Research on seismic anisotropy and attenuation plays a significant role in exploration geophysics. To enhance the imaging quality for complicated structures, we develop several effective improvements for anisotropic a...Research on seismic anisotropy and attenuation plays a significant role in exploration geophysics. To enhance the imaging quality for complicated structures, we develop several effective improvements for anisotropic attenuation effects in reverse-time migration (Q-RTM) on surface and vertical seismic profiling (VSP) acquisition geometries. First, to suppress pseudo-shear wave artifact and numerical instability of the commonly used anisotropic pseudo-acoustic wave equations, an optimized pure P-wave dispersion relation is derived and the corresponding pure-mode wave equation is solved by combining the finite-difference and Possion methods. Second, a simplified anisotropic pure-mode visco-acoustic wave equation (PVAWE) based on standard linear solid model is established. Third, a time-dispersion correlation strategy is applied to improve the modeling accuracy. Fourth, we extend a target-oriented scheme to anisotropic attenuated modeling and imaging. Instead of the conventional wavefield modeling and RTM, the proposed approach can extract available wavefield information near the target regions and produce high imaging resolution for target structures. Last, both anisotropic surface and VSP Q-RTMs are executed by combining optimized PVAWE, time-dispersion correlation and target-oriented algorithm. Modeling examples demonstrate the advantages of our schemes. Moreover, our modified Q-compensated imaging workflow can be regarded as a supplement to the classical anisotropic RTM.展开更多
For large-scale 3D seismic data,target-oriented reservoir imaging is more attractive than conventional full-volume migration,in terms of computation efficiency.Gaussian beam migration(GBM)is one of the most robust dep...For large-scale 3D seismic data,target-oriented reservoir imaging is more attractive than conventional full-volume migration,in terms of computation efficiency.Gaussian beam migration(GBM)is one of the most robust depth imaging method,which not only keeps the advantages of ray methods,such as high efficiency and flexibility,but also allows us to solve caustics and multipathing problems.But conventional Gaussian beam migration requires slant stack for prestack data,and ray tracing from beam center location to subsurface,which is not easy to be directly applied for target-oriented imaging.In this paper,we modify the conventional Gaussian beam migration scheme,by shooting rays from subsurface image points to receivers to implement wavefield back-propagation.This modification helps us to achieve a better subsurface illumination in complex structure and allows simple implementation for target reservoir imaging.Significantly,compared with the wavefi eld-based GBM,our method does not reconstruct the subsurface snapshots,which has higher efficiency.But the proposed method is not as efficient as the conventional Gaussian beam migration.Synthetic and field data examples demonstrate the validity and the target-oriented imaging capability of our method.展开更多
Some Triptorelin<sup>®</sup> (TRP) conjugates of triphenylmethanol derivatives (TPMs) with optimized hydrophobicity were synthesized by reacting 2-substituted methoxy benzenes with 1,3,5-trioxane, fol...Some Triptorelin<sup>®</sup> (TRP) conjugates of triphenylmethanol derivatives (TPMs) with optimized hydrophobicity were synthesized by reacting 2-substituted methoxy benzenes with 1,3,5-trioxane, followed by the conjugation with TRP and sebacic acid to produce TRP-TPMs derivatives. Comparative antiproliferative assays between TRP-TPMs conjugates and the corresponding non-covalent physical mixtures of the TPMs derivatives and TRP were used to treat human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3) and mouse preadipocytes (3T3-L1) cells. TRP-TPMs conjugates at the 50 μM inhibited cell proliferation in CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 21% - 37%, 24% - 73%, 37% - 56%, respectively following incubation for 72 h. These findings indicate that TRP-TPMs derivatives have the potential to enhance the biological activity of TRP.展开更多
Tibet,the only provincial-level impoverished region,is facing great challenges in getting rid of poverty,such as widespread poverty and weak infrastructure.Since 2012,Tibet has launched its "five in one" pro...Tibet,the only provincial-level impoverished region,is facing great challenges in getting rid of poverty,such as widespread poverty and weak infrastructure.Since 2012,Tibet has launched its "five in one" project and has gradually formed a layout for a large poverty-展开更多
