Hepatocellular carcinoma (HCC) is a cancer with high incidence and mortality rates worldwide. In the various treatment methods for HCC, the lack of cancer cell specificity and the development of multidrug resistance (...Hepatocellular carcinoma (HCC) is a cancer with high incidence and mortality rates worldwide. In the various treatment methods for HCC, the lack of cancer cell specificity and the development of multidrug resistance (MDR) are two major obstacles in the treatment of HCC. P-glycoprotein (P-gp) is an ATP-dependent drug efflux pump that can reduce the accumulation of drugs in cells and make cancer cells acquire drug resistance. D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) can inhibit the activity of ATP-dependent P-gp and serves as an effective excipient for overcoming tumor multidrug resistance (MDR). TPGS has been approved by the FDA as a safe adjuvant and is widely used in drug delivery systems. The biological and physicochemical properties of TPGS provide multiple advantages for its application in drug delivery, such as high biocompatibility, enhanced drug solubility, improved drug permeation, and selective antitumor activity. In recent years, more and more studies have found that using TPGS-modified nanomaterials to load chemotherapy drugs to treat tumors can effectively reverse the drug resistance of tumors, including HCC. This review summarizes and discusses the role of TPGS in reversing tumor drug resistance and the therapeutic effects of TPGS-based drugs on drug-resistant HCC.展开更多
Multiple drug resistance(MDR)is a tough problem in developing hepatocellular carcinoma(HCC)therapy.Here,we developed TPGS-coated cationic liposomes with Bcl-2 siRNA corona to load doxorubicin(Dox)i.e.,Bcl-2 siRNA/Dox-...Multiple drug resistance(MDR)is a tough problem in developing hepatocellular carcinoma(HCC)therapy.Here,we developed TPGS-coated cationic liposomes with Bcl-2 siRNA corona to load doxorubicin(Dox)i.e.,Bcl-2 siRNA/Dox-TPGS-LPs,to enhance anticancer effect of Dox in HCC-MDR.TPGS i.e.,d-α-tocopheryl polyethylene glycol 1000 succinate,inhibited Pglycoprotein(P-gp)efflux pump and Bcl-2 siRNA suppressed anti-apoptotic Bcl-2 protein.The Bcl-2 siRNA loaded in the liposomal corona was observed under transmission electron microscopy.The stability and hemolysis evaluation demonstrated Bcl-2 siRNA/Dox-TPGSLPs had good biocompatibility and siRNA-corona could protect the liposomal core to avoid the attachment of fetal bovine serum.In drug-resistant cells,TPGS effectively prolonged intracellular Dox retention time and siRNA-corona did improve the internalization of Dox from liposomes.In vitro and in vivo anticancer effect of this dual-functional nanostructure was examined in HCC-MDR Bel7402/5-FU tumor model.MTT assay confirmed the IC50 value of Dox was 20–50 fold higher in Bel7402/5-FU MDR cells than that in sensitive Bel7402 cells.Bcl-2 siRNA corona successfully entered the cytosol of Bel7402/5-FU MDR cells to downregulate Bcl-2 protein levels in vitro and in vivo.Bcl-2 siRNA/Dox-TPGS-LPs showed superior to TPGS-(or siRNA-)linked Dox liposomes in cell apoptosis and cytotoxicity assay in Bel7402/5-FU MDR cells,and 7-fold greater effect than free Dox in tumor growth inhibition of Bel7402/5-FU xenograft nude mice.In conclusion,TPGS-coated cationic liposomes with Bcl-2 siRNA corona had the capacity to inhibit MDR dual-pathways and subsequently improved the anti-tumor activity of the chemotherapeutic agent co-delivered to a level that cannot be achieved by inhibiting a MDR single way.展开更多
TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concen...TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concentration(CMC),low drug loading(DL)and poor tumor target limit its further clinical application.To overcome these drawbacks,the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials,ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material.The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin(DOX)-loaded micelles at neutral aqueous solutions.The micelles exhibited the lower CMC(8.2×10^(−5) mg/ml),higher DL(10.8%)and long-term storage and circulation stability,and showed enhanced cellular uptake,apoptosis,cytotoxicity,and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH(5.0),MDR reversal of TPGS,and synergistic effect of DOX and TPGS.Therefore,the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.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
