Study On The Drug Delivery System Of Redox/pH Dual Responsive Manganese Dioxide Nanosheets

In order to combine the diagnosis and treatment of tumor,and to grasp the best time for treatment and make timely adjustment of treatment plan,in this work manganese dioxide nanosheets are prepared,which are able to be specifically degraded into Mn2+ in the tumor microenvironment enabling nuclear magnetic resonance imaging?MRI?.A MnO₂/HA/CDDP drug delivery system with pH/Redox dual sensitive characteristics was finally constructed,which has the function of diagnosis and treatment.The specific content of this work is as follows:1.Preparation and characterization of manganese dioxide nanosheets.Manganese dioxide nanosheets were prepared by the method of oxidation reduction.By ultraviolet visible spectrum scan the maximum absorption wavelength was determined to be 367 nm.The Zeta potential was-22.31±0.03 mV.Based on the structure of X-ray photoelectron spectroscopy?XPS?and X-ray energy dispersive spectroscopy?EDX?,the main component of this system was manganese dioxide,which was diamond-like lamellar structure under transmission electron microscopy?TEM?with an average thickness of 0.23 nm.2.Synthesis and characterization of MnO₂/HA/CDDP nanoparticles.MnO₂ nanosheets were used as the carrier to conjugate the targeting molecule hyaluronic acid?HA?,and then loaded with cisplatin?CDDP?,which was designed as a drug delivery system-MnO₂/HA/CDDP with the property of tumor diagnosis and treatment.Based on the investigation on its stability,after modification with hyaluronic acid,the stability of the manganese dioxide nanosheets was excellent,and the size of MnO₂/HA/CDDP nanoparticles was 190.53±0.28 nm,and the Zeta potential was 26.21±0.17 mV.The sucessfully prepared MnO₂/HA/CDDP nanoparticles were further confirmed by morphology,X-ray photoelectron spectroscopy,fourier transform infrared spectroscopy,thermogravimetric analysis and so on.The in vitro release of MnO₂/HA/CDDP showed that MnO₂/HA/CDDP could release the drug at low pH and high glutathione concentration,and reached the maximum cumulative release at 2 h.The results of magnetic resonance imaging in vitro showed that the prepared drug delivery system had the characteristics of pH/redox dual sensitivity and the degradation of Mn2+ could enable MRI imaging.3.Cytologic evaluation of MnO₂/HA/CDDP nanoparticles.The human lung adenocarcinoma cell line A549 was used as a cell model to investigate the cellular uptake of the drug delivery system and its effects on cell growth,cell cycle and apoptosis.The results showed that the carrier itself of the drug delivery system had no significant effect on the cells.In addition,the drug delivery system was able to arrest the cells at G2/M phase,which was beneficial to the late cell apoptosis and to promote cell death,providing the experimental basis for further in vivo study.4.Pharmacokinetics and in vivo imaging of MnO₂/HA/CDDP nanoparticles.The results showed that the half-life of MnO₂/HA/CDDP group was 1.65 times that of the CDDP group in vivo,which indicated that the drug delivery system had a slow release property.By comparing the near-infrared fluorescence imaging results,the drug delivery system had a targeting effect.The results of nuclear magnetic resonance imaging in mice showed that the drug delivery system had the ability of nuclear magnetic resonance imaging after degradation attumor site,suggesting that the drug delivery system has a tumor targeting diagnosis effect.5.Pharmacodynamic evaluation of MnO₂/HA/CDDP nanoparticles.By analyzing the changes of body weight,relative tumor volume and tumor inhibition rate,the study indicated that the carrier had good biocompatibility,and the drug delivery system was able to deliver more drugs to the target of tumor.The pathology by HE staining showed that the drug system could reduce the toxicity of cisplatin?CDDP?to the kidneys while maintaining the antitumor activity of the chemotherapeutic drug.In summary,this research has successfully constructed a novel drug delivery system of MnO₂/HA/CDDP nanoparticles.This drug system was characterized by a series of experiments,and the drug delivery system was evaluated in vitro and in vivo for its ability of tumor diagnosis and treatment.The results showed that the drug delivery system with pH/redox dual sensitive characteristics,can deliver more drugs to the target site of tumor causing siginificant tumor growth inhibition,and nuclear magnetic resonance imaging can be achieved by the degradation of MnO₂ in response to the tumor microenvirement,achieving the dual function of tumor diagnosis and treatment.This work is of great significance for the study of tumor targeting diagnosis and treatment.