Epidemiological studies indicate that treatment with metformin, an AMP-activated protein kinase (AMPK) activator, reduces the incidence of cancers. Activation of AMPK has also been reported to oppose tumor progression...Epidemiological studies indicate that treatment with metformin, an AMP-activated protein kinase (AMPK) activator, reduces the incidence of cancers. Activation of AMPK has also been reported to oppose tumor progression in diverse types of cancers and offers promising cancer therapy. Furthermore, AMPK is a primary regulator of energy metabolism and has also been implicated in cell cycle progression, angiogenesis, cell transformation, migration, and cancer. We have recently synthesized novel flavonoids, namely, triphenylmethanol derivatives (TPMs), but the effectiveness of the TPMs on the activity of AMPK remains unclear. We hypothesized that the novel TPMs would inhibit cancer cell proliferation through the activation of AMPK isoforms in cells. The effects of TPMs on prostate cells (PC-3) were investigated. Cells were exposed to TPMs for either 12 or 24 hr. at the respective doses of 0, 25, 50 100, and 200 µM based on the cell viability studies by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole) (MTT) assay. The results indicate that cells exposed to the respective doses of TPMs increased both phospho- and total-AMPKα1 in a dose- and time-dependent manner. The effects of the increases for the phospho- and total-AMPKα in cells were greater for the 24-hr than the 12-hr. incubation. Further studies are currently going on to elucidate the specificities of the said insults in increasing the phospho- and total-AMPKα activities and for the other respective isoforms.展开更多
Peramivir was a novel and highly potent neuraminidase(NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability(only 3%) due to the high polarity(log P of-1.4) and the...Peramivir was a novel and highly potent neuraminidase(NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability(only 3%) due to the high polarity(log P of-1.4) and the low membrane permeability across the intestine. To utilize the PEPT1-mediated prodrug strategy to improve the oral absorption and develop the oral alternative, seven amino acid ester prodrugs and seven amino acid amide prodrugs have been synthesized. The permeability of these prodrugs across Caco-2 cells were screened. Peramivr-(CH_2)_2-l-Val and Peramivir-l-Ile were of the highest permeability in ester prodrugs and amide prodrugs, respectively, and then they were selected for further studies. Glycylsarcosine(gly-sar) uptake by Caco-2 could be inbihited by Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile in a concentration-dependent manner, and the IC 50 was 1.34 ± 0.31 m M and 1.78 ± 0.48 m M, respectively. The direct uptake of Peramivir-(CH_2)_2-l-Val and Peramivirl-Ile in MDCK-PEPT1 cells were significantly higher than in MDCK mock cells, and could be markedly inhibited by gly-sar. The uptake of Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile(0.01 to 50 m M) in MDCK-hPEPT1 cells conformed to Michaelis–Menten Equation. The oral bioavailability of peramivir was 65.3% and 37.3% after the oral administration of Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile to rats, respectively. The oral absorption and bioactivation of Peramivir-(CH_2)_2-l-Val was rapid and extensive, and no Peramivir-(CH_2)_2-l-Val was found in plasma. Because the amide bond was relatively stable, Peramivir-l-Ile could not be totally converted to the parent drug in vivo. Peramivir-(CH_2)_2-l-Val with good oral profiles and rapid bioactivation might be a promising prodrug for the further clinic development. The present study also corroborated the idea that the PEPT1-mediated prodrug approach has enormous promise for improving the oral absorption of poorly absorbed drug.展开更多
16 ADT carboxylate esters were prepared by means of esterification and these compounds were expected to increase the bioavailability of 4-hydroxyanehole trithione.In vivo studies showed that ADT concentration of 3a in...16 ADT carboxylate esters were prepared by means of esterification and these compounds were expected to increase the bioavailability of 4-hydroxyanehole trithione.In vivo studies showed that ADT concentration of 3a in plasma was much higher than that of ATT during 120 min.Compound 3a could reach blood peak values of ADT at 660.6 ng/mL which was about 14 times of that by ATT.Additionally,the acute toxicity assay indicated high safety of compound 3a that the maximum tolerated dose was no less than 3.25 g/kg.展开更多
