Anti-tumor Strategies Aimed At Tumor Vasculature

The vascular system is spread across tissues and organs in the body and is the main way of substance exchange between tissues and blood.Given the exuberant metabolic activity of tumor tissues,vascular system plays an irreplaceable role in tumor progression.Therefore,tumor vessels have been recognized as a promising target for tumor treatment.In recent years,tumor vascular targeted therapy has developed rapidly and has gradually become a hot spot in current research.However,for now,the existing drugs for vascular targeted therapy still cannot meet the clinical application standards to some extent.Therefore,it is of great significance to design nano-carriers with various biological functions to improve the efficacy of vascular targeted therapy by combining with nanotechnology.Aiming at the characteristics of tumor vascular system,a series of anti-tumor strategies based on vascular targeted therapy are designed and constructed in this paper.Detailed works are as follows:In chapter one,we reviewed the structure and function of tumor vessels,and summarized the existing vascular targeted therapies that aimed at the characteristics of tumor vessels,including anti-angiogenesis,vascular disrupting therapy and vascular infarction therapy.In addition,we summarized the progress of anti-tumor strategies based on the combination of these vascular targeted therapies with nanotechnology.In chapter two,we aimed at tumor vasculature to design an anti-tumor strategy by combining vascular disrupting agents(VDAs)with photothermal effects to synergistically destroy tumor vessels.We prepared fibrinogen-conjugated Au NPs(f Au NPs).Based on the fact that DMXAA could selectively disrupt tumor vessels and lead to the activation of coagulation cascade,resulting in the assemble of f Au NPs in tumor vessels.Afterward,under near-infrared irradiation,the tumor vascular would be further destroyed by photothermal effect,achieving the combination of VDAs with photothermal therapy for enhanced tumor vascular disruption.By in vitro and in vivo experiments,we demonstrated the successfully assemble of f Au NPs and their photothermal effect.Then,we investigated the effect of this combined strategy in mouse tumor models,which showed that this strategy could effectively destroy tumor vessels,cut off nutrition supply,and significantly inhibit tumor growth.In addition,the enhanced vascular damage effect can prevent distant metastasis.This strategy can effectively enhance tumor vascular destroy and has great potential in tumor therapy.In chapter three,based on coagulation cascade reaction and biological orthogonal reaction,we constructed a tumor gelation strategy(a ECM)for cutting off tumor metabolism.We prepared azido-modified fibrinogen(Fb-N₃)and aza-dibenzocyclooctyne functionalized prothrombin(Ptb-DBCO).Under ultrasound,the tumor-specific accumulation of Fb-N₃could be triggered by micro-wound.Subsequently,the Ptb-DBCO was also accumulated through bioorthogonal reaction between DBCO and N₃groups.The accumulated prothrombin would easily translate to thrombin and further induced the coagulation reaction.The retiform clots besiege the tumor,resulting in an a ECM fibrin gel for blocking nutrient exchange.Through in vitro and in vivo experiments,we successfully verified the controlled formation of a ECM gel.By cell behavior analysis and metabolic analysis,we found that a ECM gel could cut off material transport and lead to tumor-specific starvation,thus inhibiting tumor growth.In a mouse tumor model,this strategy was proved to inhibit tumor growth significantly.Besides,the physical barrier could also prevent distant metastasis.Most importantly,a ECM gelation can be induced by clinical procedures such as surgery or radiotherapy,meaning that this strategy may be translated into clinical combination therapy.In chapter four,we present the design of a synergetic tumor vascular infarction strategy via photo-induced coagulation activation and fibrinolysis inhibition corporately.Through a gold nanorod-based nanosystem,coagulation initiator thrombin and fibrinolytic inhibitor tranexamic acid were co-loaded.With photo-initiated cascade reaction,thrombin and tranexamic acid can be released from the nanosystem to activate the coagulation and inhibit the fibrinolysis within tumor vessels.Through integrating the two physiological reaction,fortified clots will be established and tumor vessels can be steadily occluded,the result of which will affect the metabolism of tumor and thus inhibiting the tumor growth.In vitro and in vivo experiments,we have successfully demonstrated the successful activation of coagulation and inhibition of fibrinolytic system,and infarction of vascular,thereby inhibiting tumor growth.This strategy offers an elegant solution for improving the therapeutic effect of vascular occlusion therapy and opens an alternative path for the advance of current tumor vascular infarction strategy.