Vadimezan,one of the typical vascular disrupting agents(VDAs) currently in clinical trials,has been extensively implemented for cancer research,whereas its clinical efficacy is adversely affected by the inevitable sid...Vadimezan,one of the typical vascular disrupting agents(VDAs) currently in clinical trials,has been extensively implemented for cancer research,whereas its clinical efficacy is adversely affected by the inevitable side effects.Inspired by Vadimezaninduced intratumoral coagulation activation and hypoxia aggravation,we report a strategy by utilizing these biological effects to achieve targeted delivery and activation of hypoxia-activated prodrug(HAP) thus to maximize the therapeutic effect of Vadimezan.By encapsulating HAP tirapazamine into poly(lactic-co-glycolic acid)(PLGA) nanocarriers along with the modification of clot-binding peptide,the obtained nanoplatform could target tumors under the coagulation activation effect of Vadimezan.Meanwhile,the aggravated hypoxia tumor microenvironment induced by Vadimezan can also boost hypoxia-activated chemotherapy.In the murine tumor model,this strategy showed 80.0% suppression of tumor growth,indicating its great potential in tumor treatment.This study offers an ingenious tactic for the combination of vascular disrupting therapy and hypoxia-activated chemotherapy,which may open up a window of the VDAs-based combination therapy.展开更多
Tumor vascular infarction has been regarded as a promising therapy in tumor treatment.However,due to the limited activity of designed coagulation agents,resulting from the challenges of inducing sustained and complete...Tumor vascular infarction has been regarded as a promising therapy in tumor treatment.However,due to the limited activity of designed coagulation agents,resulting from the challenges of inducing sustained and complete thrombosis and associated selectivity issues,the traditional vascular infarction strategy consequently results in treatment failure.Here,we report a photo-initiated coagulation activation and fibrinolysis inhibition approach to achieve synergetic tumor vascular infarction via gold nanorods(AuNRs)-based nanosystem for the co-delivery of coagulation initiator thrombin and fibrinolysis inhibitor tranexamic acid.With a photo-initiated cascade reaction,thrombin and tranexamic acid could be released from the nanosystem to activate coagulation and inhibit the fibrinolysis within tumor vessels.By integrating these two physiological reactions,fortified clots were formed,and tumor vessels were occluded steadily,affecting the metabolism of the tumor cells,thereby inhibiting tumor growth.This strategy might open an alternative path for the advancement of the current tumor vascular infarction strategy.展开更多
基金supported by the National Natural Science Foundation of China(52073219 and 51833007)the National Key Research and Development Program of China(2019YFA0905603)。
基金supported by the National Key Research and Development Program of China (2022YFB3804600)the National Natural Science Foundation of China (22135005, 52073218,52273301, 51833007, and 51988102)+2 种基金Jiangsu Province Science Foundation for Youths (BK20200241)the Fundamental Research Funds for the Central Universities (2042022kf1162)the Center for Electron Microscopy at Wuhan University for their substantial supports for Transmission electron microscopy (JEM-2100)。
基金supported by the National Natural Science Foundation of China (51988102,51833007,22135005,52173136 and 21721005)
文摘Vadimezan,one of the typical vascular disrupting agents(VDAs) currently in clinical trials,has been extensively implemented for cancer research,whereas its clinical efficacy is adversely affected by the inevitable side effects.Inspired by Vadimezaninduced intratumoral coagulation activation and hypoxia aggravation,we report a strategy by utilizing these biological effects to achieve targeted delivery and activation of hypoxia-activated prodrug(HAP) thus to maximize the therapeutic effect of Vadimezan.By encapsulating HAP tirapazamine into poly(lactic-co-glycolic acid)(PLGA) nanocarriers along with the modification of clot-binding peptide,the obtained nanoplatform could target tumors under the coagulation activation effect of Vadimezan.Meanwhile,the aggravated hypoxia tumor microenvironment induced by Vadimezan can also boost hypoxia-activated chemotherapy.In the murine tumor model,this strategy showed 80.0% suppression of tumor growth,indicating its great potential in tumor treatment.This study offers an ingenious tactic for the combination of vascular disrupting therapy and hypoxia-activated chemotherapy,which may open up a window of the VDAs-based combination therapy.
基金supported by the National Natural Science Foundation of China(grant nos.51988102,51833007,51690152,51533006,and 21721005)the National Key Research and Development Program of China(grant no.2019YFA0905603).
文摘Tumor vascular infarction has been regarded as a promising therapy in tumor treatment.However,due to the limited activity of designed coagulation agents,resulting from the challenges of inducing sustained and complete thrombosis and associated selectivity issues,the traditional vascular infarction strategy consequently results in treatment failure.Here,we report a photo-initiated coagulation activation and fibrinolysis inhibition approach to achieve synergetic tumor vascular infarction via gold nanorods(AuNRs)-based nanosystem for the co-delivery of coagulation initiator thrombin and fibrinolysis inhibitor tranexamic acid.With a photo-initiated cascade reaction,thrombin and tranexamic acid could be released from the nanosystem to activate coagulation and inhibit the fibrinolysis within tumor vessels.By integrating these two physiological reactions,fortified clots were formed,and tumor vessels were occluded steadily,affecting the metabolism of the tumor cells,thereby inhibiting tumor growth.This strategy might open an alternative path for the advancement of the current tumor vascular infarction strategy.
