Design And Synthesis Of NIR-controlled Heat/Hydrogen Sulfide Releasing Nanomedicines And Its Synergistic Anticancer Properties

Photothermal Therapy（PTT）is a new type of non-invasive cancer treatment method.Photothermal agents absorb light energy and release heat to achieve thermal ablation of tumors.Nanoparticles accumulate at the tumor site through enhanced permeability and retention（EPR）effect.The illumination of local tumor site can achieve in-situ cancer treatment.However,simply relying on heat to kill cancer cells would lead to the expression of Hsp90 protein in cells,producing a heat shock response.The synergistic treatment of tumors with different treatment methods can complement each other’s strengths and cooperate with each other,thereby enabling more effective tumor therapy.Thiourea can release H₂S gas in response to heat.H₂S gas can induce apoptosis of cancer cells,damage mitochondria of cancer cells and protect normal cells.Based on this,in this thesis,we propose a synergistic treatment strategy of light-controlled heat release/hydrogen sulfide release for tumor therapy.We prepared Pd nanocrystals with good photoacoustic and photothermal properties,which can be used to guide the imaging,tracking and diagnosis of lesions.Thiourea molecules were modified on the surface of the Pd nanocrystals to obtain Pd-SC（NH₂）₂nano-medicines,which combined two modes of photothermal and gas therapy to treat tumors synergistically.In this work,we explored the therapeutic effect of the nano-medicine on cancer cells and solid tumors.The full text is divided into five chapters.In the first chapter,we summarized the current status of cancer,photothermal therapy,gas therapy,and proposed the research ideas of this project.In the second chapter,Pd-SC（NH₂）₂nano-medicines were prepared and characterized by physicochemical properties.The photothermal,photoacoustic and hydrogen sulfide release performance of Pd-SC（NH₂）₂nano-medicines in aqueous solution under 808 nm NIR radiation was further explored.The prepared 20 nm Pd-SC（NH₂）₂nano-medicines have a uniform tetragonal morphology and good dispersibility in water.The successful loading of thiourea was qualitatively determined by energy chromatography X-ray spectroscopy（EDS）,and the content of loaded thiourea was quantitatively analyzed by the simultaneous thermal analyzer TG-DTA,and the loading capacity was 8.5 wt%.In the third chapter,the dark toxicity and photothermal/gas synergistic performance of Pd-SC（NH₂）₂nano-medicines on cancer cells（4T1-mouse breast cancer cells,CT26-mouse colon cancer cells）and normal cells（L02-human normal liver cells）were explored in vitro.The cell death can be observed qualitatively by calcein/propidium iodide（Calcein-AM/PI）staining.The efficacy of killing cancer cells and protecting normal cells by Pd-SC（NH₂）₂nano-medicines was quantitatively analyzed by CCK-8 intuitive histogram.Annxin V-YF488/PI staining was used to explore the way of killing cancer cells.In the fourth chapter,we explored the therapeutic effect of Pd-SC（NH₂）₂nano-medicines on 4T1 tumor-bearing mice in vivo.After the tail vein injection of Pd-SC（NH₂）₂nano-medicines,the nano-medicines accumulated in the tumor site through EPR effect.After three weeks of treatment,the tumor growth was effectively inhibited,indicating that Pd-SC（NH₂）₂nano-medicines had a good photothermal/gas synergistic therapeutic effect.There were no significant differences in liver function,kidney function,blood routine testing,and histopathological analysis,indicating that the Pd-SC（NH₂）₂nano-medicines had no toxic side effects.In the fifth chapter,we summarized the whole thesis including the preparation,characterization and applications at the cellular and animal levels of the Pd-SC（NH₂）₂nano-medicines.We further prospect more possible applications of the nano-medicines.