MoS₂ And WS₂-based Multifunctional Nanoprobes Used For Photodynamic Therapy

Cancer is still a main cause of death worldwide currently.The traditional cancer treatment options are mainly chemotherapy,surgery and radiotherapy.However,these treatments still face some problems:chemotherapy often causes systematic side effects,sugery is always associated with high recurrence rate,radiotherapy is often under the limitation of cumulative radiation dose and it inevitably harmes the normal cells.In recent years,photodynamic therapy has been extensively used for the clinical treatment of solid tumors,mainly due to its advantages over conventional options such as its invasive nature,the ability to treat patients with repeated doses without initiating the resistance,fast recovering process with almost no scarring,good applicability,little side effects,imaging-guided diagnosis,therapy and therapeutic monitoring and so on.However,because of some shortcomings,including the poor solubility,low signal to noise ratio of fluorescence imaging,poor selectivity of most photosensitizers,and the low efficiency of PDT caused by the hypoxia of cancer cells,the photosensitizers-based fluorescence imaging and PDT in the clinical applications has been challenged.On these problems,functionalized two dimensional transition metal dichalcogenides(TMDs)have been extensively used for the biomedicine area,due to its similarity to the structure of graphene and its unique physical and chemical properties.On the basis of the previous studies,MoS2 and WS2-based multifunctional nanoprobes have been designed for imaging of tumor cells and PDT in this thesis.The works of this thesis are as follows:1.MoS2 nanoplates-based multifunctional nanoprobe used for imaging of intracellular ATP and controllable photodynamic therapyThis work designed a MoS2 nanoplate-based nanoprobe for fluorescence imaging of intracellular ATP and photodynamic therapy(PDT)via ATP-mediated controllable release of 1O2.The nanoprobe was prepared by simply assembling chlorine e6(Ce6)labelled ATP aptamer on MoS2 nanoplates,which have favorable biocompatibility,unusual surface-area-to-mass ratio,strong affinity to single-stranded DNA,and can quench the fluorescence of Ce6.After the nanoprobe was internalized into the cells and entered ATP-abundant lysosomes,its recognition to ATP led to the release of the single-stranded aptamer from MoS2 nanoplates and thus recovered the fluorescence of Ce6 at an excitation wavelength of 633 nm,which produced a highly sensitive and selective method for imaging of intracellular ATP.Meanwhile,the ATP-mediated release led to the generation of 1O2 under 660-nm laser irradiation,which could induce tumor cell death with a lysosomal pathway.The experimental results showed the nanoprobe could response to ATP sensitively and specially.Furthermore,when the nanaoprobe reached 2.5 ?M,the cell viability(%)was more than 80%;however,when the cells were treated with 66 J cm-2 laser irradiation,the growth inhibition(%)of cells was 77%;these results fully demonstrated the nanoprobe had low dark toxicity and high phototoxicity.In a word,the controllable PDT provided a model approach for design of multifunctional theranostic nanoprobes.2.WS2 nanosheets-based Cyt c-activatable and 02-supplying multifunctional nanoprobe used for therapeutic monitoring of hypoxic tumor cellsThe poor selectivity of most photosensitizers is one of the major problems in photodynamic therapy(PDT),which inevitably induces the severe side effects.Besides,due to the big dependence of PDT on O2,the PDT is inhibited to a large extent in the hypoxic tumor cells.To overcome these problems,a cytochrome c(Cyt c)activitable and O2-supplying multifunctional nanoprobe was designed for improving the efficiency of PDT and therapeutic monitoring.The nanoprobe was designed by noncovalently assembling the doubly labled DNA aptamer-one end with Hemin tag and the other end with MB tag,on the surface of PEGylated WS2 nanosheet,which was further functionalized with a mitochondria-targeting ligand-triphenyl phosphine(TPP).Once the nanoprobe was selectively taken up by the cancer cells,it would selectively accumulate within the energized mitochondria,which contained Cyt c and a large amount of reactive oxygen species,especially the H2O2.Then the Cyt c bound specially with the DNA aptamer,leading to the release of DNA aptamer from the WS2 nanosheet and the recovery of fluorescence of MB and catalytic activity of Hemin.At the same time,the H2O2 was catalysed by the Hemin to generate O2,relieving the hypoxia of the tumor cells.Under the 660-nm laser irradiation,MB induced the generation of 1O2 in the presence of abundant O2 for photosensitizing mitochondrial cell death.After the permeability of mitochondrial membrane,the lighted MB translocated from the mitochondria to the cytoplasm,which provided a method for in-situ therapy monitoring.The experimental results showed that the prepared WS2-PEG5000-TPP had acceptable stability and strong quenching ability of the fluorescence of MB.This provided the possibility of improving the signal to noise ratio of photosensitizer-based fluorescence imaging and controllable PDT.In a word,the nanoprobe could not only specially recognize the tumor cells and relieve the hypoxia for high efficiency of PDT,but also could efficiently be used for efficient in-situ imaging,therapy and therapeutic monitoring.This work provided a new paradigm for designing multifunctional nanoprobe used for improving the tumor selectivity and hypoxia as well as imaging,therapy and therapeutic monitoring.