Photodynamic Therapy Of Metal Organic Framework Materials

To date,cancer has become the number one killer of human health owing to its difficult to cure,easy to transfer,and high mortality.Among all clinical cancer treatments,chemotherapy is an effective anti-tumor method.However,the further application of chemotherapy is severely restricted by the problems of traditional cancer drugs,including poor water solubility,easy to be cleared,low selectivity,and toxic side effects,etc.Thus the multifunctional delivery nanosystem is designed and developed,and expected to"smartly"solve the above problems.Among which,as a new type of nanocarrier,metal organic framework materials(MOF)are widely studied in the field of cancer treatment,due to their high drug load capacity,biodegradability,structural and compositional tunability,and controlled size and shapes.The nano MOF delivery system used for photodynamic therapy can not only exert the advantages of the carrier itself,but also be easy to combine with other cancer treatment methods,which solve the problem of inhibited photodynamic therapy efficiency by tumor environmental factors.On the basis of these,we has carried out a series of researches on multifunctional metal organic framework materials for photodynamic therapy of tumor in this paper.The work focuses on the following aspects:In chapter 1,we gave a brief introduction to metal organic framework nanomaterials for biomedical application,including the synthesis,imaging and treatment of metal organic framework nanomaterials.In addition,two aspects of current photodynamic therapy were summarized,namely the problems and challenges faced by photodynamic therapy and the synergistic treatment strategies of photodynamic therapy.In chapter 2,by using reactive oxygen species(ROS)-induced nitric oxide(NO)production,we designed a tumor-specific response nanosystem for NO-based gas therapy and NO-sensitized photodynamic therapy(PDT).The nanosystem(L-Arg@PCN@Mem)was constructed by loading the natural NO donor L-Arg into porphyrinic metal organic framework(PCN)and then coating with cancer cell membrane.Under near infrared light(NIR)irradiation,L-Arg@PCN@Mem as a nanophotosensitive agent produced a large amount of reactive oxygen species that can be directly used for PDT,while a part of ROS took the role of oxidative to convert L-Arg into NO for combined gas therapy.More importantly,due to the long half-life and the far diffusion radius of NO compared with that of ROS,NO converted from ROS was an active species with greater advantages in cancer treatment than ROS.Therefore NO could sensitize PDT,especially PDT in hypoxic tumor environment.In addition,benefited from the coated cancer cell membrane,L-Arg@PCN@Mem had a stronger ability to bio-target toward homologous cancer cells,and efficient target and accumulation of nanoparticles in the tumor region enhanced the therapeutic effect of tumor.In chapter 3,an adenosine-triphosphate-regulated(ATP-regulated)ion transport nanosystem(SQU@PCN,porphyrinic porous coordination network(PCN)incorporated with squaramide(SQU))was designed and synthesized for homeostatic perturbation therapy(HPT)and sensitizing photodynamic therapy(PDT)of tumors.In response to a high expression of ATP in the tumor,SQU@PCN nanotransport was decomposed because of the strong coordination of ATP with metal ligand.Subsequently,incorporated SQU was released and then simultaneously transported chloride ions across membrane of the cell and lysosome along with the chloride ion concentration gradient.On the one hand,influx of chloride ions by SQU increased intracellular ion concentration,which disrupted ion homeostasis and further induced tumor cell apoptosis.On the other hand,SQU-medicated coupling transport of H~+/Cl~-across the lysosomal membrane alkalized the lysosome,resulting in inhibition of autophagy.Since activated autophagy by traditional PDT would resist and suppress PDT,the SQU-mediated autophagy inhibition would eliminate the process above,sensitizing the therapeutic efficacy of PDT.Experimental results revealed that combined HPT and sensitized PDT could realize tumor eradication while blocking metastasis.In chapter 4,a Mn(III)-sealed metal-organic framework(MOF)nanosystem based on coordination between Mn(III)and porphyrin(TCPP)via a one-pot method was designed and constructed.Mn(III)as a sealer,not only quenched TCPP-based fluorescence but also inhibited reactive oxygen species(ROS)generation,which made MOFs an“inert”theranostic nanoparticle.Interestingly,upon endocytosis by tumor cells,MOFs were disintegrated into Mn(II)and free TCPP by intracellular glutathione(GSH)in tumor cells,owing to redox reaction between Mn(III)and GSH.This disintegration would lead to consumption of antioxidant GSH and activated Mn(II)-based magnetic resonance imaging as well as TCPP-based fluorescent imaging.More importantly,such a GSH-regulated TCPP release could implement controllable ROS generation under irradiation,which avoided side effects(inflammation and damage of normal tissues).As a consequence,after unlocking by GSH,Mn(III)-sealed MOFs could accurately position tumors by dual-mode tumor imaging,and significantly improve therapeutic efficiency of photodynamic therapy(PDT)by combining controlled ROS generation and GSH depletion.