Hesperetin,an abundant bioactive component of citrus fruits,is poorly water-soluble,resulting in low oral bioavailability.We developed new formulations to improve the water solubility,antioxidant activity,and oral abs...Hesperetin,an abundant bioactive component of citrus fruits,is poorly water-soluble,resulting in low oral bioavailability.We developed new formulations to improve the water solubility,antioxidant activity,and oral absorption of hesperetin.Two nano-based formulations were developed,namely hesperetin-TPGS(D-α-tocopheryl polyethylene glycol 1000 succinate)micelles and hesperetin-phosphatidylcholine(PC)complexes.These two formulations were prepared by a simple technique called solvent dispersion,using US Food and Drug Administration(FDA)-approved excipients for drugs.Differential scanning calorimetry(DSC)and dynamic light scattering(DLS)were used to characterize the formulations’physical properties.Cytotoxicity analysis,cellular antioxidant activity assay,and a pharmacokinetic study were performed to evaluate the biological properties of these two formulations.The final weight ratios of both hesperetin to TPGS and hesperetin to PC were 1:12 based on their water solubility,which increased to 21.5-and 20.7-fold,respectively.The hesperetin-TPGS micelles had a small particle size of 26.19 nm,whereas the hesperetin-PC complexes exhibited a larger particle size of 219.15 nm.In addition,the cellular antioxidant activity assay indicated that both hesperetin-TPGS micelles and hesperetin-PC complexes increased the antioxidant activity of hesperetin to 4.2-and 3.9-fold,respectively.Importantly,the in vivo oral absorption study on rats indicated that the micelles and complexes significantly increased the peak plasma concentration(Cmax)from 2.64μg/mL to 20.67 and 33.09μg/mL and also increased the area under the concentration–time curve of hesperetin after oral administration to 16.2-and 18.0-fold,respectively.The micelles and complexes increased the solubility and remarkably improved the in vitro antioxidant activity and in vivo oral absorption of hesperetin,indicating these formulations’potential applications in drugs and healthcare products.展开更多
This study aimed to investigate the ability of the novel materials D-α-tocopheryl poly(2-ethyl-2-oxazoline) succinate(TPOS) to construct pH-sensitive liposomes. TPOS was initially synthesized and characterized by TLC...This study aimed to investigate the ability of the novel materials D-α-tocopheryl poly(2-ethyl-2-oxazoline) succinate(TPOS) to construct pH-sensitive liposomes. TPOS was initially synthesized and characterized by TLC, FTIR, and ~1H-NMR. The buffering capacity of polyethylene glycol-distearoyl phosphatidylethanolamine(PEG-DSPE) and TPOS was determined by acid-base titration, and TPOS displayed a slower downtrend and gentler slope of titration curve than PEG-DSPE within pH 7.4–5.0. Studies on the in vitro drug release demonstrated that TPOS modified docetaxel(DOC) liposomes(TPOS-DOC-L) had a slower drugrelease rate at pH 7.4 similar to PEGylated-DOC liposomes(PEG-DOC-L), whereas the release rate reached approximately 86.92% ± 1.69% at pH 6.4. In vitro cellular uptake assays by microplate reader, and flow cytometry revealed that TPOS modified coumarin 6 liposomes(TPOS-C6-L) had stronger cellular uptake at pH 6.4 than that at pH 7.4( P < 0.01). Conversely, for PEGylated C6 liposomes(PEG-C6-L) and conventional C6 liposomes(C6-L), very similar cellular uptakes were exhibited at different pH values. Confocal laser scanning microscopy images showed that PEG-C6-L and C6-L were mainly located in