Highly water soluble esters of scutellarin with variable molecular weight polyethylene glycol (PEG) were prepared via PEGylation. The physicochemical properties and the stabilities under different conditions were in...Highly water soluble esters of scutellarin with variable molecular weight polyethylene glycol (PEG) were prepared via PEGylation. The physicochemical properties and the stabilities under different conditions were investigated. By PEG modification, the greatly increased water solubility and desirable partition coefficient of scuteUarin were obtained, and the results showed that these conjugates were potential prodrugs for the oral delivery of scuteUarin.展开更多
A simple and sensitive high performance liquid chromatography with fluorescence detection (HPLC-FD) has been developed for simultaneous quantification of doxorubicin (DOX) and its dipeptide conjugate prodrug (PDO...A simple and sensitive high performance liquid chromatography with fluorescence detection (HPLC-FD) has been developed for simultaneous quantification of doxorubicin (DOX) and its dipeptide conjugate prodrug (PDOX) in mice plasma. The chromatographic separation was carried out on an Amethyst C18-H column with gradient mobile phase of 0.1% formic acid and 0.1% formic acid in acetonitrile at a flow rate of 1.0 mL/min. The excitation and emission wavelengths were set at 490 and 550 nm, respectively. The method was comprehensively validated. The limits of detection were low up to 5.0 ng/mL for DOX and 25.0 ng/mL for PDOX. And the limits of quantification were low up to 12.5 ng/mL for DOX and 50 ng/mL for PDOX, which were lower than those for most of the current methods. The calibration curves showed good linearity (R2 〉 0.999) over the concentration ranges. The extraction recoveries ranged from 84.0% to 88.2% for DOX and from 85.4% to 89.2% for PDOX. Satisfactory intra-day and inter-day precisions were achieved with RSDs less than 9.1%. The results show that the developed HPLC-FD method is accurate, reliable and will be helpful for preclinical pharmacokinetic study of DOX and PDOX.展开更多
Ferroptosis is a new mode of cell death,which can be induced by Fenton reactionmediated lipid peroxidation.However,the insufficient H2O2 and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent...Ferroptosis is a new mode of cell death,which can be induced by Fenton reactionmediated lipid peroxidation.However,the insufficient H2O2 and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent ferroptosis.Herein,a self-supplying lipid peroxide nanoreactor was developed to co-delivery of doxorubicin(DOX),iron and unsaturated lipid for efficient ferroptosis.By leveraging the coordination effect between DOX and Fe3+,trisulfide bond-bridged DOX dimeric prodrug was actively loaded into the core of the unsaturated lipids-rich liposome via iron ion gradient method.First,Fe3+could react with the overexpressed GSH in tumor cells,inducing the GSH depletion and Fe2+generation.Second,the cleavage of trisulfide bond could also consume GSH,and the released DOX induces the generation of H2O2,which would react with the generated Fe2+in step one to induce efficient Fenton reaction-dependent ferroptosis.Third,the formed Fe3+/Fe2+couple could directly catalyze peroxidation of unsaturated lipids to boost Fenton reaction-independent ferroptosis.This iron-prodrug liposome nanoreactor precisely programs multimodal ferroptosis by integrating GSH depletion,ROS generation and lipid peroxidation,providing new sights for efficient cancer therapy.展开更多
Objective: To discuss the possibility of dexamethasone-dextran as a colon-specific dexamethasone prodrug. Methods: Dexamenthasone-dextran conjugate was synthesized with succinate as a cross-linker. The release of dexa...Objective: To discuss the possibility of dexamethasone-dextran as a colon-specific dexamethasone prodrug. Methods: Dexamenthasone-dextran conjugate was synthesized with succinate as a cross-linker. The release of dexamethasone was determined after the incubation of the prodrug with the contents of different parts of gastrointestinal(GI) tract of rats. Results: By HPLC analysis, it was shoWn that dexamethasone-dextran contained 9.2 mg dexamethasone per l00 mg dextran. conjugate. During 160 min incubation, the concentration of dexamethasone released in the contents of colon and cecum was 2.7 times as high as that released in the contents of proximal small intestine and distal small intestine. But no dexametha sone was released in the contents of stomach. Conclusion: Dexamethasone-dextran conjugate can be ed as a colon-specific dexamethasone prodrug to selectively deliver the drug to colon.展开更多
