Construction Of A Nano-drug Delivery System Loaded With Noranistrisulfide And Indocyanine Green And Its Antitumor Activity

Cancer has become the biggest killer endangering human health.Traditional therapies are expensive and drug stabilities are poor.Their side effects to patients are large,and the anti-tumor effects can not reach expected purposes.In recent years,nanomedicine has made breakthrough progress,and has been widely studied and applied in tumor treatment.Nanomaterials can be used as drug carriers,enriched in tumor sites through EPR effect（Enhanced Permeability and Retention Effect,EPR）and then taken up by cells,which could effectively improve the utilization rate of drugs.MSN（Mesoporous Silica Nanoparticles,MSN）has a huge surface area,which can adsorb drugs on its surface,and its huge pore volume can store more small molecules.Hydrogen sulfide（H₂S）plays an essential role in both normal physiology and pathophysiology.It is worth mentioning that it also has anti-tumor activity.At present,hydrogen sulfide donors reported in current research are water-soluble（such as Na HS and Na₂S）and fat-soluble,which have some application bottlenecks in the practical application process.The main causes are too fast release rate,weak stability in vivo and no targeting.Therefore,there are many studies on hydrogen sulfide donors in combination with other drugs or materials to enhance their stability.In recent years,various photothermal materials with strong near-infrared absorbance have shown excellent application prospects in the photothermal therapy of tumors（PTT）.However,the researches on the combination of PTT and hydrogen sulfide donors are limited.In this paper,MSN was used as an anti-tumor drug carrier to construct a new anti-tumor nano drug delivery system,and the following investigations were mainly carried out:（1）5-（4-hydroxyphenyl）-3H-1,2-dithiole-3-thione（ADT-OH）and Indocyanine Green（ICG）were co-loaded on MSN to construct a novel anti-tumor nano drug delivery system ADT-OH&ICG@MSN.ADT-OH is a fat-soluble hydrogen sulfide donor that releases hydrogen sulfide to kill tumor cells.ICG,a cyanine dye,is also a photothermal material,which converts light energy into heat energy under near-infrared light irradiation and inhibits the growth of tumor cells.MSN was used as a drug carrier to load ADT-OH and ICG.The photothermal treatment of ICG cooperated with the treatment of hydrogen sulfide donor ADT-OH to achieve anti-tumor effect.The results were characterized by TEM,Zeta potential,UV-vis,FTIR,TG,DTG,DTA,etc.The photothermal conversion efficiency and antitumor activity of the drug delivery system were also studied.（2）In order to further improve the stability in vivo transmission and active tumor targeting of the ADT-OH&ICG@MSN to enhance anti-tumor activity,the system was wrapped with methylated hyaluronic acid（HA）.Studies have shown that CD44receptor protein is highly expressed on the surface of tumor cells,which can specifically bind to HA.The binding of HA on ADT-OH&ICG@MSN@HA to CD44 receptor on tumor could enhance the accumulation of ADT-OH&ICG@MSN@HA in tumor,thus enhancing the anti-tumor activity.There is a large amount of hyaluronidase（HAase）in tumor tissue,which degrades the gel shell of HA and releases the drug.After the 808nm laser was irradiated,the photothermal material ICG played an active role to produce a large number of reactive oxygen species,and ADT-OH released hydrogen sulfide for synergistic treatment.Fluorescence spectrum experiments showed that the stability of the hyaluronic acid modified carrier was stronger than that of the unmodified carrier,and only under the action of hyaluronidase,the hyaluronic acid coated on the surface would be degraded and hydrogen sulfide would be released.In vitro cell experiments showed that ADT-OH&ICG@MSN@HA coated with m-HA had enhanced stability,active tumor targeting and better anti-tumor activity.