Construction Of Redox-Responsive Targeted Nanodiamond Drugs And Their Antitumor Effects

Nanodiamonds are widely used in anti-tumor medicine because of their advantages such as high biocompatibility,large specific surface area,easy surface modification,low toxicity and high chemical stability.The tumor microenvironment plays a key role in the occurrence,development,spread and treatment of tumors.Therefore,it is of great significance for the treatment of cancer to construct a nano drug with targeted function and responsive release of tumor microenvironment based on the characteristics of tumor microenvironment.Based on the excellent characteristics of nanodiamonds,a new nano drug loading system is constructed in this paper,and further anti-tumor effects are performed.The main contents are as follows:1.Combining the two characteristics of high concentration of glutathione(GSH)in the tumor microenvironment and high expression of folate receptors on the surface of tumor cells,a targeted and controlled-release nanomedicine based on ND was designed(ND-PEG-FA/-SS-DOX,NPFSSD).In vitro drug release of NPFSSD revealed that NPFSSD basically did not release the drug in the physiological environment(pH 7.4),but the disulfide bond was broken in PBS(pH 5.0)including 10 mM GSH,which leads to cumulative drug release of 58.05%,indicating that the system is GSH responsive drug release.2.Techniques such as laser confocal microscopy,flow cytometry,and cell-free tracking experiments have shown that NPFSSD mainly endocytoses into cells through folic acid receptor-mediated methods.In the lysosomal environment of tumor cells,high concentration of GSH regulates the drug release,and the drug fluorescence signal appears.Therefore,NPFSSD is localized in the lysosome,thereby significantly inhibiting tumor growth.The amount of endocytosis of NPFSSD is related to the expression of folate receptor on the cell surface.However,due to the low GSH content in normal cells,there is little drug release,showing that the nano-drug system can greatly reduce the side effects on normal cells.In vivo imaging experiments of tumor-bearing mice indicated that NPFSSD may accumulate mainly at tumor sites through a combination of active and passive targeting.The results demonstrated that NPFSSD system contributes to the integration of diagnosis and treatment and has great potential application in cancer treatment.3.Based on the preliminary laboratory basis,the nanomedicine NPHF/D was further characterized and tumor cell endocytosis was explored.The dispersibility of NPHF/D has been found to be good,which is beneficial to entering cells.In vitro experiments show that NPHF/D system enters tumor cells and is located in lysosomes.The low pH in the lysosomal environment stimulates drug dissociation.As time progresses,DOX migrates further into the nucleus.Combined with the fact that NPHF/D does not emit fluorescence under a laser confocal microscope,it proves that it is an "OFF-ON" change in the fluorescence of NPHF/D in tumor cells,indicating that it has a tumor diagnostic function.