Homodimeric prodrug-based self-assembled nanoparticles,with carrier-free structure and ultrahigh drug loading,is drawing more and more attentions.Homodimeric prodrugs are composed of two drug molecules and a pivotal l...Homodimeric prodrug-based self-assembled nanoparticles,with carrier-free structure and ultrahigh drug loading,is drawing more and more attentions.Homodimeric prodrugs are composed of two drug molecules and a pivotal linkage.The influence of the linkages on the self-assembly,in vivo fate and antitumor activity of homodimeric prodrugs is the focus of research.Herein,three docetaxel(DTX)homodimeric prodrugs are developed using different lengths of diselenide bond-containing linkages.Interestingly,compared with the other two linkages,the longest diselenide bond-containing linkage could facilitate the self-delivery of DTX prodrugs,thus improving the stability,circulation time and tumor targeting of prodrug nanoassemblies.Besides,the extension of linkages reduces the redox-triggered drug release and cytotoxicity of prodrug nanoassemblies in tumor cells.Although the longest diselenide bond-containing prodrug nanoassemblies possessed the lowest cytotoxicity to 4T1 cells,their stable nanostructure maintained intact during circulation and achieve the maximum accumulation of DTX in tumor cells,which finally“turned the table”.Our study illustrates the crucial role of linkages in homodimeric prodrugs,and gives valuable proposal for the development of advanced nano-DDS for cancer treatment.展开更多
Novel water-soluble prodrugs of combretastatin A-4 (5-8) were synthesized and evaluated for their in vitro cytotoxicity against lung carcinoma A549. Compound 5, bearing phosphoryl choline (PC) moiety, showed 90% i...Novel water-soluble prodrugs of combretastatin A-4 (5-8) were synthesized and evaluated for their in vitro cytotoxicity against lung carcinoma A549. Compound 5, bearing phosphoryl choline (PC) moiety, showed 90% inhibition at 32 ktg/mL concentration after 24 h. The findings showed the PC derivative would be a promising candidate for the development of new water-soluble prodrug of cytotoxic combretastatin A-4,展开更多
Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs...Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs.However,potential application of MCT1 to facilitate the oral delivery is still unclear.Irregular oral absorption,poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU).Herein,we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages.Interestingly,due to high MCT1 affinity and good gastrointestinal stability,5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold)and oral bioavailability(4.1-fold)compared to 5-FU.More surprisingly,stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells,which provides an ideal foundation for the improvement of oral bioavailability.In summary,good gastrointestinal stability,high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs,and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.展开更多
The curcumin prodrugs, which could be selectively activated in tumor cells, were prepared to establish a basis for the targeted chemotherapy for cancer. On the basis of the molecular structure of curcumin, the N-maleo...The curcumin prodrugs, which could be selectively activated in tumor cells, were prepared to establish a basis for the targeted chemotherapy for cancer. On the basis of the molecular structure of curcumin, the N-maleoyl-L-valine-curcumin (NVC), N-maleoyl- glycine-curcumin (NGC) were chemically synthesized and identified by IR and NMR spectroscopy. After treatment with these two prodrugs for 6--24 h, the rates of growth inhibition on human bladder cancer EJ cells and renal tubular epithelial (HKC) cells were detected by MTT colorimetry. Our results showed that after the treatment with 20 μmol/L--40 μmol/L NVC and NGC for 6--24 h, the growth inhibitory effects on EJ cells were 6.71%-65.13 % (P〈0.05), 10. 96 %-73.01 % (p〈0. 05), respectively, in both dose- and time-dependent manners. When compared with the curcumin of same concentrations, the growth inhibitory effects of these two prodrugs on HKC cells were significantly decreased (P〈0.01). It is concluded that activation of curcumin prodrugs via hydrolysis functions of cellular esterase could inhibit the growth activities of tumor cells, and reduce the side effects on normal diploid cells. This provided a novel strategy for further exploration of tumor targeted chemotherapeutic drugs.展开更多
A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity an...A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 μmol/L and 2530 μmol/L, respectively.展开更多
基金supported by the National Key R&D Program of China(2021YFA0716902)National Natural Science Foundation of China(42004119,42174156)+1 种基金the Fundamental Research Funds for the Central Universities,CHD(300102261306)the National Engineering Research Center of Offshore Oil and Gas Exploration,No.6 Courtyard,Taiyanggong South Street,Chaoyang District,Beijing,100028.
