Objective: The aim of this study was to detect apoptosis rates of Her-2 overexpression breast cancer cells, which were administrated with vitamin E succinate (VES) combined with paclitaxel at different dosages, or ...Objective: The aim of this study was to detect apoptosis rates of Her-2 overexpression breast cancer cells, which were administrated with vitamin E succinate (VES) combined with paclitaxel at different dosages, or administrated alone; to discuss the mechanism of their actions. Methods: Using immunohistochemical method to detect Her-2 expression of MDA- MB-453 cells. Using TUNEL assay to detect apoptosis rates of MDA-MB-453 ceils, with the concentrations at 10, 20 mg/L of VES and 50, 100 nmol/L of paclitaxel, and also combined together for 24 or 48 h. Then compared apoptosis action of various combinations. Results: The expression rate of 95% Her-2 was interval (63.32%, 69.60%); VES and paclitaxel both induced apoptosis of MDA-MB-453 cells, and it is dose to time dependence. It was strongest in apoptosis at 10 mg/L VES and 100 nmol/L paclitaxel in MDA-MB-453 cells 48 h later. Conclusion: VES and paclitaxel both induced apoptosis of MDA-MB-453 cells. It is stronger when the two drugs are administrated together. The mechanism is probably related to reduction of bcl-2 expression, so as to be more sensitive to paclitaxel. Synergistic effect is also possible for the two drugs influence tumor cells in different growing phases.展开更多
Vitamin E succinate was synthesized in organic solvents using a modified Novozym-435 as catalyst.In order to improve the catalytic performance of Novozym-435,the enzyme was modified using acetic anhydride, propionic a...Vitamin E succinate was synthesized in organic solvents using a modified Novozym-435 as catalyst.In order to improve the catalytic performance of Novozym-435,the enzyme was modified using acetic anhydride, propionic anhydride and succinic anhydride separately.We found that both the hydrolytic activity and the thermal stability of the modified Novozym-435 were enhanced compared with the unmodified enzyme.The modified Novozym-435 catalysts were used to synthesize the succinate derivative of vitamin E.Compared with the native Novozym-435,the catalytic activity of the modified novozym-435 in promoting the synthesis of vitamin E succinate was dramatically increased,with the novozym-435 modified with succinic anhydride(N435-S)as the most active catalyst.Conditions for the synthesis of vitamin E succinate were also optimized.A mixture of tert-butanol and DMSO(volume ratio of 2︰3)was the most suitable medium for the reaction,whereas the appropriate molar ratio of vitamin E to succinic anhydride and reaction temperature were 1︰5 and 40°C,respectively.Under these reaction conditions,the yield of vitamin E succinate reached 94.4%.N435-S could be reused for five batches.展开更多
Objective:Tn investigate the growth inhibition and apoptosis induced by vitamin E suceinate (VES) on human breast cancer cells and to analyze the possible mechanism in this process. Methods: Human breast cancer ce...Objective:Tn investigate the growth inhibition and apoptosis induced by vitamin E suceinate (VES) on human breast cancer cells and to analyze the possible mechanism in this process. Methods: Human breast cancer cell line Bcap-37 was treated with VES for 12, 24 and 48 h at the concentrations of 5, 10and 20 μg/ml. Then MTT assay was employed to detect the inhibitory effect of VES on the growth of breast cancer cells. Flow cytometry was used to analyze the cell cycle and apoptosis. To find out whether the Fas/FasL pathway was involved in this process, RT-PCR and flow cytometry assay were used to detect the Fas expression at the mRNA and protein level. Results: VESexhibited a significant inhibitory effect