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
为延长盐酸吉西他滨(1)的半衰期、提高生物利用度,采用逆相蒸发法制备聚乙二醇1000维生素E琥珀酸酯(TPGS)修饰的1脂质体(1-LP),并考察其性质和在大鼠体内的药动学行为。结果表明,所得1-LP的粒径为(212.6±7.2)nm、z电位为(-31.1...为延长盐酸吉西他滨(1)的半衰期、提高生物利用度,采用逆相蒸发法制备聚乙二醇1000维生素E琥珀酸酯(TPGS)修饰的1脂质体(1-LP),并考察其性质和在大鼠体内的药动学行为。结果表明,所得1-LP的粒径为(212.6±7.2)nm、z电位为(-31.1±2.9)m V、包封率为(70.56±1.92)%、载药量为(7.41±0.05)%。绘制了1-LP和1水溶液在p H 7.4磷酸盐缓冲液中的体外释药曲线,并用几种常用模型拟合试验数据。结果二者的释药数据均用双指数模型拟合效果较好(R^2为0.996和0.947)。对比研究了SD大鼠尾静脉注射给予1-LP或市售1注射液后的药动学行为。血浆中的药物浓度采用HPLC法测定。所得主要药动学参数为:t_(1/2)(4.12±0.73)和(1.32±0.10)h,AUC_(0→∞)(37.57±1.09)和(9.64±0.20)mg·L·h^(-1),MRT_(0→∞)(6.06±0.28)和(1.67±0.04)h。展开更多
Multidrug resistance （MDR） operated by P-glycoprotein （P-gp） is one of the major causes in the treatment failure of cancers. In this work, docetaxel-loaded mixed micelles comprised of 1,2-distearoyl-sn-glycero-3-p...Multidrug resistance （MDR） operated by P-glycoprotein （P-gp） is one of the major causes in the treatment failure of cancers. In this work, docetaxel-loaded mixed micelles comprised of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy （polyethylene-glycol）2000 （DSPE-PEG2000）, D-α-Tocopherylpolyethylene glycol 1000 succinate （TPGSIooo） and DSPE-PEG2000-folate were developed to overcome MDR and reduce the side effect of docetaxel in cancer therapy. The diameters of micelles ranged from 13 to 26 nm and the encapsulation efficiencies were all above 85%. The influences of DSPE-PEG2000 and TPGSIooo ratios on the micellar characteristics and anti-resistant tumors effects were evaluated. Micelles with high TPGS1000 amount showed an increased cellular uptake and stronger cytotoxicity against MDR KBv cells. Moreover, the micelles modified by targeting ligand of folic acid exhibited better antitumor effect on folate receptor over-expressing KBv cells. The study provides a method for overcoming MDR in cancer therapy.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
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.
文摘为延长盐酸吉西他滨(1)的半衰期、提高生物利用度,采用逆相蒸发法制备聚乙二醇1000维生素E琥珀酸酯(TPGS)修饰的1脂质体(1-LP),并考察其性质和在大鼠体内的药动学行为。结果表明,所得1-LP的粒径为(212.6±7.2)nm、z电位为(-31.1±2.9)m V、包封率为(70.56±1.92)%、载药量为(7.41±0.05)%。绘制了1-LP和1水溶液在p H 7.4磷酸盐缓冲液中的体外释药曲线,并用几种常用模型拟合试验数据。结果二者的释药数据均用双指数模型拟合效果较好(R^2为0.996和0.947)。对比研究了SD大鼠尾静脉注射给予1-LP或市售1注射液后的药动学行为。血浆中的药物浓度采用HPLC法测定。所得主要药动学参数为:t_(1/2)(4.12±0.73)和(1.32±0.10)h,AUC_(0→∞)(37.57±1.09)和(9.64±0.20)mg·L·h^(-1),MRT_(0→∞)(6.06±0.28)和(1.67±0.04)h。
基金National Natural Science Foundation of China(Grant No.81273454 and 81473156)Beijing National Science Foundation(Grant No.7132113)+1 种基金National Key Basic Research Program(Grant No.2013CB932501)Doctoral Foundation of the Ministry of Education(Grant No.20130001110055)
文摘Multidrug resistance （MDR） operated by P-glycoprotein （P-gp） is one of the major causes in the treatment failure of cancers. In this work, docetaxel-loaded mixed micelles comprised of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy （polyethylene-glycol）2000 （DSPE-PEG2000）, D-α-Tocopherylpolyethylene glycol 1000 succinate （TPGSIooo） and DSPE-PEG2000-folate were developed to overcome MDR and reduce the side effect of docetaxel in cancer therapy. The diameters of micelles ranged from 13 to 26 nm and the encapsulation efficiencies were all above 85%. The influences of DSPE-PEG2000 and TPGSIooo ratios on the micellar characteristics and anti-resistant tumors effects were evaluated. Micelles with high TPGS1000 amount showed an increased cellular uptake and stronger cytotoxicity against MDR KBv cells. Moreover, the micelles modified by targeting ligand of folic acid exhibited better antitumor effect on folate receptor over-expressing KBv cells. The study provides a method for overcoming MDR in cancer therapy.
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.