文摘Research on seismic anisotropy and attenuation plays a significant role in exploration geophysics. To enhance the imaging quality for complicated structures, we develop several effective improvements for anisotropic attenuation effects in reverse-time migration (Q-RTM) on surface and vertical seismic profiling (VSP) acquisition geometries. First, to suppress pseudo-shear wave artifact and numerical instability of the commonly used anisotropic pseudo-acoustic wave equations, an optimized pure P-wave dispersion relation is derived and the corresponding pure-mode wave equation is solved by combining the finite-difference and Possion methods. Second, a simplified anisotropic pure-mode visco-acoustic wave equation (PVAWE) based on standard linear solid model is established. Third, a time-dispersion correlation strategy is applied to improve the modeling accuracy. Fourth, we extend a target-oriented scheme to anisotropic attenuated modeling and imaging. Instead of the conventional wavefield modeling and RTM, the proposed approach can extract available wavefield information near the target regions and produce high imaging resolution for target structures. Last, both anisotropic surface and VSP Q-RTMs are executed by combining optimized PVAWE, time-dispersion correlation and target-oriented algorithm. Modeling examples demonstrate the advantages of our schemes. Moreover, our modified Q-compensated imaging workflow can be regarded as a supplement to the classical anisotropic RTM.
文摘For large-scale 3D seismic data,target-oriented reservoir imaging is more attractive than conventional full-volume migration,in terms of computation efficiency.Gaussian beam migration(GBM)is one of the most robust depth imaging method,which not only keeps the advantages of ray methods,such as high efficiency and flexibility,but also allows us to solve caustics and multipathing problems.But conventional Gaussian beam migration requires slant stack for prestack data,and ray tracing from beam center location to subsurface,which is not easy to be directly applied for target-oriented imaging.In this paper,we modify the conventional Gaussian beam migration scheme,by shooting rays from subsurface image points to receivers to implement wavefield back-propagation.This modification helps us to achieve a better subsurface illumination in complex structure and allows simple implementation for target reservoir imaging.Significantly,compared with the wavefi eld-based GBM,our method does not reconstruct the subsurface snapshots,which has higher efficiency.But the proposed method is not as efficient as the conventional Gaussian beam migration.Synthetic and field data examples demonstrate the validity and the target-oriented imaging capability of our method.
文摘Some Triptorelin<sup>®</sup> (TRP) conjugates of triphenylmethanol derivatives (TPMs) with optimized hydrophobicity were synthesized by reacting 2-substituted methoxy benzenes with 1,3,5-trioxane, followed by the conjugation with TRP and sebacic acid to produce TRP-TPMs derivatives. Comparative antiproliferative assays between TRP-TPMs conjugates and the corresponding non-covalent physical mixtures of the TPMs derivatives and TRP were used to treat human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3) and mouse preadipocytes (3T3-L1) cells. TRP-TPMs conjugates at the 50 μM inhibited cell proliferation in CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 21% - 37%, 24% - 73%, 37% - 56%, respectively following incubation for 72 h. These findings indicate that TRP-TPMs derivatives have the potential to enhance the biological activity of TRP.
