Design,Synthesis And Application Of New Multifunctional Photosensitizers For Tumor Phototherapy

Tumor phototherapy,a non-invasive treatment with better selectivity and lower toxicity has recently attracted growing attention in oncotherapy.However,the wide applications of traditional photosensitizers have been restricted due to the absence of targeting therapy,photobleaching,phototoxicity,insufficient therapeutic depth,and oxygen dependence,thus leading to unsatisfactory clinical performance.Furthermore,traditional photosensitizers have many other problems to be solved,such as poor specific enrichment at tumor site,insufficient penetration depth of photosensitizer excitation light,poor toxicity of the subcellular structure binding sites and tumor microenvironment resistance to the photosensitizer penetration.To overcome the potential weaknesses of traditional photosensitizers and develop more efficient alternatives,this paper would take into account the following three aspects:(1)the improvement of the tumor selectivity;(2)improve the penetration depth;(3)the combined phototherapy with tumor microenvironment responsiveness to improve efficiency.Therefore,we designed and fabricated three kinds of new photosensitizers,which were applied for tumor imaging and phototherapy.The work mainly includes:1.A Rhodamine Derivatives-based Tumor Targeting PhotosensitizerIn this part,rhodamine conjugated to iridium forming chelate was designed and fabricated to allow rhodamine to be activated to triplet excited state.And the introduction of indomethacin was aimed to target tumor by specifically binding to tumor overexpression enzyme-cyclooxygenase-2.In vitro studies revealed that the rhodamine derivative IM-rho-Ir could efficiently generate cytotoxicity 1O2 under irradiation with negligible dark toxicity.In addition,cells in vitro and the living imaging results showed that IM-rho-Ir would be selectively accumulated in tumor issue thereby achieving tumor targeting diagnosis and treatment.2.Study On Bodipy Derivatives-based Near-infrared Absorbing PhotosensitizerIn this chapter,bodipy with near-infrared absorption capability was synthesized.By introducing iridium a near-infrared absorbing photosensitizer was developed.In vitro studies showed that the synthesized Bodipy-Ir exhibited high absorption efficiency from 700 nm to 850 nm as well as high 1O2 yield rate.The results also showed that Bodipy-Ir had great photoacoustic imaging capability and performed well in photoacoustic imaging in vivo,which hold great potential for the cancer diagnosis,imaging,and therapy.3.Bimetallic-based Intelligent Nanoagents for Effective Combination PhototherapyIn this part,a tumor microenvironment(TME)-responsive intelligent bimetallic nanoagents(HSA-Pd-Fe-Ce6 NAs)composed of human serum albumin(HSA),palladium-iron(Pd-Fe)bimetallic particles and chlorin e6(Ce6)was designed for effective combination phototherapy.The Pd-Fe part of the HSA-Pd-Fe-Ce6 nanoparticles would react with the endogenous hydrogen peroxide(H2O2)in an acidic ambience within tumor to generate cytotoxic superoxide anion free radical through the "Fenton-like reaction".Coupled with highly toxic singlet oxygen(1O2)caused by the Ce6 component under the irradiation of 660 nm laser resulted in better tumor-killing effects in hypoxia surroundings.Besides,this nanoagents could result in hyperpyrexia induced cell apoptosis because of superior absorption performance in near-infrared wavelength window bringing about excellent photothermal conversion efficiency.Therefore,the multifunctional nanoagents are powerful and provide a new avenue for effective combination phototherapy.