Reactive Oxygen Species Induced By Multifunctional Inorganic Nanomaterials For Tumor Therapy

Reactive oxygen species(ROS)based cancer therapies have attracted much attentions these years.Compared with normal cells,the higher level of ROS induced by high metabolism,mitochondrial dysfunction,and other reasons of tumor cells involves in regulating the processes of tumor occurrence,invasion,and metastasis.However,the further elevated level of ROS in tumors can also lead to tumor cells death via the peroxidation of biological macromolecules such as lipids,proteins and nucleic acids.Therefore,by using external excitation sources to produce ROS or utilizing the internal unique hallmarks of tumor microenvironment to in situ generate ROS in tumor tissues,these strategies can selectively kill tumor cells and avoid damages to normal cells.Consequently,as compared with traditional methods,ROS based strategies with the advantages of high specificity,good biosecurity,high efficiency and non-invasiveness have been successfully applied in the clinical treatments of surface tumors(such as skin cancer)and luminal tumors(such as esophageal cancer and bladder cancer).Nevertheless,ROS based strategies have limited activation efficiency of producing ROS in deep-seated tumors.Taking clinical photodynamic therapy(PDT)as an example,the penetration depth of visible light in tissues is not enough(usually less than 1 cm)to reach deep tumors for ROS generation due to the scattering,reflection,and even absorption by biological tissues.In addition,the complicated tumor microenvironment(such as high concentration of glutathione,etc.)can resist oxidative stress by reducing ROS in the process of PDT,thus result in the unappealing outcomes of ROS based anti-tumor effect.Therefore,it is urgently needed to develop ROS based noval strategies with deeper penetration depth,and tumor microenvironment modulating abilities,aiming for enhancing the therapeutic effect of deep-seated tumors.In view of the above challenges,two kinds of inorganic sensitizers have deen developed to respond to clinically avaliable excitation sources(X-ray and ultrasound)with higher tissue penetrability.In addition,accompanied by the modulation of tumor microenvironment,the lacal ROS production and tumor killing effects were further enhanced.The main innovative results are as follows:(1)Na Ce F₄:Gd,Tb nano-scintillator,which acted as a direct X-ray responsive photosensitizer,was constructed to produce ROS for multimodal imaging guided synchronous radiodynamic therapy(RDT)and radiotherapy(RT).Na Ce F₄:Gd,Tb nano-scintillator with uniform rold-like morphology was synthesized by high temperature method.Under X-ray irradiation,Na Ce F₄:Gd,Tb could absorb energies of multiple secondary simultaneously,to generate superoxide anion(·O₂^-)for RDT.Meanwhile,the X-ray attenuation ability of Na Ce F₄:Gd,Tb could also enhance the sensitivity of tumors to RT simultaneously.For the imaging,Na Ce F₄:Gd,Tb as tri-modal imaging probes was able to conduct X-ray excited fluorescence(XEF),computed tomography(CT)imaging as well as T₂-weighted magnetic resonance imaging(MRI).Both in vitro and in vivo studies demonstrated that Na Ce F₄:Gd,Tb could integrate trimodal XEF/CT/T₂-MR imaging and synchronous RDT enhanced RT of tumors into a whole,without causing significant system toxicity to the mice.This work broke the routine design of fluorescence resonance energy transfer(FRET)effect depended strategy,with no need of constructing complex energy converter-PS nanocomposite,greatly enhanced the therapeutic effect of X-ray excited RDT.(2)Tumor microenvironment responsive Pt Cu₃ nanocage,which acted as a direct ultrasound responsive sonosensitizer and nanozymes,was developed to conduct GSH depletion and chemodynamic therapy(CDT)enhanced sonodynamic therapy(SDT).Pt Cu₃nanocage was synthesized by solvothermal method.Under ultrasound(US)irradiation,Pt Cu₃ as an inorganic sonosensitizer could generate ROS including singlet oxygen(¹O₂)for SDT.Meanwhile,Pt Cu₃as nanozyme mimicking horseradish peroxidase(HRP)could conduct Fenton-like reaction in the conditions of week acidity and high concentration of hydrogen peroxide(H₂O₂)to in situ generate·OH for CDT.More interestingly,Pt Cu₃as another nanozyme mimicking glutathione peroxidase(GSH-Px)could dynamically and continuely deplete high concentration of GSH inside tumors,efficiently relieving antagonism effect of GSH to ROS for improving the level of oxidative stress.For the imaging,Pt Cu₃performed well in photoacoustic imaging(PAI)and enhanced CT imaging.Both in vitro and in vivo studies demonstated that Pt Cu₃ could conduct PA/CT imaging guided GSH depletion and CDT to enhance SDT of tumors synchronously,without causing significant system toxicity to the mice.This work developed a new type of multifunctional and tumor microenvironment responsive inorganic sonosensitizer,which also worked as two kinds of nanozymes mimicking HRP and GSH-Px,to realize GSH depletion enhanced CDT and SDT in multimodal imaging guided ways.To address the existed limitations of low excitation efficiency and negative regulation of tumor microenvironment faced by ROS generation strategies for deep tumors so far,direct X-ray or US responsive inorganic sensitizers with tumor microenvironment responsive and modulative abilities were prepared in this paper for RDT,RT,CDT and SDT,promising in maximizing the benefit of deep tumor treatments.