文摘Tibet,the only provincial-level impoverished region,is facing great challenges in getting rid of poverty,such as widespread poverty and weak infrastructure.Since 2012,Tibet has launched its "five in one" project and has gradually formed a layout for a large poverty-
文摘Epidemiological studies indicate that treatment with metformin, an AMP-activated protein kinase (AMPK) activator, reduces the incidence of cancers. Activation of AMPK has also been reported to oppose tumor progression in diverse types of cancers and offers promising cancer therapy. Furthermore, AMPK is a primary regulator of energy metabolism and has also been implicated in cell cycle progression, angiogenesis, cell transformation, migration, and cancer. We have recently synthesized novel flavonoids, namely, triphenylmethanol derivatives (TPMs), but the effectiveness of the TPMs on the activity of AMPK remains unclear. We hypothesized that the novel TPMs would inhibit cancer cell proliferation through the activation of AMPK isoforms in cells. The effects of TPMs on prostate cells (PC-3) were investigated. Cells were exposed to TPMs for either 12 or 24 hr. at the respective doses of 0, 25, 50 100, and 200 µM based on the cell viability studies by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole) (MTT) assay. The results indicate that cells exposed to the respective doses of TPMs increased both phospho- and total-AMPKα1 in a dose- and time-dependent manner. The effects of the increases for the phospho- and total-AMPKα in cells were greater for the 24-hr than the 12-hr. incubation. Further studies are currently going on to elucidate the specificities of the said insults in increasing the phospho- and total-AMPKα activities and for the other respective isoforms.
基金supported by National Natural Science Founda-tion of China(81360485 and 81560577)National Natural Science Foundation of Jiangxi(20132BAB215023)
文摘Peramivir was a novel and highly potent neuraminidase(NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability(only 3%) due to the high polarity(log P of-1.4) and the low membrane permeability across the intestine. To utilize the PEPT1-mediated prodrug strategy to improve the oral absorption and develop the oral alternative, seven amino acid ester prodrugs and seven amino acid amide prodrugs have been synthesized. The permeability of these prodrugs across Caco-2 cells were screened. Peramivr-(CH_2)_2-l-Val and Peramivir-l-Ile were of the highest permeability in ester prodrugs and amide prodrugs, respectively, and then they were selected for further studies. Glycylsarcosine(gly-sar) uptake by Caco-2 could be inbihited by Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile in a concentration-dependent manner, and the IC 50 was 1.34 ± 0.31 m M and 1.78 ± 0.48 m M, respectively. The direct uptake of Peramivir-(CH_2)_2-l-Val and Peramivirl-Ile in MDCK-PEPT1 cells were significantly higher than in MDCK mock cells, and could be markedly inhibited by gly-sar. The uptake of Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile(0.01 to 50 m M) in MDCK-hPEPT1 cells conformed to Michaelis–Menten Equation. The oral bioavailability of peramivir was 65.3% and 37.3% after the oral administration of Peramivir-(CH_2)_2-l-Val and Peramivir-l-Ile to rats, respectively. The oral absorption and bioactivation of Peramivir-(CH_2)_2-l-Val was rapid and extensive, and no Peramivir-(CH_2)_2-l-Val was found in plasma. Because the amide bond was relatively stable, Peramivir-l-Ile could not be totally converted to the parent drug in vivo. Peramivir-(CH_2)_2-l-Val with good oral profiles and rapid bioactivation might be a promising prodrug for the further clinic development. The present study also corroborated the idea that the PEPT1-mediated prodrug approach has enormous promise for improving the oral absorption of poorly absorbed drug.
文摘16 ADT carboxylate esters were prepared by means of esterification and these compounds were expected to increase the bioavailability of 4-hydroxyanehole trithione.In vivo studies showed that ADT concentration of 3a in plasma was much higher than that of ATT during 120 min.Compound 3a could reach blood peak values of ADT at 660.6 ng/mL which was about 14 times of that by ATT.Additionally,the acute toxicity assay indicated high safety of compound 3a that the maximum tolerated dose was no less than 3.25 g/kg.
基金supported by the National Natural Science Foundation of China(No.30070935,30271614)
文摘Highly water soluble esters of scutellarin with variable molecular weight polyethylene glycol (PEG) were prepared via PEGylation. The physicochemical properties and the stabilities under different conditions were investigated. By PEG modification, the greatly increased water solubility and desirable partition coefficient of scuteUarin were obtained, and the results showed that these conjugates were potential prodrugs for the oral delivery of scuteUarin.