lysosomes. By contrast, TPOS-C6-L showed broader cytoplasmic release and distribution at 4 h. MTT assay showed that the cytotoxicity of TPOS-DOC-L was similar to that of PEG-DOC-L and conventional DOC liposomes(DOC-L) at the same DOC concentration and at pH 7.4, but was much lower than those at pH 6.4 after 48 h of incubation. The apoptosis of PEG-DOC-L and DOC-L had no remarkable improvement with decreased pH from 7.4 to 6.4. Meanwhile, TPOS-DOC-Lsignificantly induced the apoptosis of HeLa cells with decreased pH. Therefore, TPOS can be a biomaterial for the construction of a pH-sensitive drug delivery system.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
维生素E琥珀酸酯(vitamin E succinate,RRR-α-tocopheryl succinate,VES)是维生素E的一种酯化衍生物。对维生素E家族在肿瘤预防和治疗中作用的研究始于20世纪60年代。实验证据显示,VES是维生素E家族中抗肿瘤效果最好的化合物之一,能有...维生素E琥珀酸酯(vitamin E succinate,RRR-α-tocopheryl succinate,VES)是维生素E的一种酯化衍生物。对维生素E家族在肿瘤预防和治疗中作用的研究始于20世纪60年代。实验证据显示,VES是维生素E家族中抗肿瘤效果最好的化合物之一,能有效抑制多种肿瘤,但对正常的细胞和组织没有明显的不良反应。近年来大量的研究对VES抗肿瘤的作用机制也作了进一步的探讨。本文从4个方面阐述VES抗肿瘤机理的研究进展:①VES的分子结构、化学性质和运送载体;②VES抑制肿瘤细胞增殖的机制;③VES诱导肿瘤细胞凋亡的机制;④VES抑制肿瘤转移的机制。全面了解VES抗肿瘤的机理,将有助于发现新的抗癌药物靶点,促进研发安全有效的肿瘤预防和治疗性药物。展开更多
研究了以4-二甲氨基吡啶为催化剂,由α-生育酚和琥珀酸酐合成α-生育酚琥珀酸酯(α-TOS)的酯化反应工艺和反应动力学。该合成反应最佳条件为:α-生育酚与琥珀酸酐配比为1∶3;催化剂用量1.5%;反应温度50℃;反应时间4 h,产率达84.5%,样品...研究了以4-二甲氨基吡啶为催化剂,由α-生育酚和琥珀酸酐合成α-生育酚琥珀酸酯(α-TOS)的酯化反应工艺和反应动力学。该合成反应最佳条件为:α-生育酚与琥珀酸酐配比为1∶3;催化剂用量1.5%;反应温度50℃;反应时间4 h,产率达84.5%,样品的纯度大于96%。通过对反应规律的研究,结果表明,在本实验条件下该合成反应表现为二级不可逆反应,表观活化能Ea=83.4 k J。展开更多
基金Project supported by the National Natural Science Foundation of China(Nos.51773176,51522304,and U1501243)the Natural Science Foundation of Zhejiang Province(No.LY17H300002),China
文摘Hesperetin,an abundant bioactive component of citrus fruits,is poorly water-soluble,resulting in low oral bioavailability.We developed new formulations to improve the water solubility,antioxidant activity,and oral absorption of hesperetin.Two nano-based formulations were developed,namely hesperetin-TPGS(D-α-tocopheryl polyethylene glycol 1000 succinate)micelles and hesperetin-phosphatidylcholine(PC)complexes.These two formulations were prepared by a simple technique called solvent dispersion,using US Food and Drug Administration(FDA)-approved excipients for drugs.Differential scanning calorimetry(DSC)and dynamic light scattering(DLS)were used to characterize the formulations’physical properties.Cytotoxicity analysis,cellular antioxidant activity assay,and a pharmacokinetic study were performed to evaluate the biological properties of these two formulations.The final weight ratios of both hesperetin to TPGS and hesperetin to PC were 1:12 based on their water solubility,which increased to 21.5-and 20.7-fold,respectively.The hesperetin-TPGS micelles had a small particle size of 26.19 nm,whereas the hesperetin-PC complexes exhibited a larger particle size of 219.15 nm.In addition,the cellular antioxidant activity assay indicated that both hesperetin-TPGS micelles and hesperetin-PC complexes increased the antioxidant activity of hesperetin to 4.2-and 3.9-fold,respectively.Importantly,the in vivo oral absorption study on rats indicated that the micelles and complexes significantly increased the peak plasma concentration(Cmax)from 2.64μg/mL to 20.67 and 33.09μg/mL and also increased the area under the concentration–time curve of hesperetin after oral administration to 16.2-and 18.0-fold,respectively.The micelles and complexes increased the solubility and remarkably improved the in vitro antioxidant activity and in vivo oral absorption of hesperetin,indicating these formulations’potential applications in drugs and healthcare products.
