Membrane-derived Nanomaterials For Hepatic Carcinoma Theranostics

Membrane-based materials have a good biocompatibility,which can not only self-assemble into stable vesicular structure,but can be also used for other nanocarriers'surface modification,leading to the prolonged blood circulation in vivo,and escape from immune system.Among various types of membrane,cancer cell membrane as a natural membrane material,has the high stability and biocompatibility,and the cancer cell membrane vesicles or membrane-coated nanoparticles will be greately uptaken by homologous cancer cells,due to the specific protein components on membrane.Besides,with the rapid development of nano-biomimic technology,the application of artificial membrane vesicles has drawn significant attention in the biomedical felid.The molecular skeleton of such artificial membrane vesicle can be inserted with chemical bonds or groups sensitive to tumor microenvironment?TME?,such as H₂O₂,hypoxia,low pH,glutathione?GSH?,matrix metalloproteinase?MMP?,and so on.As a result,the artificial membrane vesicles intelligently responding to specific stimulus in TME will increase the accuracy of drug release and minimize the side effects to optimize the therapy in vivo.In this study,we designed and synthesized two types of membrane-derived nanocarriers to explore their applications in tumor theranostics.The main contents are as follows:1.A core-shell nanoprobe?SSAP-Ce6@CCM?with inner core doped with magnetic nanobeads and photosensitizer Ce6,while the surface coated with a layer of cancer cell membrane,was prepared for MR/NIR dual-modal imaging and photodynamic therapy?PDT?of hepatocellular carcinoma.Magnetic nanobeads are considered as one of the ideal MRI contrast agents.Photosensitizer Ce6 can not only generate reactive oxygen species?ROS?to destroy cancer cells,but also emit NIR fluorescence for imaging under the excitation of exogenous 670 nm laser.The outlayer of cancer cell membrane enormously improve the stability and biocompatibility of nanoparticle,as well as enhance the diagnosis and treatment effect.The results demonstrated that the coating of cancer cell membranesignificantlyincreasedtheinternalizationof SSAP-Ce6@CCM into cancer cell,thereby enhancing the theranostic effect of dual-modal imaging and PDT therapy both in vitro and in vivo.Therefore,SSAP-Ce6@CCM might be served as a promising theranostic nanoprobe for cancer treatment.2.Programmable vesicular nanodevices based on the triblock copolymer containing poly?ethylene glycol??PEG?and poly?caprolactone??PCL?with peroxalate esters?PO?as hydrogen peroxide-responsive linkage,were developed as carriers for the delivery of hypoxia-activated prodrug?AQ4N?and glucose oxidase?GOD?.The programmable vesicular nanodevices loaded with AQ4N and GOD?denoted as PAG?could be selectively activated by the high level of H₂O₂ in tumor microenvironment to further improve the permeability of membranes for glucose entrance.Afterwards,the oxidation of glucose that catalyzed by the encapsulated GOD would produce amplified H₂O₂ amounts which in turn could induce complete destruction of PAG for fast release of AQ4N and GOD.Ultimately,the PAG could exert programmable therapeutic effects from following three aspects:1)starvation therapy by cutting off the energy supply from glucose through GOD catalysis;2)oxidative cytotoxicity by increasing tumor oxidative stress after H₂O₂ amplification;3)chemotherapy of AQ4N activated by the intensified tumor hypoxia microenvironment after oxygen consumption.The stimuli amplification,controlled drug release,synergistic therapy and corresponding mechanisms of PAG have been demonstrated both in vitro and in vivo,and the biocompatibility also has been systematically investigated.Taken together,the here presented work could provide significant new insights for cancer treatment.