Theoretical Exploration Of Novel Two-Photon Absorption Photosensitizers Based On Ru(â…¡) Complexes

In recent years,photodynamic therapy（PDT）has attracted more and more attention as a non-invasive medical technique for the clinical treatment of cancer.Among them,two-photon photodynamic therapy（TP-PDT）provides a new idea for cancer treatment because of its advantages such as small skin damage,deep light penetration into tissues and accurate localization.However,most of the current two-photon absorption photosensitizers have some shortcomings,such as poor solubility,low yield of singlet oxygen（¹O₂）,small two-photon absorption cross section（δ）,and high price,which restrict their practical application in medical treatment seriously.In addition,type I photosensitizer is a promising project to solve tumor hypoxia.However,the working mechanism of type I photosensitizer has not been clearly understood theoretically,how to design type I photosensitizer has become the bottleneck in the development of current photodynamic therapy technology.This paper intends to use quantum chemical methods to solve the above problems existing in two-photon absorption photosensitizers.It intends to reasonably design existing photosensitizers to optimize and improve the performance of molecular materials,evaluate their photophysical properties as photosensitizers,and the possibility of producing reactive oxygen species（ROS）through type I mechanism,and provide new ideas and reliable theoretical clues for the design and synthesis of new photosensitizers in subsequent experiments.The main research contents of this paper are as follows:（1）Theoretical study on photophysical properties of Ru（Ⅱ）/Zn（Ⅱ）based polypyridine complex photosensitizers for two-photon photodynamic therapy.The wide application of TP-PDT is faced with the problems of few types of two-photon absorption photosensitizers,high cost and low optical absorption.So it has become an urgent problem to design new photosensitizers with strong two-photon absorption,high water solubility,long triplet excited state lifetime and low cost.At present,Ru（Ⅱ）polypyridine complexes have been extensively used in the study of photosensitizers experimentally and even in clinical trials（such as TLD1433）,but the mechanism of their excited states and singlet oxygen generation is still lacking in comprehensive understanding and explanation at the microscopic level.Based on this,we used density functional theory（DFT）and time-dependent density functional theory（TDDFT）to investigate the one/two-photon absorption properties,type I/â…¡ mechanisms,solvation free energy and lipophilicity of a series of novel Ru（Ⅱ）/Zn（Ⅱ）based polypyridine complexes as photosensitizers.The results suggest that based on the complex 1（（E,E′）-4,4′-bis[p-（N,N-dimethylamino）styryl]-2,2′-bipyridine Ru（Ⅱ）complex）,replacing Ru（Ⅱ）center with Zn（Ⅱ）（complex 2）can effectively prolong the triplet excited state lifetime while reducing the cost and environmental pollution;and the azetidine heterospirocycles were introduced into the ligands（complex 3）,which effectively reduced the vibration relaxation of the ligand groups and improved the water solubility;and further,the further introduction of acetylenyl groups subtly enhanced the light absorption,significantly improved the two-photon response（complex 4）.After evaluation,all studied complexes met the requirement of a photosensitizer,and could be used as potential candidates for TP-PDT.In particular,complex 4 has the advantages of high solvation free energy,large two-photon absorption cross section,long triplet state lifetime,good chemical reactivity,low cost and easy to be scavenged by organisms.Moreover,all complexes can not only produce ¹O₂through the type â…¡ mechanism,but also produce superoxide free radicals(O₂^{·（-）})through the type I mechanism,thus realizing the purpose of killing tumors.Overall,this contribution may provide important clue to formulate clear design principles for type I/â…¡ PSs and rational design of PSs with high ISC rates,long lifetime,and therapeutic excitation wavelengths.（2）Theoretical study on photophysical properties of Ru（Ⅱ）complex photosensitizers with pyrene modified ligands.Currently,Ru（Ⅱ）complexes used in clinical trials,such as TLD1433,are limited by the relatively small two-photon absorption cross section and the short triplet excited state lifetime,which limits the wide spread and application of this photosensitizer.We studied the photophysical properties of a series of pyrene modified Ru（Ⅱ）complexes by using DFT and TDDFT.On the basis of optimizing the ground state and excited state geometry,the electronic structure,one and two-photon absorption spectra and solvation free energy were simulated theoretically.The triplet excited state lifetime was estimated,and the possibility of its being used as a type I or â…¡ mechanism of photosensitizer was analyzed.The results show that replacing methoxy with pyrene chromophores can greatly increase the triplet excited state lifetime of the complex.Furthermore,the addition of acetylenyl groups subtly enhanced two-photon absorption cross section.Complex 3b takes into account both of these excellent properties,with large two-photon absorption cross section and long lifetime,which makes it a promising candidate for TP-PDT.In addition,complex 1a,2a,1b and 2b can not only produce ¹O₂through type â…¡ mechanism,but also produce superoxide free radicals(O₂^{·（-）})through type I mechanism,realizing the possibility of reacting with proteins,lipids and DNA to kill cancer cells,and alleviating oxygen deficiency in tumor tissues to a certain extent.It is hoped that this study can provide theoretical basis and reference for the design and synthesis of efficient photosensitizers in the experiment.