on the growth of human breast cancer cells, presenting in a dose- and time-dependant manner. The apoptotic rate of Bcap 37 cells was 0.6%, rose to 21.0% and 37.5% after treated with VES for 24 and 48 h at the concentration of 20 μg/ml. Fas mRNA transcription was upregulated after VES treatment and cell surface Fas expression increased according to the flow cytometry assay. Concluslon:Significant growth inhibition and apoptosis are induced in human breast cancer cells after treated with VES. The modulation of Fas/FasL pathway may related to the upregulation of Fas molecule on the cancer cell surface.展开更多
目的:明确维生素E琥珀酸酯(vitamin E succinate,VES)诱导的人口腔鳞癌Tca8113细胞的凋亡作用,初步探讨其凋亡机制。方法:PI单染色和Annexin Ⅴ-PI双染色后,流式细胞术检测VES对细胞周期的影响及细胞凋亡率;RT-PCR、west-ernblot法检测...目的:明确维生素E琥珀酸酯(vitamin E succinate,VES)诱导的人口腔鳞癌Tca8113细胞的凋亡作用,初步探讨其凋亡机制。方法:PI单染色和Annexin Ⅴ-PI双染色后,流式细胞术检测VES对细胞周期的影响及细胞凋亡率;RT-PCR、west-ernblot法检测促凋亡基因bax在mRNA水平和蛋白水平上的表达。结果:VES能显著抑制Tca8113细胞的生长,诱导出现典型的凋亡峰,bax基因及蛋白表达上调。结论:VES能诱导口腔鳞癌细胞Tca8113的凋亡,该作用可能与bax基因表达上调有关。展开更多
目的 了解带有死亡结构域的Fas相关蛋白(FADD)在维生素E琥珀酸酯(VES)诱导胃腺癌细胞凋亡过程中的作用。方法 以人胃腺癌SGC-7901细胞作为靶细胞,采用 Western Blot法、Lipofect转染法、DAPI染色法探讨FADD在VES诱导SGC-7901细胞凋...目的 了解带有死亡结构域的Fas相关蛋白(FADD)在维生素E琥珀酸酯(VES)诱导胃腺癌细胞凋亡过程中的作用。方法 以人胃腺癌SGC-7901细胞作为靶细胞,采用 Western Blot法、Lipofect转染法、DAPI染色法探讨FADD在VES诱导SGC-7901细胞凋亡过程中的作用。结果 经不同剂量VES处理后,SGC-7901细胞中FADD蛋白表达增加,呈剂量-效应关系;该细胞经FADD反义寡核苷酸转染与正义寡核苷酸转染相比,VES处理的细胞中FADD蛋白表达下降;用FADD反义寡核苷酸转染SGC-7901细胞后,降低了VES诱导的细胞凋亡率。结论FADD在VES诱导SGC-7901细胞凋亡过程中起着重要的作用。展开更多
Aim: To investigate the activity of RRR-α-tocopheryloxybutyric acid (TOB), an ether analog of RRR-α-tocopheryl succinate (VES), in prostate cancer cells. Methods: VES and TOB were used to treat prostate cancer...Aim: To investigate the activity of RRR-α-tocopheryloxybutyric acid (TOB), an ether analog of RRR-α-tocopheryl succinate (VES), in prostate cancer cells. Methods: VES and TOB were used to treat prostate cancer LNCaP, PC3, and 22Rvl cells and primary-cultured prostate fibroblasts. The proliferation rates were determined by MTT assay, the cell viabilities were determined by trypan blue exclusion assay, and the cell deaths were evaluated by using Cell Death Detection ELISA kit. The protein expression levels were determined by Western blot analysis. Results: The MTT growth assay demonstrated that TOB could effectively suppress the proliferation of prostate cancer cells, but not normal prostate fibroblasts. Mechanism dissections revealed that TOB reduced cell viability and induced apoptosis in prostate cancer cells similar to VES. In addition, both TOB and VES suppressed prostate-specific antigen (PSA) at the transcriptional level leading to reduced PSA protein expression. Furthermore, vitamin D receptor (VDR) expression increased after the addition of TOB. Conclusion: Our data suggests that the VES derivative, TOB, is effective in inhibiting prostate cancer cell proliferation, suggesting that TOB could be used for both chemopreventive and chemotherapeutic purposes in the future.展开更多
Objective: The aim of our study was to detect whether Vitamin E Succinic Acid (VES) could regulate the expression level of DR5 in the cells and further elucidate the potential mechanisms involving that VES enhances th...Objective: The aim of our study was to detect whether Vitamin E Succinic Acid (VES) could regulate the expression level of DR5 in the cells and further elucidate the potential mechanisms involving that VES enhances the effect of mDRA-6 to eradicate leukemia Raji and K562 cells. Methods: MTT method was used to detect the growth inhibition of VES and mDRA-6 to Raji and K562 cells. Annexin V-FITC/PI double staining assay was used to analysis the apoptosis of leukemia cell. Flow cytometry was used to detect the cell surface DR5 expression. Immunoblotting technique