| Background:At present the commonly used drug delivery system of transcatheter arterial chemoembolization(TACE)is oil-water mixed system,sudden drug release and poor embolization effect In recent years,amphiphilic Janus particles have been widely used in the fields of biosensing,drug delivery,and cancer therapy due to their outstanding performance in improving emulsion stability due to their properties of reducing surface tension.Objective:In this study,"vascular embolization agent",a key scientific issue which has important influence on cancer interventional therapy and great clinical application prospect,is selected for investigation.Amphiphilic Janus particles were introduced into the embolization agent system for the first time,and a new structural lipiodol droplet embolization system was developed which not only improved the stability of emulsion but also increased the slow release of drugs.The kind of new structural lipiodol droplet in animal have several advantages such as imaging,viscoelastic deformation and distal embolization,achieving complete organ necrosis after embolization,which is expected to bring new ideas for tumor interventional therapy in clinical patients.Methods:(1)Construction of Janus particle-engineered structural lipiodol droplet embolization system.Amphiphilic Janus particles with adjustable structure and chemical composition were prepared by emulsion polymerization.Janus particles were used as stabilizer,combined with lipiodol through shear emulsification technology to self-assemble into oil-water emulsion agent Optical microscopy,confocal microscopy and computed tomography(CT)were used to verify its physicochemical properties.The particle size of the structural lipiodol droplet was regulated by changing the concentration of Janus particles,the proportion of lipiodol and water,etc.Finally,the test was carried out according to the test requirements for clinical application,and the optimal preparation conditions and formula were obtained with regard to the particle size and morphology as well as the preparation of arterial embolic agent.(2)Evaluation of biological function in vitro.drug encapsulation rate,drug release level and cytotoxicity tests were conducted to test the loading,release and toxicity of the embolic agents.The viscosity and modulus of the droplet microspheres were measured by rheometer to verify the properties of shear thinning and viscoelastic deformation.With force exerted the droplets adopted different shapes.CT scan was used to verify the development capability of the droplets after viscoelastic deformation.The packing densities of structural lipiodol droplets and 8Spheres? microspheres were calculated by sedimentation method to verify the compact packing of structural lipiodol droplets due to viscoelastic deformation.Structural lipiodol droplets were injected into capillary glass tubes and the liver acellular model of SD rats to further evaluate the viscoelastic deformation ability,developing ability,and embolization ability of the embolizing agent in blood vessels,providing a solid support for subsequent animal experiments in vivo.(3)Evaluation of biological function in vivo.The structural lipiodol droplets,lipiodol and 8Spheres? microspheres were delivered into the right kidney artery of New Zealand rabbits through the kidney embolization test The tracer,embolization,atrophy,and lesion of the kidney of structural lipiodol droplets in the kidney were studied.The immediate and long-term distribution of embolization agents in the kidney and the effect of renal embolization were examined by CT scan.Biochemical and pathological experiments were performed to verify the biological safety and degree of necrosis of renal embolization in each experimental group,and to evaluate the ability and effect of embolizing agents for arterial embolization.Results:(1)By adjusting the concentration of amphiphilic Janus particles and the ratio of lipiodol to water,shear emulsification technology can be used to prepare on-demand structural lipiodol droplets in the 40-500 micron size range to match clinical requirements.The structural lipiodol droplets showed good stability.Under confocal microscope,there was a layer of dense Janus particles on the surface of the oil droplets,and the particle size basically did not change when stored at room temperature for more than 12 months.At the same time,it had good development property under CT.And 10 g structural lipiodol droplets could be prepared at one time,and it is convenient to use after rapid packaging,disinfection,and operation.(2)The encapsulation rate of cisplatin in the Janus particle-engineered structural lipiodol droplets embolization agent was up to 90%.Under the condition of pH 5.5,the 24 h release reached 78.5%,and the survival rate of HepG2 cells decreased to about 15%.The energy storage modulus of structural lipiodol droplets measured by rheometer is about 700 Pa.The prepared structural lipiodol droplets embolizer had good viscoelastic deformation ability,and could be shaped into ellipsoid,dumbbell,and snowman shapes.It showed good accumulation effect in capillary glass tube and the capillary glass tube with finer inner diameter by deformation under stress.The packing density of structural lipiodol droplets is higher than that of 8Spheres? microspheres used in clinical practice.In the liver acellular model of SD rat,structural lipiodol droplets could embolize not only the supplying arteries,but also the small terminal vessels through deformation,and the embolization effect is good.(3)The Janus particle-engineered structural lipiodol droplet embolization agent had good stability and viscoelasticity in the embolization of New Zealand white rabbits,which can achieve the effect of dense accumulation in blood vessels,and has good embolization efficiency for blood supplying arteries.Due to the unique viscoelastic deformability of structural lipiodol droplets,they could move distally to embolize smaller vessels(less than 40μm in size).It could be traced under CT,and the position of structural lipiodol droplets in blood vessels could be clearly observed after embolization.14 days after embolization,the right kidney was completely necrotic and atrophic in the structural lipiodol droplets,and there was almost no recirculation or non-targeted embolization.The results of biochemical detection also indicated that the structural lipiodol droplets was safe and effective.The structural lipiodol droplets showed the best embolization performance compared with the lipiodol and 8Spheres? microspheres.Conclusion:The Janus particle-engineered structural lipiodol droplet embolization agent basically solves the problems of emulsion instability,sudden drug release and poor embolization effect in the existing clinical iodide oil embolization system.It can embolize not only the thick supplying artery,but also the small blood vessels at the end,achieving efficient intravascular embolization and tracer effect It is expected to provide new ideas and techniques for clinical tumor interventional therapy. |
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