Construction Of Nano-systems Regulating Tumor Reactive Oxygen Species For Tumor Therapy

The reactive oxygen species（ROS）levels in tumor cells are significantly higher than normal cells.To avoid the oxidative stress state and resist the damage caused by excessive intracellular reactive oxygen species,the level of the antioxidant system in tumor cells for scavenging reactive oxygen species will also be up-regulated accordingly.Therefore,this high-level state of intracellular redox homeostasis makes tumor cells more sensitive to elevated reactive oxygen species and more susceptible to damage caused by exogenous reactive oxygen species.Selectively elevating tumor intracellular reactive oxygen species has been shown to be an effective strategy to achieve tumor cell killing.In recent years,with the rapid development of nanotechnology,its potential in regulating tumor reactive oxygen species has gradually attracted researchers’attention.This paper designs a variety of nano-systems around how to selectively regulate tumor reactive oxygen species for tumor therapy.The research content of this paper is mainly divided into three parts:1.The distribution of photosensitizers,a basic component of photodynamic therapy,is closely related to photodynamic efficacy.We proposed a strategy for enhancing the tumor targeting and penetration of photosensitizers to elevate tumor reactive oxygen species.We delivered the unnatural sugar（Ac₄Man NAz）modified with azide（N₃）group to tumor cells,which expressed the azide group on the cell membrane as an exogenous ligand through the glycometabolism engineering of cells.And then dibenzocyclooctyne（DBCO）-modified photosensitizer Ce6（DBCO-Ce6）delivered Ce6 to tumor cells via the bioorthogonal reaction of DBCO with N₃.In addition,through the ligand transport by extracellular vesicles secreted by the labelled cells,tumor cells far away from the vascular was labelled with azide group,achieving the efficient delivery of photosensitizers,which showing a significant tumor inhibition after laser irradiation.2.The degradation of tumor reactive oxygen species-responsive polymers is limited by the intracellular level of endogenous reactive oxygen species.We constructed a ROS-responsive cycle-amplifying degradable polymer to elevate tumor reactive oxygen species and enhance tumor immunotherapy.The polymer consists of cinnamaldehyde（CA）and a ROS-responsive thioacetal bond（TA）,with side-chain indoleamine 2,3-dioxygenase 1（IDO-1）inhibitor 1-methyl-DL-tryptophan（1-MT）modifying to reverse the tumor immunosuppressive microenvironment.After the polymer self-assembled nanoparticles(SANP_1-MT)entering tumor cells,TA groups of the polymer can rapidly release CA in response to endogenous ROS in tumor cells.Released CA disrupted mitochondrial function and further increased the level of intracellular ROS,achieving cycle-amplifying degradation.Meanwhile,elevated levels of reactive oxygen species caused intracellular redox homeostasis disruption and induced immunogenic death（ICD）,which combined with the IDO inhibitory effect of 1-MT,synergistically enhanced tumor immunotherapy.3.Further,we propose a strategy to synergistically intervene in tumor redox homeostasis and elevate the level of tumor reactive oxygen species.We designed a PEG-modified dendrimer pCASS（pCASS-PEG）,which composed of cinnamaldehyde（CA）as the ROS generator and disulfide bonds as the glutathione（GSH）depleting agent.pCASS-PEG could self-assemble to nanoparticle DCS in aqueous solution.After entering cells,the responsive-released CA and disulfide bonds increase reactive oxygen species and consume GSH respectively,and synergistically disrupt redox homeostasis,thereby causing ICD.Meanwhile,the abundant amino groups of dendrimers can load small interfering RNAs（si RNAs）through electrostatic interactions.To inhibit the upregulation of tumor cell programmed death-ligand 1（PD-L1）caused by negative feedback regulation of ICD,we loaded PD-L1-targeting si RNA（si PD-L1）to inhibit the PD-1/PD-L1 pathway,to achieve efficient tumor immunotherapy and effectively inhibit tumor metastasis.In conclusion,this paper has constructed a series of nano-systems that regulate tumor reactive oxygen species,proposed an efficient strategy for synergistically amplifying tumor oxidative stress,and developed multifunctional nanomaterials that disrupt redox homeostasis in tumor cells.It provides a new idea for the application of nano-systems in tumor therapy.