Nanosystems Enhanced Tumor Vascular Permeability To Amplify The Efficacy Of Tumor Therapy

Currently,platelets have been proven to play a crucial role in promoting the tumor development and tumor metastasis.It has been proven that platelets play a crucial role in the maintenance of tumor vascular barriers.The tumor inflammatory microenvironment releases amounts of molecules,such as thrombin and reactive oxygen species,resulting in the continuous activation of platelets at the tumor site.Then,activated platelets release these molecules to reduce vascular permeability to maintain tumor vessel integrity and homeostasis,such as 5-hydroxytryptamine and serotonin.The platelet well-maintained tumor vascular integrity then could severely limit the drug accumulation,oxygen perfusion and immune cells infiltration in tumors,causing the tumor resistance to various treatment modalities.In addition,platelets also play a crucial role in promoting tumor metastasis.Platelets can aggravate the tumor metastasis by promoting the infiltration of tumor cells into blood vessels,maintaining the survival of circulating tumor cells,increasing the extravasation of tumor cells.Clinical trials have also confirmed that the overall survival time of patients with high serum platelets is generally shorter,and the tumor metastasis is the main cause of the death of cancer patients.In view of the crucial role of platelets in the tumor metastasis of and tumor treatment resistance,platelet function inhibition has become an effective choice for effective tumor therapy sensitization of and reduction of metastasis.At present,many small molecular platelet inhibitors have been developed to solve problems of tumor metastasis such as ticagrelor and abciximab.However,in clinical and basic research,these platelet inhibitors could not effectively solve the problem of cancer treatment resistance.Meanwhile,the effects of these platelets inhibitors on extending tumor survival is not obvious.This phenomenon is owing to the characteristics of platelets.In short,platelets can be activated through multiple pathways,such as thrombin pathways.These small molecules often act on only one of these pathways and do not effectively inhibit tumor cell-mediated multiple pathway platelet activation.Therefore,finding new effective multi-functional platelet function inhibitors to sensitize tumor therapies and inhibit tumor metastasis has become an urgent problem to be solved.The theory of this article was built on the key role of perfluorocarbon(PFC)in platelet inhibition found in clinical and basic research.Meanwhile,platelets play key roles in maintaining the tumor vascular barriers and reducing tumor metastasis.In this study,we constructed Albumin(HSA)based Perfluorocarbon nanosystems.The main research contents are two parts as follow.:(1)Perfluorocarbon nanosystems medicated platelet inhibition for sensitizing tumor therapiesPlatelets play a crucial role in maintaining the tumor vessel barriers.The vascular tumor vessel barriers severely limit the drug delivery,oxygen perfusion and immune cells infiltration in the tumor.Therefore,breaking the tumor vascular barrier becomes an effective way to improve the efficacy of ttumor therpies.Studies have shown that traditional small molecular platelet inhibitors could not effectively inhibit platelet activation in tumors.In this section,the high platelet inhibition capacity of PFCs were used to construct the perfluorotributylamine loaded albumin nanoparticles(PFTBA@HSA)to achieve effective platelet inhibition.Then,PFTBA@HSA could break the tumor vessel barriers to increase the drug accumulation,oxygen perfusion and immune cells infiltration in tumors,leading to significantly enhanced multiple cancer treatment efficacies.Through clot retraction and blood cell analysis,it was confirmed that PFTBA@HSA has better in vitro platelet inhibition ability than other PFC@HSAs.The results of tumor vessel morphological characterization and vascular permeability characterization demonstrated that PFTBA@HSA can significantly enhance the permeability of tumor blood vessels,while possessing no significant effect on the vascular permeability of normal tissues.The in vivo oxygen delivery,drug accumulation assay and immune cell infiltration characterization demonstrated that perfluorocarbon nanosystems can effectively increase the infiltration and accumulation of oxygen,drugs and immune cells in tumors.After receiving a variety of cancer treatments,PFTBA@HSA significantly increased the efficacy of tumor radiotherapy and chemotherapy as well as immunotherapy.(2)Perfluorocarbon nanoparticles medicated platelet inhibition to block tumor metastasisAs we proved aboved,PFTBA@HSA could effectively inhibit platelet activation and reverse tumor hypoxia.Then,we speculated that PFTBA@HSA could block tumor metastasis by reducing the tumor metastasis tendency and reducing the survival of circulating tumor cells in the blood circulation.Through the in vitro tumor cells adhesion and tumor cells invasion assay,we confirmed that PFTBA@HSA could significantly reduce the adhesion and invasiveness of tumor cells to collagen.The in situ tumor metastasis assessment demonstrated that PFTBA@HSA can effectively reduce the expression of tumor metastatic proteins by reversing tumor hypoxia through two-stage oxygen delivery,including MMP-2 and Twist.In addition,through CT26 and 4T1 acute lung metastasis models,we demonstrated that PFTBA@HSA could inhibit the survival of circulating tumor cells in vivo,leading to extended survival time.Therefore,PFTBA@HSA nanoparticles can effectively reduce tumor metastasis.In this research,based on the role of platelets in the maintenance of tumor vascular barrier and the promotion of tumor metastasis,a perfluorocarbon albumin nanosystem with high platelet inhibition ability was designed.The system could effectively inhibit the platelets activation in vivo,which in turn break the platelets maintained tumor vessel barriers,causing enhanced drug accumulation,oxygen perfusion and immune cell infiltration in the tumors.Then,the efficacies of tumor chemotherapy,radiotherapy and immunotherapy were enhanced.Moreover,perfluorocarbons have been widely used as blood substitutes in clinical.These designs provide new and effective options.Therefore,perfluorocarbon albumin nanosystem could be used as a novel and promising method for sensitization the tumor therapy in clinical.