Preparation And Evaluation Of Anti-tumor Activity For Graphene Oxide-based Magneticin Situ Hydrogel

Graphene oxide(GO) has large surface area, good biocompatibility and has attracted wide attention in biomedical field. In this paper, a kind ofgraphene oxide-based magnetic in situhydrogel was preparedto practice thermo-chemotherapy on tumor,while combining with alternating magnetic field(AMF). Firstly, ferroferric oxide nanoparticles(IONP) and water-soluble polymer polyethylene imine(PEI) were grafted onto the surface of GO by hydrothermal synthesis method. Thena magnetocaloric therapeutic agent(GO/IONP/PEI) was synthesised, which had superparamagnetic and good dispersibilityin water. GO/IONP/PEI was characterized by using FT-IR, TEM, hysteresis curve, magnetic-heat transfer effect, particle size and potential measurement, etc. And the anticancer drug doxorubicin hydrochloride(DOX)was loaded onto GO/IONP/PEI by π-π stacking. Then, a blank hydrogel(CS/β-GP-Gel) with temperature-sensitivity and biodegradability wasprepared from chitosan(CS) and sodium β-glycerophosphate(β-GP). GO/IONP/PEI-DOX was physically mixed with CS/β-GP-Gel to prepare a new drug system-- graphene oxide-based magnetic in situhydrogel(GO/IONP/PEI-DOX-Gel). With the drug loading rate, the gelation temperatureand gelation time as the indicators, to choose the optimumformulation andpreparing technology. Finally,Kunming female mice were used as the animal modelin the pharmacokinetic experiment of GO/IONP/PEI-DOX-Gel.S180 tumor-bearing mice were used as the animal modelin the pharmacodynamics and biodistribution experimentsin vivo. While AMF was carried on to combine with GO/IONP/PEI-DOX-Gel.The experimental results showed that GO/IONP/PEI nanocomposite was superparamagnetic,and had good water dispersibility and magnetic-thermal conversion effect, which could be used as a tumor hyperthermia therapeutic agent.GO/IONP/PEI-DOX-Gel gelation temperature is 38 ℃, the release rate under the condition of 42℃was higher than that of 37℃. Under the condition of pH5.0, the drug release rate was higher than that of pH7.2. Theseresults showed that the drug release characteristic of GO/IONP/PEI-DOX-Gel depended on temperature and pH value. The pharmacokinetic experiment results showed that GO/IONP/PEI-DOX-Gel could improve the bioavailability and prolong the residence time of DOX in vivo. Thebiodistribution study results showed that GO/IONP/PEI-DOX-Gel, after intra-tumorally injected into the S180 tumor bearing mice, could significantly increase the drug concentration and prolong the residence time of the drug in tumor tissues. The pharmacodynamic experiment results showed that when compared with DOX solution,half-lifeand AUMC of GO/IONP/PEI-DOX-Gel extended to 2.75 timesand 2 times,GO/IONP/PEI-DOX-Gel could inhibit the growth of tumor cells. And then, combined with AMF, relative tumor volume reduced from 1.25 to 0.5, tumor weight reduced from 0.2g to 0.1g, the tumor inhibition effect ofGO/IONP/PEI-DOX-Gel was significantly enhanced. The pathological results showed that when combined with AMF,the damage effect of GO/IONP/PEI-DOX-Gel ontumor tissues was much stronger, and without obvious toxicity to normal tissues. The in vitro andin vivoexperiment results showed that when combined with AMF,GO/IONP/PEI-DOX-Gel could improve the anti-tumor effect of DOX and reduce the toxicity of chemotherapy drugs to the normal tissues. This research could provide a theoretical basis for the clinical treatment of tumor.