrated that HA-PFP-NPs can achieve efficient therapeutic effects in solid tumors.