was used to detect the DR5 protein expression. Results: MTT detection showed that 10 μmol/L mDRA-6 on the cell death rates of Raji and K562 cells were 21.98% and 5.23%, respectively. While increasing concentration of VES (5 μmol/L, 10 μmol/L, 20 μmol/L) and mDRA-6 both on the cell viability of Raji or K562 cells, the mortality of Raji cells elevated to 24.67%, 35.65% (P<0.01) and 40.22% (P<0.01), respectively. Similarly, the mortality of K562 cells increase to 6%, 7.89% (P<0.01) and 8.67% (P<0.01), respectively. To further specify the increased cell death rate induced by mDRA-6 and VES, the treated cells were analyzed by Annexin-V/PI staining assay. As shown in Fig. 1, the apoptosis rates of Raji and K562 cells treated with 2 μg/mL mDRA-6 for 12 h were 20.79% and 7.74%. Compared with this, the proportion of apoptotic cells increased upon exposure to 2 μg/mL mDRA-6 combination with 10 μmol/L VES, the apoptosis rates of Raji and K562 cells were 43.18% and 16.99%, respectively. To examine the anticancer effects of a combination strategy based on mDRA-6 and VES. We analyzed whether VES could elevated the expression level of DR5 on Raji and K562 cytomembrane by FACS. Interestingly, after treated with 10 μmol/L VES for 12 h, the expression level of DR5 on Raji and K562 cell surface increased from 50.66% to 70.08%, and 15.02% to 16.38%, respectively. Immune imprinting technology test showed that, different concentrations of VES could increase Raji and K562 cell DR5 protein expression. Conclusion: VES enhances the effect of mDRA-6 to eradicate leukemia Raji and K562 cells. The proper mechanism is VES could enhance the Raji and K562 cell membrane expression of DR5, and VES can also enhance the DR5 protein expression of cells.展开更多
Heparosan is a natural precursor of heparin biosynthesis in mammals. It is stable in blood circulation but can be degraded in lysosomes, showing good biocompatibility and long circulation features. So heparosan can be...Heparosan is a natural precursor of heparin biosynthesis in mammals. It is stable in blood circulation but can be degraded in lysosomes, showing good biocompatibility and long circulation features. So heparosan can be designed as anticancer drug carriers to increase tumor selectivity and improve the therapeutic effect. A novel redox-sensitive heparosancystamine-vitamin E succinate(KSV) micelle system was constructed for intracellular delivery of doxorubicin(DOX). Simultaneously, the redox-insensitive heparosan-adipic acid dihydrazide-vitamin E succinate copolymer(KV) was synthesized as control. DOX-loaded micelles(DOX/KSV) with an average particle size of 90–120 nm had good serum stability and redox-triggered depolymerization. In vitro drug release test showed that DOX/KSV micelles presented obvious redox-triggered release behavior compared with DOX/KV. Cytotoxicity and cell uptake were investigated using MGC80-3 tumor cells and COS7 fibroblast-like cells. The cell survival rate of blank micelles was more than 90%, and the cytotoxicity of DOX/KSV in MGC80-3 cells was higher than in COS7 cells, indicating that the carrier has better biocompatibility and less toxicity side effect. The cytotoxicity of DOX/KSV against MGC80-3 cells was significantly greater than that of free DOX and DOX/KV. Furthermore, compared with DOX/KV in MGC80-3 cells, DOX/KSV micelles uptook more anticancer drugs and then released DOX faster into the cell nucleus. The micelles were endocytosed by multiple pathways, but clathrin-mediated endocytosis was the main pathway. Therefore, heparosan polysaccharide could be a potential option as anticancer carrier for enhancing efficacy and mitigating toxicity.展开更多
