Thrombin-based Strategy For Cancer Starvation Therapy

Cancer,an important disease,has severely affected human health,and its fatality rate remains high all year round.Up till now,a variety of cancer treatment strategies have been developed,including phototherapy,chemotherapy,gene therapy,and immunotherapy.However,these methods have their own limitations,which hinder their more effective clinical applications.As a new cancer treatment modality,cancer starvation therapy has received increasing attention and investigations by researchers.For the cancer starvation therapy,the selection of a suitable molecule is essential.However,some molecules for cancer starvation therapy,such as sunitinib,bevacizumab,and sorafenib,are all exogenous molecules,which may cause safety issues during the cancer treatment process.Therefore,the development of endogenous substances for cancer starvation therapy is highly desirable for achieving safe cancer treatment.Thrombin is a common enzyme in animals.Its properties have been studied by scientists for more than a hundred years,but few researchers have used thrombin as a starvation agent in tumor treatment.One important reason is that its uncontrollable release will cause severe thrombosis and even lead to death.In this thesis,we designed and constructed two responsive systems,a p H-responsive nanosystem and a temperature-responsive injectable hydrogel system.The first work mainly introduces the use of p H-responsive zinc ion coordinated metal organic framework material ZIF-8 to achieve effective loading of thrombin.By using a one-pot method,Zn DT nanoparticles were synthetized by encapsulating thrombin and doxorubicin.Through p H-response,Zn DT could effectively and accurately control the release of thrombin,meanwhile the released thrombin maintained extremely high activity.Through observing the results of fluorescent labeling and ultrasound doppler blood flow imaging,the effective coagulation effect of thrombin could be clearly observed.In addition,in vivo experiments successfully proved the effectiveness of combined treatment of tumor starvation therapy and chemotherapy;the second work mainly uses hydrogenated soybean phospholipids and glyceryl dioleate to effectively encapsulate thrombin,gambogic acid and indocyanine green to construct a injectable thermo-sensitive hydrogel material ICG/GA/thrombin/hydrogel.It shows a better therapy effect of tumor starvation therapy combined with low temperature phototherapy under near-infrared laser.To summarize,this thesis realized efficacious cancer treatment by precisely controlling the release of thrombin,which we believe may broaden the application of thrombin in the biomedical field and may provide new ideas for the development of novel anticancer systems.