Cardiovascular disease is the leading cause of global mortality,with anticoagulant therapy being the main prevention and treatment strategy.Recombinant hirudin(r-hirudin)is a direct thrombin inhibitor that can potenti...Cardiovascular disease is the leading cause of global mortality,with anticoagulant therapy being the main prevention and treatment strategy.Recombinant hirudin(r-hirudin)is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous(SC)and intravenous(IV)administration,but there is a risk of haemorrhage via SC and IV.Thus,microneedle(MN)provides painless and sanitary alternatives to syringes and oral administration.However,the current technological process for the micro mould is complicated and expensive.The micro mould obtained via three-dimensional(3D)printing is expected to save time and cost,as well as provide a diverse range of MNs.Therefore,we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch.The results show that r-hirudin-loaded and hyaluronic acid(HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models.These results indicate that based on 3D printing technology,MNs combined with r-hirudin are expected to achieve diverse customizableMNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.展开更多
Tumor cells transform into endothelial cells by epithelial-to-mesenchymal transition,which is characterized by vasculogenic mimicry(VM).VM not only accelerates tumor progression but also increases drug-induced resista...Tumor cells transform into endothelial cells by epithelial-to-mesenchymal transition,which is characterized by vasculogenic mimicry(VM).VM not only accelerates tumor progression but also increases drug-induced resistance.However,very little is currently known about the molecular determinants that enable VM.Targeting VM might bring a new breakthrough in cancer treatment.Thrombin is the key enzyme of the blood coagulation system and could contribute to tumor progression.Nevertheless,the association between thrombin and VM formation remains largely unknown.We found that VM was associated with the overall survival of non-small-cell lung cancer(NSCLC)patients,and that thrombin expression was closely related to VM formation.This research revealed that thrombin induced VM formation via PAR-1-mediated NF-κB signaling cascades.The novel thrombin inhibitors r-hirudin and DTIP inhibited VM formation and spontaneous metastases in subcutaneous tumors.Clinical pathological analysis confirmed that NSCLC patients with thrombin-positive/PAR-1-high expression had the poorest prognosis and were the most likely to form VM.The promotional activity of thrombin in VM formation and tumor metastasis was abolished in PAR-1-deficient NSCLC cells.The EGFR inhibitor gefitinib had no effect on VM and increased VEGF expression in tumors.The combination therapy of DTIP and gefitinib achieved a better therapeutic effect than either agent alone.This study is the first to illustrate that thrombin substantially contributes,together with PAR-1,to VM formation and to illustrate that VM might be a target of r-hirudin and DTIP to suppress tumor progression.The anticoagulants r-hirudin and DTIP could be employed for antitumor therapy.Combination therapy with DTIP with an EGFR inhibitor might achieve superior therapeutic effects.展开更多
基金supported by the National Natural Science Foundation of China (NSFC 81902995)the project funded by China Postdoctoral Science Foundation (2018M641936)
文摘Cardiovascular disease is the leading cause of global mortality,with anticoagulant therapy being the main prevention and treatment strategy.Recombinant hirudin(r-hirudin)is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous(SC)and intravenous(IV)administration,but there is a risk of haemorrhage via SC and IV.Thus,microneedle(MN)provides painless and sanitary alternatives to syringes and oral administration.However,the current technological process for the micro mould is complicated and expensive.The micro mould obtained via three-dimensional(3D)printing is expected to save time and cost,as well as provide a diverse range of MNs.Therefore,we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch.The results show that r-hirudin-loaded and hyaluronic acid(HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models.These results indicate that based on 3D printing technology,MNs combined with r-hirudin are expected to achieve diverse customizableMNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.
基金supported by the National Natural Science Foundation of China(NSFC 81902995 and NSFC 81673498)the Science and Technology Commission of Shanghai Municipality(STCSM 16431904600)a project funded by China Postdoctoral Science Foundation(2018M641936)..
文摘Tumor cells transform into endothelial cells by epithelial-to-mesenchymal transition,which is characterized by vasculogenic mimicry(VM).VM not only accelerates tumor progression but also increases drug-induced resistance.However,very little is currently known about the molecular determinants that enable VM.Targeting VM might bring a new breakthrough in cancer treatment.Thrombin is the key enzyme of the blood coagulation system and could contribute to tumor progression.Nevertheless,the association between thrombin and VM formation remains largely unknown.We found that VM was associated with the overall survival of non-small-cell lung cancer(NSCLC)patients,and that thrombin expression was closely related to VM formation.This research revealed that thrombin induced VM formation via PAR-1-mediated NF-κB signaling cascades.The novel thrombin inhibitors r-hirudin and DTIP inhibited VM formation and spontaneous metastases in subcutaneous tumors.Clinical pathological analysis confirmed that NSCLC patients with thrombin-positive/PAR-1-high expression had the poorest prognosis and were the most likely to form VM.The promotional activity of thrombin in VM formation and tumor metastasis was abolished in PAR-1-deficient NSCLC cells.The EGFR inhibitor gefitinib had no effect on VM and increased VEGF expression in tumors.The combination therapy of DTIP and gefitinib achieved a better therapeutic effect than either agent alone.This study is the first to illustrate that thrombin substantially contributes,together with PAR-1,to VM formation and to illustrate that VM might be a target of r-hirudin and DTIP to suppress tumor progression.The anticoagulants r-hirudin and DTIP could be employed for antitumor therapy.Combination therapy with DTIP with an EGFR inhibitor might achieve superior therapeutic effects.