Nanocarriers have emerged as a promising cancer drug delivery strategy.Multi-drug resistance caused by overexpression of multiple-drug excretion transporters in tumor cells is the major obstacle to successful chemothe...Nanocarriers have emerged as a promising cancer drug delivery strategy.Multi-drug resistance caused by overexpression of multiple-drug excretion transporters in tumor cells is the major obstacle to successful chemotherapy.Vitamin E derivatives have many essential functions for drug delivery applications,such as biological components that are hydrophobic,stable,water-soluble enhancing compounds,and anticancer activity.In addition,vitamin E derivatives are also effective mitocan which can overcome multi-drug resistance by binding to P glycoproteins.Here,we developed a carboxymethyl chitosan/vitamin E succinate nano-micellar system(O-CMCTS-VES).The synthesized polymers were characterized by Fourier Transform IR,and 1H NMR spectra.The mean sizes of O-CMCTS-VES and DOX-loaded nanoparticles were around 177 nm and 208 nm.The drug loading contents were 6.1%,13.0%and 10.6%with the weight ratio of DOX to O-CMCTS-VES corresponding 1:10,2:10 and 3:10,and the corresponding EEs were 64.3%,74.5%and 39.7%.Cytotoxicity test,hemolysis test and histocompatibility test showed that it had good biocompatibility in vitro and in vivo.Drug release experiments implied good pH sensitivity and sustained-release effect.The DOX/O-CMCTS-VES nanoparticles can be efficiently taken up by HepG2 cancer cells and the tumor inhibition rate is up to 62.57%.In the in vivo study by using H22 cells implanted Balb/C mice,DOX/O-CMCTS-VES reduced the tumor volume and weight efficiently with a TIR of 35.58%.The newly developed polymeric micelles could successfully be utilized as a nanocarrier system for hydrophobic chemotherapeutic agents for the treatment of solid tumors.展开更多
To study effects of vitamin E (VE) and selenium (Se) on dynamic variation rules, functions and metabolisms of different free radicals, 2 weeks age chicks were reared using four kinds of dietaries that differed in ...To study effects of vitamin E (VE) and selenium (Se) on dynamic variation rules, functions and metabolisms of different free radicals, 2 weeks age chicks were reared using four kinds of dietaries that differed in their VE and Se content. Free radicals in blood and tissues of broiler chicks were detected directly or indirectly using electron spin resonance (ESR) testing and biology chemistry methods. Results showed that NO free radical contents were decreasing due to the increasing of VE supplement in dietary and VE level was negatively correlated with NO free radicals. High Se supplement dietaries had the trend to induce the produce of NO free radicals. High VE and Se level dietaries significantly enhanced activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in serum and liver. Depending on time, SOD and GSH-Px activities were declining and increasing respectively, which indicated that being short of VE and/or Se in dietaries could link to the produce of O-2, H2O2 free radicals. With the deficiency lasting, organism would continuously produce large amounts of O-2 free radicals but H2O2 free radicals were just produced explosively at the beginning of deficiency and than tended to be steady. Low VE and/or Se levels in dietaries could remarkably enhance malondialdehyde(MDA)contents in tissues and the effect of low Se was stronger. VE and Se in dietary had synergic effect on metabolisms of NO, O-2 and H2O2 free radicals.展开更多