基金supported by National Natural Science Foundation of China (81102394)Natural Science Foundation of Liaoning Province (20170540575)
文摘This study aimed to investigate the ability of the novel materials D-α-tocopheryl poly(2-ethyl-2-oxazoline) succinate(TPOS) to construct pH-sensitive liposomes. TPOS was initially synthesized and characterized by TLC, FTIR, and ~1H-NMR. The buffering capacity of polyethylene glycol-distearoyl phosphatidylethanolamine(PEG-DSPE) and TPOS was determined by acid-base titration, and TPOS displayed a slower downtrend and gentler slope of titration curve than PEG-DSPE within pH 7.4–5.0. Studies on the in vitro drug release demonstrated that TPOS modified docetaxel(DOC) liposomes(TPOS-DOC-L) had a slower drugrelease rate at pH 7.4 similar to PEGylated-DOC liposomes(PEG-DOC-L), whereas the release rate reached approximately 86.92% ± 1.69% at pH 6.4. In vitro cellular uptake assays by microplate reader, and flow cytometry revealed that TPOS modified coumarin 6 liposomes(TPOS-C6-L) had stronger cellular uptake at pH 6.4 than that at pH 7.4( P < 0.01). Conversely, for PEGylated C6 liposomes(PEG-C6-L) and conventional C6 liposomes(C6-L), very similar cellular uptakes were exhibited at different pH values. Confocal laser scanning microscopy images showed that PEG-C6-L and C6-L were mainly located in lysosomes. By contrast, TPOS-C6-L showed broader cytoplasmic release and distribution at 4 h. MTT assay showed that the cytotoxicity of TPOS-DOC-L was similar to that of PEG-DOC-L and conventional DOC liposomes(DOC-L) at the same DOC concentration and at pH 7.4, but was much lower than those at pH 6.4 after 48 h of incubation. The apoptosis of PEG-DOC-L and DOC-L had no remarkable improvement with decreased pH from 7.4 to 6.4. Meanwhile, TPOS-DOC-Lsignificantly induced the apoptosis of HeLa cells with decreased pH. Therefore, TPOS can be a biomaterial for the construction of a pH-sensitive drug delivery system.
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。
文摘维生素E琥珀酸酯(vitamin E succinate,RRR-α-tocopheryl succinate,VES)是维生素E的一种酯化衍生物。对维生素E家族在肿瘤预防和治疗中作用的研究始于20世纪60年代。实验证据显示,VES是维生素E家族中抗肿瘤效果最好的化合物之一,能有效抑制多种肿瘤,但对正常的细胞和组织没有明显的不良反应。近年来大量的研究对VES抗肿瘤的作用机制也作了进一步的探讨。本文从4个方面阐述VES抗肿瘤机理的研究进展:①VES的分子结构、化学性质和运送载体;②VES抑制肿瘤细胞增殖的机制;③VES诱导肿瘤细胞凋亡的机制;④VES抑制肿瘤转移的机制。全面了解VES抗肿瘤的机理,将有助于发现新的抗癌药物靶点,促进研发安全有效的肿瘤预防和治疗性药物。
文摘研究了以4-二甲氨基吡啶为催化剂,由α-生育酚和琥珀酸酐合成α-生育酚琥珀酸酯(α-TOS)的酯化反应工艺和反应动力学。该合成反应最佳条件为:α-生育酚与琥珀酸酐配比为1∶3;催化剂用量1.5%;反应温度50℃;反应时间4 h,产率达84.5%,样品的纯度大于96%。通过对反应规律的研究,结果表明,在本实验条件下该合成反应表现为二级不可逆反应,表观活化能Ea=83.4 k J。