To obtain the wound dressings which can accelerate healing effectively,vitamin E D-α-Tocopherol polyethylene glycol succinate(vitamin E TPGS),one of the common derivatives of the unstable vitamins E,was successfully ...To obtain the wound dressings which can accelerate healing effectively,vitamin E D-α-Tocopherol polyethylene glycol succinate(vitamin E TPGS),one of the common derivatives of the unstable vitamins E,was successfully incorporated into P(LLA-CL)nanofibers by electrospinning.Electron microscopy showed that the smooth cylindrical fibers were obtained,albeit with a small amount of beading visible for the vitamins-loaded fibers.The diameters of the P(LLA-CL)fibers decreased with the addition of vitamins.The incorporation of the vitamin E TPGS in the electrospun fibers was confirmed by Fourier transform infrared spectroscopy(FTIR).Moreover,X-ray diffraction(XRD)indicated that vitamin E TPGS existed in the amorphous physical form after electrospinning.Fibers containing vitamin E TPGS showed a sustained release profile over more than 100 h in vitro.Antibacterial tests demonstrated that fibers loaded with vitamin E TPGS were effective in inhibiting the growth of E.coli and S.aureus.MTT assay showed that the fibers could promote the proliferation of L929 fibroblasts.These results above demonstrate the potential of P(LLA-CL)/vitamins E TPGS(P/E)as advanced wound dressing materials.展开更多
Interconnected cells,Configurable Logic Blocks(CLBs),and input/output(I/O)pads are all present in every Field Programmable Gate Array(FPGA)structure.The interconnects are formed by the physical paths for connecting th...Interconnected cells,Configurable Logic Blocks(CLBs),and input/output(I/O)pads are all present in every Field Programmable Gate Array(FPGA)structure.The interconnects are formed by the physical paths for connecting the blocks.The combinational and sequential circuits are used in the logic blocks to execute logical functions.The FPGA includes two different tests called interconnect testing and logical testing.Instead of using an additional circuitry,the Built-in-Self-Test(BIST)logic is coded into an FPGA,which is then reconfigured to perform its specific operation after the testing is completed.As a result,additional test circuits for the FPGA board are no longer required.The FPGA BIST has no area overhead or performance reduction issues like conventional BIST.A resource-efficient testing scheme is essential to assure the appropriate operation of FPGA look-up tables for effectively testing the functional operation.In this work,the Configurable Logic Blocks(CLBs)of virtex-ultrascale FPGAs are tested using a BIST with a simple architecture.To evaluate the CLBs’capabilities including distributed modes of operation of Random Access Memory(RAM),several types of configurations are created.These setups have the ability to identify 100%stuck-at failures in every CLB.This method is suitable for all phases of FPGA testing and has no overhead or performance cost.展开更多
文摘Hepatocellular carcinoma (HCC) is a cancer with high incidence and mortality rates worldwide. In the various treatment methods for HCC, the lack of cancer cell specificity and the development of multidrug resistance (MDR) are two major obstacles in the treatment of HCC. P-glycoprotein (P-gp) is an ATP-dependent drug efflux pump that can reduce the accumulation of drugs in cells and make cancer cells acquire drug resistance. D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) can inhibit the activity of ATP-dependent P-gp and serves as an effective excipient for overcoming tumor multidrug resistance (MDR). TPGS has been approved by the FDA as a safe adjuvant and is widely used in drug delivery systems. The biological and physicochemical properties of TPGS provide multiple advantages for its application in drug delivery, such as high biocompatibility, enhanced drug solubility, improved drug permeation, and selective antitumor activity. In recent years, more and more studies have found that using TPGS-modified nanomaterials to load chemotherapy drugs to treat tumors can effectively reverse the drug resistance of tumors, including HCC. This review summarizes and discusses the role of TPGS in reversing tumor drug resistance and the therapeutic effects of TPGS-based drugs on drug-resistant HCC.