Vitamin E( VE) is an ideal antioxidant and a stabilizing agent in biological membranes. In this study,silk fibroin( SF) /hydroxybutyl chitosan( HBC) nanofibrous scaffolds are loaded with VE tocopherol polyethylene gly...Vitamin E( VE) is an ideal antioxidant and a stabilizing agent in biological membranes. In this study,silk fibroin( SF) /hydroxybutyl chitosan( HBC) nanofibrous scaffolds are loaded with VE tocopherol polyethylene glycol 1000 succinate( VE TPGS) via electrospinning. SEM images show that the average nanofibrous diameter has no significant difference when the content of VE TPGS increases to 4. 0%( SF / HBC). However,the average nanofibrous diameter decreases largely to 200 nm when the VE TPGS content reaches 6. 0%. Furthermore,VE TPGS presents a sustained release behavior from the nanofibrous scaffolds. Cell viability studies of mouse skin fibroblasts( L929) demonstrate that VE TPGS loaded SF / HBC nanofibrous scaffolds present good cellular compatibility.Moreover,the incorporation of VE TPGS could strengthen the ability of SF / HBC nanofibrous scaffolds on protecting the cells against oxidation stress using the Tertbutyl hydroperoxide( t-BHP)-induced oxidative injury model. Therefore,VE TPGS-loaded SF /HBC nanofibrous scaffolds might be potential candidates for personal skin care,wound dressing and skin tissue engineering scaffolds.展开更多
基金Supported by a grant from the Educational Department of Province Heilonjiang (No. 11521185)
文摘Objective: The aim of this study was to detect apoptosis rates of Her-2 overexpression breast cancer cells, which were administrated with vitamin E succinate (VES) combined with paclitaxel at different dosages, or administrated alone; to discuss the mechanism of their actions. Methods: Using immunohistochemical method to detect Her-2 expression of MDA- MB-453 cells. Using TUNEL assay to detect apoptosis rates of MDA-MB-453 ceils, with the concentrations at 10, 20 mg/L of VES and 50, 100 nmol/L of paclitaxel, and also combined together for 24 or 48 h. Then compared apoptosis action of various combinations. Results: The expression rate of 95% Her-2 was interval (63.32%, 69.60%); VES and paclitaxel both induced apoptosis of MDA-MB-453 cells, and it is dose to time dependence. It was strongest in apoptosis at 10 mg/L VES and 100 nmol/L paclitaxel in MDA-MB-453 cells 48 h later. Conclusion: VES and paclitaxel both induced apoptosis of MDA-MB-453 cells. It is stronger when the two drugs are administrated together. The mechanism is probably related to reduction of bcl-2 expression, so as to be more sensitive to paclitaxel. Synergistic effect is also possible for the two drugs influence tumor cells in different growing phases.
基金Supported by the Fundamental Research Funds for the Central Universities and the State Key Development Program for Basic Research of China(2007CB714304)
文摘Vitamin E succinate was synthesized in organic solvents using a modified Novozym-435 as catalyst.In order to improve the catalytic performance of Novozym-435,the enzyme was modified using acetic anhydride, propionic anhydride and succinic anhydride separately.We found that both the hydrolytic activity and the thermal stability of the modified Novozym-435 were enhanced compared with the unmodified enzyme.The modified Novozym-435 catalysts were used to synthesize the succinate derivative of vitamin E.Compared with the native Novozym-435,the catalytic activity of the modified novozym-435 in promoting the synthesis of vitamin E succinate was dramatically increased,with the novozym-435 modified with succinic anhydride(N435-S)as the most active catalyst.Conditions for the synthesis of vitamin E succinate were also optimized.A mixture of tert-butanol and DMSO(volume ratio of 2︰3)was the most suitable medium for the reaction,whereas the appropriate molar ratio of vitamin E to succinic anhydride and reaction temperature were 1︰5 and 40°C,respectively.Under these reaction conditions,the yield of vitamin E succinate reached 94.4%.N435-S could be reused for five batches.
基金Supported by the foundation of Shanghai Science and Technology Committee (No.024119105).
