Study On Preparation And Properities Of Functionalized Graphene Oxide As Carriers To Load Temozolomide

Brain glioma is a malignant tumor that occurs in the central nervous system,and chemotherapy is the main approach of clinical adjuvant therapy after surgery.Temozolomide（TMZ）is currently the most important chemotherapy drug for the treatment of brain glioma due to its exclusive and highly specific property.However,TMZ drugs have strong side effects such as nausea,vomiting,and hemolysis.The use of drug-loaded preparations can significantly reduce the side effects of TMZ.However,the current low drug loading rate of TMZ carriers such as liposomes and nanocapsules makes it difficult to achieve clinical application value.Therefore,studying new TMZ drug carriers to achieve TMZ targeting and biocompatibility is of great significance for improving the efficacy and reducing the side effects of TMZ.This study uses graphene oxide（GO）as the matrix,and selects targeted magnetic iron oxide（Fe₃O₄）and biocompatible folic acid（FA）for functional modification to prepare three functionalized GO carriers,namely GO-Fe₃O₄,GO-FA,and GO-Fe₃O₄-FA,as well as TMZ composite formulation.The structures of the three functionalized GO carriers were investigated using infrared spectroscopy（FT-IR）,X-ray diffraction（XRD）,scanning electron microscopy（SEM）,and transmission electron microscopy（TEM）.The possible simplified models of GO-Fe₃O₄,GO-FA,and GO-Fe₃O₄-FA were analyzed using density functional theory（DFT）.On this basis,the drug loading rates of the three functionalized GO carriers and their inhibitory effects on C6 glioma cells were investigated.GO-Fe₃O₄ carrier prepared by hydrothermal co-precipitation.GO and Fe₃O₄ are bound by Fe-O,Fe-C,and hydrogen bonds,which can form a stable structure.The loading study of GO-Fe₃O₄ carrier TMZ showed that when the concentration of TMZ is 1.0 mg/m L,the drug loading rate of GO-Fe₃O₄ is 51.87±0.14%,and the maximum drug loading is 0.87±0.08 mg/mg.GO-Fe₃O₄-TMZ formulation has certain magnetic properties and good sustained release properties.In phosphate buffered saline（PBS）buffer with p H=5.0,the GO-Fe₃O₄-TMZ formulation released 75%of the cumulative release after 6.0 h in vitro.Taking the mouse C6 glioma cell as a model,when the drug concentration is 600μg/m L and the incubation time is 72.0 h,the cell inhibition rate can reach 90.63%.After carboxylation treatment,GO was combined with FA to prepare the GO-FA carrier.The structural and DFT results showed that FA tends to adsorb on the front surface of graphene oxide through hydrogen bonding andπ-πinteractions,forming a stable structure without distortion.The drug loading results of GO-FA carrier showed that when the concentration of TMZ was 0.9 mg/m L,the drug loading was 0.89±0.20 mg/mg,and the drug loading rate was 89.52±0.19%.In PBS buffer with p H=5.0,after 8.0 h of in vitro release,the cumulative release of GO-FA-TMZ preparation was about 45%,indicating a certain sustained release effect.The inhibitory rate of GO-FA-TMZ preparation on mouse C6 glioma cells increased with the extension of action time and the increase of concentration.When the drug concentration was 600μg/m L and the incubation time was 72.0 h,the inhibitory rate of C6 glioma cells could reach 91.72%.GO-Fe₃O₄-FA was prepared by adding carboxylated GO-Fe₃O₄ to FA.FA and GO-Fe₃O₄ were bonded through Fe-O,hydrogen bonds,and conjugated structures to form a stable structure.FA modification enhanced the stability of the material and exhibited certain superparamagnetism.When the drug concentration was 600μg/m L and the incubation time was 72.0 h,the cell inhibition rate of GO-Fe₃O₄-FA-TMZ preparation was 92.4%.However,the maximum drug loading of this material TMZ was 0.78±0.03 mg/mg,and the drug loading rate was 34.54±0.66%,which was relatively low.How to improve the drug loading rate of GO-Fe₃O₄-FA carrier is the focus of future research.