The Study Of Multifunctional Embolic Microspheres Fabricated By Electrospray Technique For Liver Cancer Interventional Therapy

Interventional therapy is the first choice for advanced liver cancer,and transcatheter arterial chemoembolization is one of the most important basic-techniques of interventional therapy.It has the advantages of minimally invasive,fast recovery,and few postoperative complications,and can be used for interventional examinations and treatment to achieve tumor descent and provides second-stage resection opportunities for patients who initially do not meets the conditions.At the same time,it can also be combined with a variety of treatment modes for synergistical therapy to improve the therapeutic effect.As a kind of vascular embolic materials,embolic microspheres play an important role in interventional arterial embolization and have a huge market demand.However,in clinical application,it has the following three shortcomings:First of all,the lack of self-imaging embolic microspheres led to difficulties in monitoring the process of embolization and postoperative re-examination.Secondly,the solid embolic microspheres have the contradiction between the flow property and embolization.Aa a kind of mechanical embolic materials,embolic microspheres are required to have good mechanical strength to achieve good embolic properties,which leads to the large friction between the microspheres and the catheter during the injection process.Aa a result,the catheter is easy to block,and the injection technique is demanding and difficult.For malformed blood vessels,the microspheres are easy to disperse unevenly,resulting in unsatisfactory embolization effect.Thirdly,commercial embolic microspheres are difficult to achieve the combined therapy between embolism and chemotherapy,hyperthermia,radiofrequency ablation,immunotherapy and other therapies.Therefore,the development of multifunctional embolic microspheres for liver cancer interventional therapy has important medical research value and broad clinical application prospect.Three kinds of functional embolic microspheres were constructed by single or coaxial electrospray technology in this dissertation.Through the reasonable design of the matrix materials and functional components,the embolic microspheres were endowed with multiple functions to meet different clinical needs.The main research contents and findings are as follows:（1）In order to solve the problems of the lack of self-imaging embolic microspheres and the drug-loading function,DOX&Ta@Ca Alg microspheres loaded with DOX and Ta nanoparticles were constructed by single electrospray technology,which were multifunctional microspheres integrating self-imaging,chemotherapy and embolization to solve the problems of indirect imaging,and difficulties in postoperative re-examination and local sustained release administration in the clinical application.In vitro and In vivo studies indicated that DOX&Ta@Ca Alg microspheres had similar imaging abilities as iohexol（300mg I/m L）,and it could be used for long-term non-invasive postoperative re-examination,and had better tumor inhibition ability when combined with chemotherapy.（2）In order to solve the problems of the lack of MR imaging embolic microspheres and the drug-loading function,polyvinyl alcohol microspheres loaded with ferric oxide nanoparticles（Fe₃O₄@PVA）with magnetic resonance imaging function were constructed by single electrospray technology.The iron oxide nanoparticles were synthesized in situ in PVA matrix as both physical crosslinking agent of PVA and MRI contrast agent of microspheres,avoiding complex synthesis process.The produced Fe₃O₄@PVA microspheres have a regular shape,uniform particle size,and a variety of size specifications（260～960μm）,which it suitable for vascular embolism of different calibers.Doxorubicin hydrochloride can be successfully loaded by swelling adsorption method and has typical sustained release characteristics.In vitro and in vivo studies have demonstrated that Fe₃O₄@PVA microspheres not only have good embolic performance,but also have excellent T2-weighted MRI capability and biocompatibility.The development of MR imaging microspheres will promote the development of MRI-guided interventional therapy.（3）A new type of coaxial electrospray technology was developed,which separate the two processes of droplet dispersion and microsphere solidification by the stability of Pickering emulsion in the electrospray process.It not only expands the range of materials that can be prepared by electrospray process,but also facilitates the integration of a variety of functional substances to prepare multifunctional embolic microspheres.The Au@PAM microspheres loaded with gold clusters integrating the function of embolization and radiofrequency thermal response with high elasticity and deformation were successfully constructed using this process.In vitro embolization simulation experiment（chip model and decellularized model）has shown that Au@PAM microspheres have good elasticity,deformation and filling effect.In vitro RF response experiment has shown that Au@PAM microspheres have significant RF thermal effects and thermal response adhesion characteristics.In addition,the renal embolism assay of rabbit has shown that Au@PAM microspheres have good embolic effect and CT imaging function in large vessels,which can be used for postoperative re-examination.The combined therapy of embolization with radiofrequency of VX2 tumor-bearing rabbits has shown that the Au@PAM microspheres significantly improved the synergistic anti-tumor effect of radiofrequency ablation and transcatheter artery embolization on liver cancer,and had a good regulatory effect on the postoperative tumor microenvironment.In summary,this dissertation has carry out a series of studies about embolic microspheres by electrospray technology around the clinical needs of embolic microspheres in five aspects,including imaging,injection fluency,embolism,multi-functionality and safety.In view of the lack of self-imaging embolic microspheres,X-ray self-imaging embolic microspheres suitable for current digital subtraction angiography（DSA）technology guided interventional surgery and MR visual embolic microspheres suitable for MRI-guided interventional surgery under development were constructed to meet the needs of different clinical imaging equipment.Aiming at the contradiction between properties of fluidity and embolism of solid embolic microspheres,a kind of gel microspheres with high elasticity and deformation was constructed.The high elasticity improves the injecting fluidity of the microspheres,while the adhesion between the microspheres at high temperature improves the firmness of the embolism to avoid the potential risk of ectopic embolism caused by high elasticity.In view of the difficulties in the combination of multiple therapies,this dissertation constructs multifunctional embolic microspheres for liver cancer intervention by electrospray technology to achieve the combined treatment of embolism and chemotherapy,embolism and radiofrequency therapy.