文摘Objective:Tn investigate the growth inhibition and apoptosis induced by vitamin E suceinate (VES) on human breast cancer cells and to analyze the possible mechanism in this process. Methods: Human breast cancer cell line Bcap-37 was treated with VES for 12, 24 and 48 h at the concentrations of 5, 10and 20 μg/ml. Then MTT assay was employed to detect the inhibitory effect of VES on the growth of breast cancer cells. Flow cytometry was used to analyze the cell cycle and apoptosis. To find out whether the Fas/FasL pathway was involved in this process, RT-PCR and flow cytometry assay were used to detect the Fas expression at the mRNA and protein level. Results: VESexhibited a significant inhibitory effect on the growth of human breast cancer cells, presenting in a dose- and time-dependant manner. The apoptotic rate of Bcap 37 cells was 0.6%, rose to 21.0% and 37.5% after treated with VES for 24 and 48 h at the concentration of 20 μg/ml. Fas mRNA transcription was upregulated after VES treatment and cell surface Fas expression increased according to the flow cytometry assay. Concluslon:Significant growth inhibition and apoptosis are induced in human breast cancer cells after treated with VES. The modulation of Fas/FasL pathway may related to the upregulation of Fas molecule on the cancer cell surface.
文摘目的:明确维生素E琥珀酸酯(vitamin E succinate,VES)诱导的人口腔鳞癌Tca8113细胞的凋亡作用,初步探讨其凋亡机制。方法:PI单染色和Annexin Ⅴ-PI双染色后,流式细胞术检测VES对细胞周期的影响及细胞凋亡率;RT-PCR、west-ernblot法检测促凋亡基因bax在mRNA水平和蛋白水平上的表达。结果:VES能显著抑制Tca8113细胞的生长,诱导出现典型的凋亡峰,bax基因及蛋白表达上调。结论:VES能诱导口腔鳞癌细胞Tca8113的凋亡,该作用可能与bax基因表达上调有关。
文摘Aim: To investigate the activity of RRR-α-tocopheryloxybutyric acid (TOB), an ether analog of RRR-α-tocopheryl succinate (VES), in prostate cancer cells. Methods: VES and TOB were used to treat prostate cancer LNCaP, PC3, and 22Rvl cells and primary-cultured prostate fibroblasts. The proliferation rates were determined by MTT assay, the cell viabilities were determined by trypan blue exclusion assay, and the cell deaths were evaluated by using Cell Death Detection ELISA kit. The protein expression levels were determined by Western blot analysis. Results: The MTT growth assay demonstrated that TOB could effectively suppress the proliferation of prostate cancer cells, but not normal prostate fibroblasts. Mechanism dissections revealed that TOB reduced cell viability and induced apoptosis in prostate cancer cells similar to VES. In addition, both TOB and VES suppressed prostate-specific antigen (PSA) at the transcriptional level leading to reduced PSA protein expression. Furthermore, vitamin D receptor (VDR) expression increased after the addition of TOB. Conclusion: Our data suggests that the VES derivative, TOB, is effective in inhibiting prostate cancer cell proliferation, suggesting that TOB could be used for both chemopreventive and chemotherapeutic purposes in the future.
