Design And Optimization Of Clay-based Magnetic Composite Colloidal Gels For Hepatocellular Carcinoma Therapy

Hepatocellular carcinoma(HCC)is the most common type of primary liver cancer(75-85%),which seriously threatens human life and health.For early solitary HCC,the surgical resection is preferred treatment.However,there are some problems after HCC resection,such as side effects of adjuvant therapy and high recurrence rate.For unresectable HCC patients,minimally invasive interventional therapies including percutaneous local ablation and transcatheter arterial embolization(TAE)are recommended as the first-line treatment.According to HCC clinical practice guidelines,it is difficult to achieve an ideal therapeutic effect with a single treatment method.Therefore,in order to further meet the needs of HCC comprehensive treatment,it is of great scientific significance to design and develop in situ implantation materials for adjuvant treatment after HCC resection or local implantation materials that can meet both TAE and local ablation of unresectable HCC at varying clinical stages.Magnetic hydrogels have been widely used in the field of tumor therapy for controllable drug release and magnetic hyperthermia.However,most of the traditional magnetic hydrogels are composed of magnetic materials mixed in polymer systems.The hydrogels via chemical crosslinking usually suffer from poor injectability,so it is difficult to inject into the focus area.In contrast,colloidal gels composed of particles are usually assembled by electrostatic forces to form threedimensional networks,which avoids toxic chemical cross-linking and possess better biocompatibility.Colloidal gel is facile to realize magnetic functionalization by employing magnetic materials as building blocks,which exhibits obvious shear thinning,self-healing properties and excellent injectability.In addition,it is facile to optimize properties of colloidal gel by adjusting the physicochemical characteristics of building blocks including size,shape and component.In conclusion,this kind of magnetic colloidal gel with biocompatibility can be injected into HCC lesion regions in situ.In combination with the excellent tissue penetration of magnetic hyperthermia,it is expected to significantly reduce the growth rate of HCC.Therefore,this paper designed and optimized the structure and performance of magnetic colloid gels,and they were used to treat HCC in different clinical stages.The main research results are as follows:(1)A magnetic(MMTF)colloidal gel was synthesized by electrostatic self-assembly of amphotropic gelatin nanoparticles(GNPs)and negatively charged magnetic montmorillonite.The hydrogel has excellent injectability and self-healing properties,which can intelligently respond to the magnetic field.The magnetic heating accelerates MMTF colloidal gel to adapt to the surgical wound as well as the uniform release of drugs.The hemostasis effect of MMTF colloidal gel is better than that of commercial hemostatic sponge.MMTF colloidal gel mediated magnetic hyperthermia combined with chemotherapy has achieved significant efficacy in the prevention of recurrence of HCC after surgical resection in mice.In addition,when postoperative local recurrence of HCC is not suitable for secondary surgery,the MMTF colloidal gel can be minimally invasive injected into the tumor area under ultrasound guidance,and further magnetic hyperthermia kill the tumor.The components of hydrogel are all medical excipients,which has a certain translational potential.(2)On the basis of excellent injectability,MMTF colloidal gel can be injected through the microcatheter,and has the potential as a vascular embolic material and nano drug carrier.In combination with the demand for CT visualization of vascular embolic materials,rhenium nanoclusters(Re NCs)with high X-ray absorption characteristics were prepared by a simple onestep liquid phase reduction method.Furthermore,MMTF/Re colloidal gel with CT imaging ability was developed using Re NCs as CT contrast agent.The introduction of Re nano contrast agent has little effect on the injectability and mechanical properties of the colloidal gel.In addition,MMTF/Re colloidal gel can embolize the central artery of the rabbit ear,and can realize the CT visualization study of gel vascular embolization through Re NCs,which is conducive to the accuracy of embolization treatment and postoperative tracking and evaluation.(3)Based on the progress in the preparation of injectable colloidal gels from clay materials in the first two chapters,this chapter studies the influence of clay material size on the injectable properties of colloidal gels using magnetic mica sheets.Compared with the micron sized clay materials,the nano sized magnetic mica and gelatin nano particles assembled(NMF)colloidal gel has the better injection performance,which can be injected without auxiliary equipment.According to both in vitro and in vivo experiments,the embolic effect of NMF colloidal gel prepared by nano size clay material is better than that of the clinical embolic agent lipiodol.Further animal experiments showed that the NMF colloidal gel had excellent therapeutic effects in both vascular embolization and local ablation of HCC.This NMF hydrogel shows great potential in multimodal minimally invasive treatment of liver cancer.