Two Dimensional Transition Metal Dichalcogenides For Biomedical Applications

Since the discovery of graphene in 2004,people have noticed that the physiochemical properties of nanosheets are quite different from their bulk counterpart due to their unique two dimensional(2D)structures,which have attracted a lot of interests in various fields including biomedical applications.Recently,a few novel 2D nanomaterials beyond graphene have emerged.Among them,2D transition metal dichalcogenides(TMDCs)are similar to graphene in high surface area and great absorbance in near-infrared(NIR)region,while different from graphene in abundant elemental compositions and active defects.These interesting properties make 2D TMDCs promising as multifunctional nano-platform for various applications.However,the biomedical applications of 2D TMDCs are still in the infant stage.In this thesis,we apply MoS2 nanosheets as a model to systematically study the applications of 2D TMDCs for biomedical theranostics.MoS2 nanosheets with diameter of 50-200 nm are synthesized according to the Morrison method,followed by modification with lipoic acid terminated polyethylene glycol(LA-PEG),resulting in enhanced physiological stability and biocompatibility.We have designed multifunctional nano theranostic agent based on MoS2 nanosheets by loading drugs or integrating with other functional nanomaterials,which could monitor their tumor accumulation depending on time and achieve imaging-guided cancer therapy.Moreover,we have synthesized ultra-small MoS2 nanodots and compared them with MoS2 nanosheets in biomedical behaviors and potential toxicity.The main results of this thesis are summarized as following:Chapter 1:This chapter provides an overview of the current research status of 2D TMDCs,including their preparation methods,modification,biomedical applications and toxicological studies,followed by the topic basis and main contents of this thesis.Chapter 2:MoS2 nanosheets prepared by chemical exfoliation were modified with LA-PEG,resulting in MoS2-PEG nanosheets with enhanced stability in physiological solutions.As a drug delivery system,MoS2-PEG nanosheets could load various kinds of drugs with high loading capacities.Using doxorubicin(DOX)as the model drug and applying the high absorbance of MoS2 nanosheets in NIR region,we have achieved targeted delivery of drug and efficient combination therapy in vitro.Moreover,the intravenously(i.v.)injected MoS2-PEG/DOX could efficiently ablate the tumors in mice by combined photothermal and chemotherapy,showing excellent synergistic effect.Chapter 3:We used the same method to synthesize and modify MoS2 nanosheets like in the previous chapter,to enhance their physiological stability and biocompatibility.MoS2-PEG nanosheets could load large quantity of Chlorin e6(Ce6)by physical adsorption due to their large surface area to mass ratio.Cellular experiments proved that the loading of Ce6 onto MoS2-PEG nanosheets could greatly enhance cellular uptake of the photosensitizer,and hence greatly improve the photodynamic effect.Moreover,we found that utilizing the high absorbance of MoS2-PEG nanosheets in NIR region,the photothermal hyperthermia of MoS2-PEG/Ce6 would further improve the photodynamic killing effect,achieving synergistic effect on killing cancer cells both in vitro and in vivo.Chapter 4:We found dimercaptosuccinic acid(DMSA)functionalized iron oxide nanoparticles(IONPs)could self-assemble on the surface of MoS2 nanosheets via sulfur chemistry,achieving MoS2-IO nanocomposites.After double PEGylation,MoS2-IO-(d)PEG showed great stability in physiological solutions.Interestingly,64Cu as a widely used positron emission radioactive element could adhere onto MoS2 nanosheets without chelating agents,providing great promise in positron emission computerized tomography(PET)in vivo.Meanwhile,the high absorbance in NIR region and superparamagnetic properties of MoS2-IO-(d)PEG make them appropriate contrast agents for photoacoustic tomography and magnetic resonance imaging.Under the guidance of tri-modal imaging,the photothermal effect of MoS2-IO-(d)PEG effectively ablated the tumors on mice.Chapter 5:We used a facile bottom-up method to synthesize MoS2 nanodots via the solvothermal decomposition of ammonium tetrathiomolybdate.We then designed a bio-clearable theranostic agent based on these ultra-small MoS2 nanodots.After the modification with glutathione(GSH),the hydrodynamic size of MoS2-GSH nanodots was smaller than 10 nm,without any aggregation or precipitation in various physiological solutions.These MoS2-GSH nanodots with high absorbance in NIR region showed no noticeable toxicity,presented great promise in killing cancer cells by photothermal therapy.PAT imaging revealed that MoS2-GSH nanodots could effectively accumulated in tumor site,which was in accordance with the biodistribution result by ICP test.Notably,different from conventional MoS2 nanosheets with larger sizes,MoS2-GSH nanodots showed quick and efficient clearance via kidney-urine route,where the majority of them cleared out from mice seven days after i.v.injection.Moreover,the ablation of tumors in mice was achieved by the photothermal effect of MoS2-GSH nanodots with significant therapy effect.In summary,in this doctoral thesis,we have used MoS2 nanosheets as the model of 2D TMDCs to study their biomedical applications.We have focused on the modification methods and their integration with other functional nanomaterials;biomedical applications such as bio-imaging,drug delivery and cancer therapy;as well as the size effect on their blood circulation,biodistribution and body clearance behaviors.Our study would promote the progress in biomedical applications of 2D TMDCs and provide clinical translation opportunities of novel theranostics,showing both scientific and practical significance.