基金financially supported by National Basic Research Program of China(973 Program,2015CB931802)Natural Science Foundation of China(31470968 and 81627901)。
文摘Multiple drug resistance(MDR)is a tough problem in developing hepatocellular carcinoma(HCC)therapy.Here,we developed TPGS-coated cationic liposomes with Bcl-2 siRNA corona to load doxorubicin(Dox)i.e.,Bcl-2 siRNA/Dox-TPGS-LPs,to enhance anticancer effect of Dox in HCC-MDR.TPGS i.e.,d-α-tocopheryl polyethylene glycol 1000 succinate,inhibited Pglycoprotein(P-gp)efflux pump and Bcl-2 siRNA suppressed anti-apoptotic Bcl-2 protein.The Bcl-2 siRNA loaded in the liposomal corona was observed under transmission electron microscopy.The stability and hemolysis evaluation demonstrated Bcl-2 siRNA/Dox-TPGSLPs had good biocompatibility and siRNA-corona could protect the liposomal core to avoid the attachment of fetal bovine serum.In drug-resistant cells,TPGS effectively prolonged intracellular Dox retention time and siRNA-corona did improve the internalization of Dox from liposomes.In vitro and in vivo anticancer effect of this dual-functional nanostructure was examined in HCC-MDR Bel7402/5-FU tumor model.MTT assay confirmed the IC50 value of Dox was 20–50 fold higher in Bel7402/5-FU MDR cells than that in sensitive Bel7402 cells.Bcl-2 siRNA corona successfully entered the cytosol of Bel7402/5-FU MDR cells to downregulate Bcl-2 protein levels in vitro and in vivo.Bcl-2 siRNA/Dox-TPGS-LPs showed superior to TPGS-(or siRNA-)linked Dox liposomes in cell apoptosis and cytotoxicity assay in Bel7402/5-FU MDR cells,and 7-fold greater effect than free Dox in tumor growth inhibition of Bel7402/5-FU xenograft nude mice.In conclusion,TPGS-coated cationic liposomes with Bcl-2 siRNA corona had the capacity to inhibit MDR dual-pathways and subsequently improved the anti-tumor activity of the chemotherapeutic agent co-delivered to a level that cannot be achieved by inhibiting a MDR single way.
基金This work is financially supported by the National Natural Science Foundation of China(No.51803001)the Research Foundation of Education Department of Anhui Province of China(No.KJ2018ZD003 and KJ2018A0006)the Academic and Technology Introduction Project of Anhui University(AU02303203).
文摘TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concentration(CMC),low drug loading(DL)and poor tumor target limit its further clinical application.To overcome these drawbacks,the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials,ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material.The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin(DOX)-loaded micelles at neutral aqueous solutions.The micelles exhibited the lower CMC(8.2×10^(−5) mg/ml),higher DL(10.8%)and long-term storage and circulation stability,and showed enhanced cellular uptake,apoptosis,cytotoxicity,and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH(5.0),MDR reversal of TPGS,and synergistic effect of DOX and TPGS.Therefore,the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.
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.
基金Science and Technology Commission of Shanghai Municipality,China(No.16410723700)“111 Project”Biomedical Textile Materials Science and Technology,China(No.B07024)UK-China Joint Laboratory for Therapeutic Textiles Based at Donghua University
文摘To obtain the wound dressings which can accelerate healing effectively,vitamin E D-α-Tocopherol polyethylene glycol succinate(vitamin E TPGS),one of the common derivatives of the unstable vitamins E,was successfully incorporated into P(LLA-CL)nanofibers by electrospinning.Electron microscopy showed that the smooth cylindrical fibers were obtained,albeit with a small amount of beading visible for the vitamins-loaded fibers.The diameters of the P(LLA-CL)fibers decreased with the addition of vitamins.The incorporation of the vitamin E TPGS in the electrospun fibers was confirmed by Fourier transform infrared spectroscopy(FTIR).Moreover,X-ray diffraction(XRD)indicated that vitamin E TPGS existed in the amorphous physical form after electrospinning.Fibers containing vitamin E TPGS showed a sustained release profile over more than 100 h in vitro.Antibacterial tests demonstrated that fibers loaded with vitamin E TPGS were effective in inhibiting the growth of E.coli and S.aureus.MTT assay showed that the fibers could promote the proliferation of L929 fibroblasts.These results above demonstrate the potential of P(LLA-CL)/vitamins E TPGS(P/E)as advanced wound dressing materials.
文摘Interconnected cells,Configurable Logic Blocks(CLBs),and input/output(I/O)pads are all present in every Field Programmable Gate Array(FPGA)structure.The interconnects are formed by the physical paths for connecting the blocks.The combinational and sequential circuits are used in the logic blocks to execute logical functions.The FPGA includes two different tests called interconnect testing and logical testing.Instead of using an additional circuitry,the Built-in-Self-Test(BIST)logic is coded into an FPGA,which is then reconfigured to perform its specific operation after the testing is completed.As a result,additional test circuits for the FPGA board are no longer required.The FPGA BIST has no area overhead or performance reduction issues like conventional BIST.A resource-efficient testing scheme is essential to assure the appropriate operation of FPGA look-up tables for effectively testing the functional operation.In this work,the Configurable Logic Blocks(CLBs)of virtex-ultrascale FPGAs are tested using a BIST with a simple architecture.To evaluate the CLBs’capabilities including distributed modes of operation of Random Access Memory(RAM),several types of configurations are created.These setups have the ability to identify 100%stuck-at failures in every CLB.This method is suitable for all phases of FPGA testing and has no overhead or performance cost.
