| Cancer,as one of the malignant diseases with complex pathogenesis,poses a serious threat to human life.Although chemotherapy remains the most widely used therapeutic option in clinical cancer therapy,its lack of specific recognition of traditional drug molecules will not only lead to poor therapeutic efficacy to tumor cells,but also cause serious toxic side effects on normal cells.Hence,the development of ‘intelligent' drug delivery systems(DDSs)has become a hot topic in anti-cancer nanomedicine research.Among these DDSs,hollow mesoporous silica nanoparticles(HMSNs)have attracted enormous attention due to their unique features including tunable particle diameter and pore size,high specific surface area,large hollow interiors,good biocompatibility and easily functionalized surface.Hence,we constructed two intelligent drug delivery systems based on HMSNs for targeted tumor therapy.The main research contents were as follows:(1)The uniformly dispersed HMSNs were prepared,and the interior of HMSNs was used for loading DOX.We sequentially modified hyaluronic acid(HA)with disulfide bonds on the surface of HMSNs to construct an enzyme and redox dual-responsive drug delivery system(DOX@HMSNs-SS-HA).The modification processes of HMSNs were confirmed by different measurements,and the results showed that the surface of HMSNs was successfully modified step by step.(2)The in vitro release of DOX@HMSNs-SS-HA was investigated,and the results showed that the DOX@HMSNs-SS-HA had enzyme and redox dual-responsive properties.Furthermore,the pH-dependent drug release results proved the acid response release ability of the system.The in vitro degradation experiment results showed that the HA long chains could be degraded and removed from the surface of HMSNs-SS-HA,and the lower the pH,the better the hydrolysis ability of HAase.These results demonstrated that the hydrolysis ability of HAase was enhanced under increased acidic conditions,which contributed to the better release of loaded drugs into cancer cells.The in vitro stability experiment results suggested the good stability and dispersity of HMSNs-SS-HA,which contributed to its physiological stability and prolonging the blood circulation time of drug delivery systems.(3)The in vitro targeting ability and cytotoxicity of DOX@HMSNs-SS-HA were investigated.As revealed by CLSM,it could be seen that DOX@HMSNs-SS-HA could target cancer cells and effectively enter cancer cells via CD44 receptor-mediated endocytosis.In addition,MTT assay and statistical analysis of flow apoptotic cells results indicated that the unloaded HMSNs and HMSNs-SS-HA nanoparticles had good biocompatibility and safety,while DOX@HMSNs-SS-HA had good anticancer efficiency to cancer cells and significant benefits to reduce the toxic side effects on normal cells.The in vivo targeting and anti-tumor ability of DOX@HMSNs-SS-HA in 4T1 tumor-bearing mice were further investigated.The IVIS spectrum imaging system results showed that DOX@HMSNs-SS-HA had a remarkable tumor-targeting ability and could be effectively accumulated at tumor site.In addition,in vivo therapeutic,H&E and immunofluorescence staining results indicated that DOX@HMSNs-SS-HA could inhibit tumor growth to the greatest extent and effectively reduce the toxic side effects of DOX on normal organs.These results demonstrated that DOX@HMSNs-SS-HA had excellent application prospects and potential advantages in anti-tumor therapy in vivo.(4)The interior of HMSNs was used to load thioridazine(THZ),the 6-mercaptopurine(6-MP)was modified on the surface of HMSNs with disulfide bonds,and the human promyelocytic leukemia cell membrane(Mem)was finally coated on the outermost layer to obtain a redox-sensitive self-identifying self-targeting drug delivery system(THZ@HMSNs-SS-MP@Mem).The successful preparation of the drug carrier was confirmed by a series of characterization methods.Then,the in vitro release of THZ@HMSNs-SS-MP@Mem under different concentrations of GSH was investigated,which proved that the drug carrier had redox responsive properties. |
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