Targeted Drug Delivery System Based On Magnetic Ordered Mesoporous Carbon Nanoparticles

Cancer therapy has attracted wispread attention from researchers.Magnetic targeted drug delivery system（MTDDS）is a novel type of targeted cancer therapy method owing to its simultaneous targeting,drug controlled release and hyperthermia.Previously,MTDDS was prepared by using magnetic carbon nanospheres and magnetic ordered mesoporous carbon nanospheres（MOMCNs）as drug carriers in our group,and their controlled-release properties were systematically investigated.However,the problems of low drug-loading capacity and targeting controlled-release still need to be solved.The drug-loading and release process mainly proceeds through physical absorption,which are unable to achieve controlled drug release in the target area;In addition,it is found that the drug carriers have poor cell infiltration ability,leading to lower drug concentration in the cancer cells and treatment efficacy.Therefore,it is imperative to design a controlled-release system that can improve drug loading and controlled-release performance and improve cancer targeting ability.In order to improve drug loading capacity and targeting controlled release performance,two kinds of magnetic targeted drug delivery carrier materials were constructed,hydrazine modified MOMCNs（Hydrazine-MOMCNs）with pH-responsive performance and folic acid（FA）modified Hydrazine-MOMCNs（FA-Hydrazine-MOMCNs）with active targeting performance,and their drug-loading and release properties,biological properties,and in vitro anti-cancer effect were explored.The detailed conclusions are as follows:1.The preparation and properties of Hydrazine-MOMCNsHydrazine-MOMCNs was synthesized from MOMCNs through amination and hydrazine modification,which can covalently bond to anti-cancer drug doxorubicin hydrochloride（DOX）,The results show that the Hydrazine-MOMCNs have a particle size of about 115 nm with good ordered mesoporous structure and regular morphology.The average pore size is 3.4 nm and the saturated magnetization（M_S）is 8.56 emu g^-1.The drug-loading and release capacity of Hydrazine-MOMCNs as drug carrier was investigated by choosing DOX as template drug molecule.The maximum drug loading capacity was 529.18 mg g^-1,which is higher than that reported in literatures and the previous works of our research group.The release of DOX from Hydrazine-MOMCNs can be controlled by pH values.With the decrease of pH value,the cumulative release rate increases.When pH is 5.5,the cumulative release rate is 76%and reaches the equilibrium at about 10 h.Drug-loading process is a comprehensive result of physical adsorption and chemical reaction,and drug-release process is the result of free diffusion and chemical bond rupture.To study the toxic effects,rat lung epithelial cells（RLE-6TN）and human cervical cancer cell（HeLa）were taking as the effector cells respectively to detect the relative survival rates of 24,48 and 72 h of Hydrazine-MOMCNs at different concentrations by using CCK-8 method.The results show that the relative cell survival rate has the concentration dependence.The relative cell survival rates of RLE-6TN and HeLa cells is 67.6?3.1%and 67.5?3.1%with carrier concentration of 100μg mL^-1 after 72 h.Investigating the blood compatibility of carrier by using hemolysis experiment.The hemolysis rate of Hydrazine-MOMCNs is less than 5%,indicating that the carrier material conforms to the requirement of hemolysis rate of medical materials.All the above indicated that the material had good biocompatibility and low cytotoxicity,and could be used as drug carrier of drug carrier system.2.The preparation and properties of FA-Hydrazine-MOMCNsFA-Hydrazine-MOMCs with targeted properties,high controlled-release properties,obvious magnetic characteristic and ordered pore structure were prepared by modifying FA molecules onto Hydrazine-MOMCNs.The morphology and particle size show no obvious change.The modification amount of FA is 64.82 mg g^-1,possessing active targeting ability.Kinetic adsorption and isothermal adsorption experiments were carried out,indicating that the drug loading of DOX is 577.12 mg g^-1 and the drug loading time is 15 h.The drug-loading process is a combination of physical adsorption and chemisorption.The release of DOX from FA-Hydrazine-MOMCNs can be controlled released by pH value,the drug release rate is 22.5%and release time is 30 h,which is mainly due to the cleavage of hydrazone bond and free diffusion.The cytotoxicity of FA-Hydrazine-MOMCNs was investigated by using RLE-6TN cells and HeLa cells as effector cells.The cell viability is concentration-dependent and time-dependent.The relative cell survival rates of RLE-6TN and HeLa cells is 68.9?4%and 70.6?3.9%with carrier concentration of 100μg mL^-1 after 72 h,indicating FA-Hydrazine-MOMCNs have good biocompatibility.The hemolysis of each group showed no hemolysis,indicating that the biocompatibility of the materials was good,which could be used as the drug carrier of the drug carrier system.3.In vitro antitumor activity of DOX-Hydrazine-MOMCNs and DOX-FA-Hydrazine-MOMCNsSelecting the He La cells as the effector cells and using the simple DOX group as the control group,and the inhibitory effects of DOX-Hydrazine-MOMCNs and DOX-FA-Hydrazine-MOMCNs on the proliferation of cancer cells with different concentrations of 24 and 48 h were detected by CCK-8method.The morphological changes of the cells after the action of the drug were observed under the inverted optical microscope,and investigating the antitumor activity of the nano drug loaded complex,which lays the basis for further studies in vivo anti-cancer properties in mice.