Construction Of Ionic Iridium Complexes And Their Applications In Cancer Therapy

Photodynamic therapy is an emerging cancer treatment method,which has attracted much attention in cancer treatment due to its advantages of high specificity,non-invasibility,low toxicity side effects and simple operation.In the process of photodynamic therapy,the design and construction of photosensitizers is very important for the realization of efficient photodynamic therapy process.Transition metal complexes play an important role in the application and development of photosensitizer due to their good photophysical properties.Transitional metal iridium complexes have attracted much attention due to its advantages of large Stokes shift,high inter-system transiting(ISC)ability.However,the traditional metal iridium complexes have poor water solubility,high dark toxicity and short wavelength light source,which severely limit their application in the development of photodynamic therapy.Therefore,researchers have tried to improve its poor water solubility by introducing various vectors or amphiphilic fragments,but its synthesis procedure is complex,time-consuming,high cost,and may also bring potential biological toxicity and other hazards.In addition,short wavelength light excitation not only has low penetration of biological tissues,but also easily causes unnecessary light damage to normal tissues,which is not conducive to the radical treatment of deep tumors.Although two-photon excitation technology and the introduction of upconversion nanoparticles solve the disadvantage of short-wavelength excitation,these methods pose new challenges for clinical application due to the complex and expensive equipment required,low conversion efficiency,high cost.Therefore,the development of carrier-free water-soluble iridium(III)complexes/iridium(III)complexes with near-infrared absorption is still of great significance for clinical photodynamic therapy.In this paper,we designed and constructed carrier-free water-soluble iridium(III)complexes and iridium(III)complexes with near-infrared absorption for the study of photodynamic therapy.Specific research contents are as follows:(1)Two iridium metal complexes(CHO-Ir-H and ppy-Ir-H)were prepared with 4,7-dihydroxy-1,10-phenanthroline as auxiliary ligands,and water-soluble iridium metal complexes(ppy-Ir-Na and CHO-Ir-Na)without carrier were obtained in a simple and convenient way,which made them have better light absorption capacity,and increased 1O2 production capacity.CHO-Ir-Na can be effectively taken up by 4T1 cells,showing low dark toxicity and good phototoxicity.For the first time,the interaction of aldehyde group in the cyclometal ligand with Cys was used to consume GSH to destroy the intracellular REDOX balance and cause cell iron death,thus achieving the dual pathway of photodynamic therapy and iron death to induce cell death.This construction strategy solves the problem of poor water solubility of traditional metal iridium complexes,further improves the therapeutic effect of iridium(III)complexes on tumor cells by destroying the REDOX balance in cells,and provides a new idea for the design of highly efficient water-soluble photosensitizers in the future.(2)Cyanine dyes with typical near-infrared absorption were combined with iridium(III)complexes through rational molecular design strategy.At the same time,the advantages of small organic photosensitizers and transition metal complexes were utilized to construct CHO-Ir-Cy photosensitizer excited by long wavelength light.Cyanine dyes with near infrared absorption properties have successfully broadened the spectrum absorption range of iridium(III)complexes.CHO-Ir-Cy can be efficiently ingested by 4T1 cells and produce a large amount of singlet oxygen under 808 nm laser irradiation to effectively kill cancer cells.At the same time,it shows good biocompatibility,high phototoxicity and low dark toxicity.The results of in vitro and cellular experiments and quantitative calculation showed that the molecular design strategy of organic photosensitizer and transition metal complex rational combination successfully retain the advantage of long wavelength excitation/emission of traditional organic photosensitizers,eliminate the drawback of almost no absorption or very poor in near infrared region for iridium metal complex,and reduc the unnecessary light damage of short wavelength excitation light to normal tissue.Making full use of the ROS production capacity of transition metal complexes with long wavelength light absorption ability is expected to achieve deeper tumor therapy.The work broadens the development space for high efficiency PSs with long wavelength light absorption ability and lays a foundation for the clinical application of transition metal iridium complex PSs.