Construction Of An Intelligent Molybdenum Disulfide Nano System For Tumor Diagnosis And Tri-Mode Combination Photothermo-/Chemo-/Immuno Therapy

Cancer has become one of the main diseases threatening human health.Accurate diagnosis and efficient therapy are effective ways to improve the survival rate of cancer patients.Chemotherapy,as a systemic treatment,is still the main treatment strategy.However,there are some disadvantages of chemotherapy,such as poor water solubility,low bioavailability,and great damage to normal tissues.It is necessary to use a suitable carrier to deliver the drugs to tumor site to improve the therapeutic efficacy and reduce side effects.In recent years,many new treatment strategies have emerged.For example,photothermal therapy not only can kill tumor cells directly,but also is able to combine with chemotherapy to inhibit the metastasis and recurrence of malignant tumors more effectively,cause tumor immunogenic cell death,and activate anti-tumor immune responses.Immunotherapy,as another novel treatment method,can activate immune response through system regulation to kill tumor cells,which is expected to become one of the most effective therapeutic ways.In order to permanently cure tumors,it is usually necessary to combine multiple treatment methods for a combination therapy.Its key technology is to construct suitable carriers to integrate different therapeutic agents into the same nanoplatform.Molybdenum disulfide nanosheets is able to be used as an excellent carrier on account of its large surface area and easiness to be prepared.Moreover,it also can be utilized as a photothermal conversion,photoacoustic imaging and CT imaging agent since it has strong absorption in the near infrared region and high X-ray attenuation coefficient.Therefore,it has been drawing tremendous attention in tumor theranostic applications.In this study,we first fabricated molybdenum disulfide nanosheets with excellent light-to-heat conversion efficiency and CT and PA imaging performance by hydrothermal method.Then,polydopamine(PDA)-coated molybdenum disulfide nanosheets(PDA@Mo S₂)were synthesized by self-polymerization of dopamine under alkaline conditions,endowing the nanosheets a large number of modifiable functional groups,good stability and biocompatibility.Thereafter,PDA@Mo S₂were conjugated with broad-spectrum anticancer drug cisplatin(Pt)and immune adjuvant 1-methyl-tryptophan(1-MT)through metal chelation and?-?conjugation,respectively.Finally,the formed drug-loaded Mo S₂nanosheets(1-MT-Pt-PDA@Mo S₂)were employedfordual-modeCT/photoacousticimaging-mediatedcombination photothermo-/chemo-/immunotherapy of melanoma tumor models.In addition,due to the photothermal heating effect and the breakdown of the metal chelating bond under acidic conditions,the drug release of 1-MT-Pt-PDA@Mo S₂were expected to be dual photothermo-/p H responsive.The results showed that the formed polydopamine-coated,cisplatin-and immune adjuvant-loaded composite nanoplatform 1-MT-Pt-PDA@Mo S₂had a particle size of about 150nm,strong near-infrared light(808 nm)absorption and good colloidal stability.In vitro results demonstrated that 1-MT-Pt-PDA@Mo S₂could be effectively uptaked by murine melanoma cells(B16 cells),resulting in a good chemotherapy effect and synergistic therapeutic effect by combining chemotherapy and photothermal therapy.Evaluation data of extracellular adenosine triphosphate(ATP)and calreticulin content of tumor cells confirmed that the combination therapy could also cause immunogenic death of tumor cells.The co-incubation of tumor cells treated by photothermal therapy and chemotherapy and immature dendritic cells verified that dendritic cells were promoted to mature ones and subsequently can further activate the immune system.In vivo results displayed that good CT and photoacoustic imaging performance was obtained using1-MT-Pt-PDA@Mo S₂as contrast agent and the combination photothermo-/chemo-/immuno therapy led to superior inhibitory effect on tumor growth.Different combined treatment methods caused necrosis and apoptosis of a large number of tumor cells,while had no damage to various organs.Combined photothermo-/chemotherapy aroused immunogenic death of tumor cells and promoted lymphocytes to type into cytotoxic T cell.Therefore,the synthesized composite nanoplatforms show great potential in applicatios of accurate diagnosis and efficient treatment of different tumors.