Optical Or Magnetic Responsive Materials Regulating Cell Behaviors For Disease Treatments

Cell is the basic biological structure and function unit in organism.When the behavior of cell such as proliferation,differentiation,apoptosis and reprogramming have changed,the organism would exhibit metabolism,growth,aging and disease,etc,accordingly.Thus,investigation of the molecular mechanism in cell behaviors would lay the basis for the drug screening and disease treatment and.In addition to cytokines or cell engineering techniques,recently the using of chemical or physical methods has become the research hotspot for regulating cell behavior.In this thesis,we are devoted to exploring the application of optical or magnetic materials in regulating tumor cell apoptosis,neuron differentiation,nerve signal conduction,and reprogramming of differentiated cells,which is aimed to develop novel stageties for treating major diseases.The main contents of this thesis are as follows:1.Neurodegenerative diseases,such as Parkinson’s and Alzheimer’s disease,and other central nervous system injuries,usually lead to irreversible apoptosis of neurons.Cell transplantation is a promising therapy for the above diseases.However,the targeted delivery of therapeutic cells to damaged areas and the directed differentiation of therapeutic cells in vivo will bethe major challenges for cell transplantation.To overcome challenges,we designed a spiral micro-robot,which integrated the function of the targeted cell delivery and in-situ stimulating cell differentiation.The 3d printing technology was applied to prepare the spiral micro structure based on biodegradable gelatin derivatives,which was used as the carrier for supporting the growth of neuron.In addition,we successfully constructeda core-shell structured magnetoelectric nanoparticles by hydrothermal and sol-gel method.The micro-robot was obtained by combining the spiral micro structure and magnetoelectric nanoparticle together.After loading with neurocyte this micro-robot could achieve the targeted delivery of neurocyte under a rotating magnetic field and degrade by the collagenase secreted from the neurocyte when reaching the targeted site.Furthermore,under the high-frequency magnetic field,the magnetoelectric nanoparticle in micro-robot could stimulate the differentiation of neurocyte,which exhibited multi-dendritic growth and the upregulated expression of neuron-specific axonal membrane proteins.This micro-robot not only provides a new strategy for the treatment of neurodegenerative diseases and brain damage,but also serves as a reference for simplifying the design of magnetic control platform for the targeted cell delivery and in-situ stimulating cell differentiation.2.In this study,the oxidative stress and endoplasmic reticulum stress(ERS)in intracellular microenvironment was induced to regulate the apoptosis of cancer cell,which aimed toenhance the therapeutic effects of chemotherapy and overcome the multidrug resistance.To fulfill this purpose,an ERS-inducer(2-DG)was chemically connected to the reactive oxygen species(ROS)-sensitive dextran derivative to obtain a multifunctional material(RDDG).After loading with conjugated polymers(C)as photo-sensitizer and doxorubicin(D)by RDDG,we obtained a multifunctional nanoparticle(RDDG/DC).The results revealed that this nanoparticle could rapidly release drug by ROS-sensitive degradation and by laser irradiation.After being effectively taken up by MCF-7 cells,the nanoparticles have profound photodynamic effect(PDT)to induce oxidative stress as well as triger the release of 2-DG and DOX along the degradation of nanoparticle under laser irradiation,which would induce the ERS and promoted the outflow of mitochondrial cytochrome C and apoptosis,finally enhancing the cytotoxicity of DOX.In addition,this nanoparticle could effectively accumulate in the tumor site in vivo,show the strongest inhibition of tumor growth and prolong the survival time of MCF-7 tumor bearing mice.Besides,this nanoparticle also exhibited the effect of overcoming tumor multidrug resistance.In summary,combination of oxidative stress,ERS and chemotherapynot only effectively regulates the pro-apoptotic microenvironment in tumor cells,but also enhances the effect of chemotherapy,which provides a new strategy to tumor therapy and has a potential application in clinical.3.In order to effectively repair the severely damaged peripheral nerve and restore the secondary motor and/or sensory functions of limb,we have developed a flexible,light-responsive and stretchable conductive hydrogel as artificial nerve,which was constructed by acrylamide and aniline copolymer.The electrical and mechanical properties of the artificial nerve were similar to the nervous tissue.At the same time,the artificial nerve still maintained a high electrical conductivity when it was mechanically stretched.The conductivity of artificial nerve was increased after irradiated by near-infrared light,which could promote the transmission of nerve bioelectrical signals.Besides,the artificial nerve could replace the damaged sciatic nerve of toad,and promote the transmission of bioelectric signals under the irradiation of near infrared light in vitro.Finally,the artificial nerve could successfully replace the damaged sciatic nerve in the rats,and restore part of the motor function even the length of the missing nerve exceeded 10 mm.This artificial nerve not only can be uased to replace the damaged sciatic nerve,but also provides a new idea for the development of photoconductive materials and their application in regulating biological signal transduction.4.The reprogramming of retinal Müller Gila(MG)cells to repair damaged retina has become one of the research hotspots in visual impairment.In this study,we aimed to investigate whether the photoelectric nanoparticles could be used to regulate MG cell reprogramming.First,we constructed photoelectric nanoparticles by interfacial polymerization,and obtained a shP53-MG cell line after knocking down the p53 by lentivirus.We found that the photoelectric nanoparticles could not directly regulate MG cells into a new cell cycle and induce their reprogramming.However,after down-regulating the expression level of P53,which is a key factor that restrained MG cell into the new cell cycle,the photoelectric nanoparticles could promote shP53-MG cells into a new cell cycle under light stimulation,and then promote transformation of shP53-MG cells into MG cells with retinal stem cell characteristics.This study provides a new method for the repair of mammalian retina by autologous cells and also confirms that the photoelectric materials could be applied in the regulation of cell reprogramming.