基金Supported by grants from the National "863 Plan" (No. 2006AA02A254)Outstanding Talent Program of Henan Province (No. 074200510014)
文摘Objective: The aim of our study was to detect whether Vitamin E Succinic Acid (VES) could regulate the expression level of DR5 in the cells and further elucidate the potential mechanisms involving that VES enhances the effect of mDRA-6 to eradicate leukemia Raji and K562 cells. Methods: MTT method was used to detect the growth inhibition of VES and mDRA-6 to Raji and K562 cells. Annexin V-FITC/PI double staining assay was used to analysis the apoptosis of leukemia cell. Flow cytometry was used to detect the cell surface DR5 expression. Immunoblotting technique was used to detect the DR5 protein expression. Results: MTT detection showed that 10 μmol/L mDRA-6 on the cell death rates of Raji and K562 cells were 21.98% and 5.23%, respectively. While increasing concentration of VES (5 μmol/L, 10 μmol/L, 20 μmol/L) and mDRA-6 both on the cell viability of Raji or K562 cells, the mortality of Raji cells elevated to 24.67%, 35.65% (P<0.01) and 40.22% (P<0.01), respectively. Similarly, the mortality of K562 cells increase to 6%, 7.89% (P<0.01) and 8.67% (P<0.01), respectively. To further specify the increased cell death rate induced by mDRA-6 and VES, the treated cells were analyzed by Annexin-V/PI staining assay. As shown in Fig. 1, the apoptosis rates of Raji and K562 cells treated with 2 μg/mL mDRA-6 for 12 h were 20.79% and 7.74%. Compared with this, the proportion of apoptotic cells increased upon exposure to 2 μg/mL mDRA-6 combination with 10 μmol/L VES, the apoptosis rates of Raji and K562 cells were 43.18% and 16.99%, respectively. To examine the anticancer effects of a combination strategy based on mDRA-6 and VES. We analyzed whether VES could elevated the expression level of DR5 on Raji and K562 cytomembrane by FACS. Interestingly, after treated with 10 μmol/L VES for 12 h, the expression level of DR5 on Raji and K562 cell surface increased from 50.66% to 70.08%, and 15.02% to 16.38%, respectively. Immune imprinting technology test showed that, different concentrations of VES could increase Raji and K562 cell DR5 protein expression. Conclusion: VES enhances the effect of mDRA-6 to eradicate leukemia Raji and K562 cells. The proper mechanism is VES could enhance the Raji and K562 cell membrane expression of DR5, and VES can also enhance the DR5 protein expression of cells.
基金We are grateful for the financial support from National Natural Science Foundation of China(81503007 and 21574059)Research Project of Wuxi Health and Family Planning Commission(Q201843)+1 种基金Natural Science Foundation of Jiangsu Province(BK20170202)the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions(PPZY2015B146).
文摘Heparosan is a natural precursor of heparin biosynthesis in mammals. It is stable in blood circulation but can be degraded in lysosomes, showing good biocompatibility and long circulation features. So heparosan can be designed as anticancer drug carriers to increase tumor selectivity and improve the therapeutic effect. A novel redox-sensitive heparosancystamine-vitamin E succinate(KSV) micelle system was constructed for intracellular delivery of doxorubicin(DOX). Simultaneously, the redox-insensitive heparosan-adipic acid dihydrazide-vitamin E succinate copolymer(KV) was synthesized as control. DOX-loaded micelles(DOX/KSV) with an average particle size of 90–120 nm had good serum stability and redox-triggered depolymerization. In vitro drug release test showed that DOX/KSV micelles presented obvious redox-triggered release behavior compared with DOX/KV. Cytotoxicity and cell uptake were investigated using MGC80-3 tumor cells and COS7 fibroblast-like cells. The cell survival rate of blank micelles was more than 90%, and the cytotoxicity of DOX/KSV in MGC80-3 cells was higher than in COS7 cells, indicating that the carrier has better biocompatibility and less toxicity side effect. The cytotoxicity of DOX/KSV against MGC80-3 cells was significantly greater than that of free DOX and DOX/KV. Furthermore, compared with DOX/KV in MGC80-3 cells, DOX/KSV micelles uptook more anticancer drugs and then released DOX faster into the cell nucleus. The micelles were endocytosed by multiple pathways, but clathrin-mediated endocytosis was the main pathway. Therefore, heparosan polysaccharide could be a potential option as anticancer carrier for enhancing efficacy and mitigating toxicity.
基金The authors wish to thank National Natural Science Foundation of China(No.51773188)Key Project of Natural Science Foundation of Shandong Province(No.ZR2020KE016)The National Key Research and Development Program of China(No.2018YFC1105602,2018YFD0900601).
