Preparation And Evaluation Of MRI Detectable Sunitinib Loaded Calcium Alginate/Polyacrylic Acid Hydrogel Microspheres

Background: Hepatocellular carcinoma(HCC)is one of the cancers with a high incidence rate.Once discovered,it has already reached the middle to late stage and missed surgical resection treatment.Transarterial chemoembolization(TACE)is a firstline treatment recommended by clinical guidelines for patients with HCC in the middle to late stage.Objective: During TACE,there are problems such as difficult biodegradability,poor imaging performance and sudden release of chemotherapeutic drugs of the embolic microspheres.To solve these problems,this paper constructs Alginic acid/polyacrylic acid hydrogel microspheres loaded with Superparamagnetism ferric oxide and sustained-release Sunitinib visible under magnetic resonance imaging(MRI).Methods: Citric acid(CA)-modified superparamagnetic iron oxide nanoparticles(SPIONS)were prepared using the coprecipitation method;Calcium alginate/poly(acrylic acid)hydrogel microspheres loaded with superparametric iron oxide nanoparticles(CA/PAA-MDMs)were prepared by dropping and photopolymerization,and Sunitinib-Calcium-alginate/poly(acrylic acid)hydrogel microspheres loaded with superparamagnetic iron oxide nanoparticles(SU-CA/PAAMDMs)were prepared by loading sunitinib malate(SU)through an ion exchange method.CA/PAA-MDMs were characterized by infrared spectroscopy,magnetic response analysis,inductively coupled plasma emission spectrometry,X-ray diffraction spectrum analysis,X-ray photoelectron spectroscopy analysis,microsphere repeated compression test,microsphere development in vitro and other methods.At the same time,the sustained-release characteristics of sunitinib were determined using an ultraviolet spectrophotometer.The hemolysis of CA/PAA-MDMs was measured.In addition,the biocompatibility of CA/PAA-MDMs was measured using mouse fibroblasts(L929)and human umbilical vein endothelial cells(HUVE)via CCK-8,and the cytotoxicity of SU-CA/PAA-MDMs on hepatocytes were determined using Hep G2 via CCK-8.Finally,the rabbit ear was used as a model to investigate the embolic effect of CA/PAA-MDMs,and pathological examination was performed.Results: In this study,SU-CA/PAA-MDMs were successfully prepared using drip injection,photopolymerization,and ion exchange methods.Through a series of verifications,it was determined that the CA/PAA-MDMs obtained in this study were black and regular circles,and that the SPIONS loaded were in the magnetite phase.The crystal form of SPIONS remained basically the same after successful loading into calcium alginate microspheres using the off-site method.In addition,it was shown that acrylic acid and calcium alginate were successfully grafted,and the mechanical properties were greatly improved compared to ordinary calcium alginate microspheres.Furthermore,the development effect under MRI was good.Drug loading and release experiments showed that 100-300 μm had a large drug loading capacity,encapsulation rate was up to 95%,and the drug release rate was slow.For 300-500 μm and 500-700 μm,the encapsulation rate reached 80% and the drug release rate was faster than for 100-300μm.Biocompatibility and cytotoxicity tests showed that the CA/PAA-MDMs had high compatibility,and SU-CA/PAA-MDMs had a significant tumor inhibitory effect.The successful establishment of the rabbit ear artery embolization experiment demonstrated the good vascular embolization ability of CA/PAA-MDMs.Histological examination confirmed the presence of microspheres in the vascular lumen.Conclusion: CA/PAAMDMs with controllable particle size could be successfully prepared by drip method.The microspheres could effectively load ferric oxide nanoparticles and sunitinib and release sunitinib slowly.CA/PAA-MDMs had the characteristics of visible under MRI,slow release of sunitinib and good biological safety,and could be used as a potential biodegradable arterial embolic agent for the treatment of liver cancer.