Objective: To evaluate the effects of Celastrus Orbiculatus extracts(COE) on metastasis in hypoxiainduced hepatocellular carcinoma cells(Hep G2) and to explore the underlying molecular mechanisms. Methods:The effect o...Objective: To evaluate the effects of Celastrus Orbiculatus extracts(COE) on metastasis in hypoxiainduced hepatocellular carcinoma cells(Hep G2) and to explore the underlying molecular mechanisms. Methods:The effect of COE(160, 200 and 240 μg/mL) on cell viability, scratch-wound, invasion and migration were studied by 3-4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2-H-tetrazolium bromide(MTT), scratch-wound and transwell assays, respectively. Co Cl2 was used to establish a hypoxia model in vitro. Effects of COE on the expressions of E-cadherin, vimentin and N-cadherin were investigated with Western blot and immuno?uorescence analysis,respectively. Results: COE inhibited proliferation and metastasis of hypoxia-induced hepatocellular carcinoma cells in a dose-dependent manner(P<0.01). Furthermore, the expression of epithelial-mesenchymal transition(EMT) related markers were also remarkably suppressed in a dose-dependent manner(P<0.01). In addition, the upstream signaling pathways, including the hypoxia-inducible factor 1α(Hif-1α) and Twist1 were suppressed by COE. Additionally, the Hif-1α inhibitor 3-5'-hydroxymethyl-2'-furyl)-1-benzylindazole(YC-1), potently suppressed cell invasion and migration as well as expression of EMT in hypoxia-induced Hep G2 cells. Similarly, the combined treatment with COE and YC-1 showed a synergistic effect(P<0.01) compared with the treatment with COE or YC-1 alone in hypoxia-induced Hep G2 cells. Conclusions: COE signi?cantly inhibited the tumor metastasis and EMT by suppressing Hif-1α/Twist1 signaling pathway in hypoxia-induced Hep G2 cell. Thus, COE might have potential effect to inhibit the progression of Hep G2 in the context of tumor hypoxia.展开更多
AIM: To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma (HCC) recurrence for up to 3 year following curative resection.
The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccines has stimulated intensive efforts to expand nanoparticle ...The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases.Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment.However,only a limited number of nanotherapies have enter clinical trials or are clinically approved.Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system(MPS),resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors.Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy.Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages.Polymer conjugation revived the parent camptothecin agent(e.g.,7-ethyl-10-hydroxy-camptothecin),enabling lipid nanoparticle encapsulation.Furthermore,macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin,increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy.When tested in a preclinical murine model of breast cancer,macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles.Furthermore,intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity.Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity.This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers.展开更多
The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations du...The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.展开更多
基金Supported by the National Natural Science Foundation of China(No.81403232 and No.81573656)Natural Science Foundation of Jiangsu Province(No.BK20171290 and No.BK2012686)Doctoral Fund of Ministry of Education of China(No.20133250120003)
文摘Objective: To evaluate the effects of Celastrus Orbiculatus extracts(COE) on metastasis in hypoxiainduced hepatocellular carcinoma cells(Hep G2) and to explore the underlying molecular mechanisms. Methods:The effect of COE(160, 200 and 240 μg/mL) on cell viability, scratch-wound, invasion and migration were studied by 3-4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2-H-tetrazolium bromide(MTT), scratch-wound and transwell assays, respectively. Co Cl2 was used to establish a hypoxia model in vitro. Effects of COE on the expressions of E-cadherin, vimentin and N-cadherin were investigated with Western blot and immuno?uorescence analysis,respectively. Results: COE inhibited proliferation and metastasis of hypoxia-induced hepatocellular carcinoma cells in a dose-dependent manner(P<0.01). Furthermore, the expression of epithelial-mesenchymal transition(EMT) related markers were also remarkably suppressed in a dose-dependent manner(P<0.01). In addition, the upstream signaling pathways, including the hypoxia-inducible factor 1α(Hif-1α) and Twist1 were suppressed by COE. Additionally, the Hif-1α inhibitor 3-5'-hydroxymethyl-2'-furyl)-1-benzylindazole(YC-1), potently suppressed cell invasion and migration as well as expression of EMT in hypoxia-induced Hep G2 cells. Similarly, the combined treatment with COE and YC-1 showed a synergistic effect(P<0.01) compared with the treatment with COE or YC-1 alone in hypoxia-induced Hep G2 cells. Conclusions: COE signi?cantly inhibited the tumor metastasis and EMT by suppressing Hif-1α/Twist1 signaling pathway in hypoxia-induced Hep G2 cell. Thus, COE might have potential effect to inhibit the progression of Hep G2 in the context of tumor hypoxia.
基金Supported by NIH Clinical Trial Registration,No.NCT00247728(this trial was cosponsored by Progen Industries Limited,Brisbane,Australia and Medigen Biotechnology Corporation,TaipeiTaiwan)to Chen PJ,Lai KL and Chang SSCTaiwan Liver Disease Consortium,the National Research Program for Biopharmaceuticals,and the National Science Council,Taiwan,NSC1002325-B-002-052NSC102-2325-B-002-079
文摘AIM: To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma (HCC) recurrence for up to 3 year following curative resection.
基金supported by grants from Zhejiang Provincial Natural Science Foundation of China(LR19H160002)National Natural Science Foundation of China(82073296 and 81773193)Research Project of Jinan Microecological Biomedicine Shandong Laboratory(JNL-2022010B).
文摘The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases.Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment.However,only a limited number of nanotherapies have enter clinical trials or are clinically approved.Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system(MPS),resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors.Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy.Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages.Polymer conjugation revived the parent camptothecin agent(e.g.,7-ethyl-10-hydroxy-camptothecin),enabling lipid nanoparticle encapsulation.Furthermore,macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin,increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy.When tested in a preclinical murine model of breast cancer,macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles.Furthermore,intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity.Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity.This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers.
基金financially supported by the National Natural Science Foundation of China(No.81773656)Liaoning Revitalization Talents Program(No.XLYC1808017,China)+1 种基金Shenyang Youth Science and Technology Innovation Talents Program(No.RC190454,China)College Student Innovation and Entrepreneurship Training Program of Shenyang Pharmaceutical University(No.X202010163141,China)。
文摘The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.