文摘Nanocarriers have emerged as a promising cancer drug delivery strategy.Multi-drug resistance caused by overexpression of multiple-drug excretion transporters in tumor cells is the major obstacle to successful chemotherapy.Vitamin E derivatives have many essential functions for drug delivery applications,such as biological components that are hydrophobic,stable,water-soluble enhancing compounds,and anticancer activity.In addition,vitamin E derivatives are also effective mitocan which can overcome multi-drug resistance by binding to P glycoproteins.Here,we developed a carboxymethyl chitosan/vitamin E succinate nano-micellar system(O-CMCTS-VES).The synthesized polymers were characterized by Fourier Transform IR,and 1H NMR spectra.The mean sizes of O-CMCTS-VES and DOX-loaded nanoparticles were around 177 nm and 208 nm.The drug loading contents were 6.1%,13.0%and 10.6%with the weight ratio of DOX to O-CMCTS-VES corresponding 1:10,2:10 and 3:10,and the corresponding EEs were 64.3%,74.5%and 39.7%.Cytotoxicity test,hemolysis test and histocompatibility test showed that it had good biocompatibility in vitro and in vivo.Drug release experiments implied good pH sensitivity and sustained-release effect.The DOX/O-CMCTS-VES nanoparticles can be efficiently taken up by HepG2 cancer cells and the tumor inhibition rate is up to 62.57%.In the in vivo study by using H22 cells implanted Balb/C mice,DOX/O-CMCTS-VES reduced the tumor volume and weight efficiently with a TIR of 35.58%.The newly developed polymeric micelles could successfully be utilized as a nanocarrier system for hydrophobic chemotherapeutic agents for the treatment of solid tumors.
基金Item supported by science and technologycommission of Shanghai (No.033919417)
文摘To study effects of vitamin E (VE) and selenium (Se) on dynamic variation rules, functions and metabolisms of different free radicals, 2 weeks age chicks were reared using four kinds of dietaries that differed in their VE and Se content. Free radicals in blood and tissues of broiler chicks were detected directly or indirectly using electron spin resonance (ESR) testing and biology chemistry methods. Results showed that NO free radical contents were decreasing due to the increasing of VE supplement in dietary and VE level was negatively correlated with NO free radicals. High Se supplement dietaries had the trend to induce the produce of NO free radicals. High VE and Se level dietaries significantly enhanced activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in serum and liver. Depending on time, SOD and GSH-Px activities were declining and increasing respectively, which indicated that being short of VE and/or Se in dietaries could link to the produce of O-2, H2O2 free radicals. With the deficiency lasting, organism would continuously produce large amounts of O-2 free radicals but H2O2 free radicals were just produced explosively at the beginning of deficiency and than tended to be steady. Low VE and/or Se levels in dietaries could remarkably enhance malondialdehyde(MDA)contents in tissues and the effect of low Se was stronger. VE and Se in dietary had synergic effect on metabolisms of NO, O-2 and H2O2 free radicals.
基金the Independent Design Project of Key Scientific and Technological Innovation Team of Zhejiang Province,China(No.2010R50012-19)the Key Student Research Training Project of Jiaxing University,China(No.851713022)+1 种基金Technology Commission of JiaxingM unicipality Program,China(No.2012AY1030)National Natural Science Foundation of China(No.31271035)
文摘Vitamin E( VE) is an ideal antioxidant and a stabilizing agent in biological membranes. In this study,silk fibroin( SF) /hydroxybutyl chitosan( HBC) nanofibrous scaffolds are loaded with VE tocopherol polyethylene glycol 1000 succinate( VE TPGS) via electrospinning. SEM images show that the average nanofibrous diameter has no significant difference when the content of VE TPGS increases to 4. 0%( SF / HBC). However,the average nanofibrous diameter decreases largely to 200 nm when the VE TPGS content reaches 6. 0%. Furthermore,VE TPGS presents a sustained release behavior from the nanofibrous scaffolds. Cell viability studies of mouse skin fibroblasts( L929) demonstrate that VE TPGS loaded SF / HBC nanofibrous scaffolds present good cellular compatibility.Moreover,the incorporation of VE TPGS could strengthen the ability of SF / HBC nanofibrous scaffolds on protecting the cells against oxidation stress using the Tertbutyl hydroperoxide( t-BHP)-induced oxidative injury model. Therefore,VE TPGS-loaded SF /HBC nanofibrous scaffolds might be potential candidates for personal skin care,wound dressing and skin tissue engineering scaffolds.