基金supported by the National Natural Science Foundation of China (Grant nos. 21375101, 81573384 and 91417301)Natural Science Foundation of Hubei Province, China (No. 2014CFA077)Innovation Seed Fund and Translational Medical Research Fund of Wuhan University School of Medicine, China
文摘A simple and sensitive high performance liquid chromatography with fluorescence detection (HPLC-FD) has been developed for simultaneous quantification of doxorubicin (DOX) and its dipeptide conjugate prodrug (PDOX) in mice plasma. The chromatographic separation was carried out on an Amethyst C18-H column with gradient mobile phase of 0.1% formic acid and 0.1% formic acid in acetonitrile at a flow rate of 1.0 mL/min. The excitation and emission wavelengths were set at 490 and 550 nm, respectively. The method was comprehensively validated. The limits of detection were low up to 5.0 ng/mL for DOX and 25.0 ng/mL for PDOX. And the limits of quantification were low up to 12.5 ng/mL for DOX and 50 ng/mL for PDOX, which were lower than those for most of the current methods. The calibration curves showed good linearity (R2 〉 0.999) over the concentration ranges. The extraction recoveries ranged from 84.0% to 88.2% for DOX and from 85.4% to 89.2% for PDOX. Satisfactory intra-day and inter-day precisions were achieved with RSDs less than 9.1%. The results show that the developed HPLC-FD method is accurate, reliable and will be helpful for preclinical pharmacokinetic study of DOX and PDOX.
基金supported by the National Natural Science Foundation of China(no.81872816)the Liaoning Revitalization Talents Program(no.XLYC180801)+1 种基金China Postdoctoral Innovative Talents Support Program(no.BX20190219)China Postdoctoral Science Foundation(no.2019M661134).
文摘Ferroptosis is a new mode of cell death,which can be induced by Fenton reactionmediated lipid peroxidation.However,the insufficient H2O2 and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent ferroptosis.Herein,a self-supplying lipid peroxide nanoreactor was developed to co-delivery of doxorubicin(DOX),iron and unsaturated lipid for efficient ferroptosis.By leveraging the coordination effect between DOX and Fe3+,trisulfide bond-bridged DOX dimeric prodrug was actively loaded into the core of the unsaturated lipids-rich liposome via iron ion gradient method.First,Fe3+could react with the overexpressed GSH in tumor cells,inducing the GSH depletion and Fe2+generation.Second,the cleavage of trisulfide bond could also consume GSH,and the released DOX induces the generation of H2O2,which would react with the generated Fe2+in step one to induce efficient Fenton reaction-dependent ferroptosis.Third,the formed Fe3+/Fe2+couple could directly catalyze peroxidation of unsaturated lipids to boost Fenton reaction-independent ferroptosis.This iron-prodrug liposome nanoreactor precisely programs multimodal ferroptosis by integrating GSH depletion,ROS generation and lipid peroxidation,providing new sights for efficient cancer therapy.
文摘Objective: To discuss the possibility of dexamethasone-dextran as a colon-specific dexamethasone prodrug. Methods: Dexamenthasone-dextran conjugate was synthesized with succinate as a cross-linker. The release of dexamethasone was determined after the incubation of the prodrug with the contents of different parts of gastrointestinal(GI) tract of rats. Results: By HPLC analysis, it was shoWn that dexamethasone-dextran contained 9.2 mg dexamethasone per l00 mg dextran. conjugate. During 160 min incubation, the concentration of dexamethasone released in the contents of colon and cecum was 2.7 times as high as that released in the contents of proximal small intestine and distal small intestine. But no dexametha sone was released in the contents of stomach. Conclusion: Dexamethasone-dextran conjugate can be ed as a colon-specific dexamethasone prodrug to selectively deliver the drug to colon.
基金This work was supported by China Postdoctoral Innovative Talents Support Program(no.BX20190219)China Postdoctoral Science Foundation(no.2019M661134)National Natural Science Foundation of China(no.81872816).
文摘Homodimeric prodrug-based self-assembled nanoparticles,with carrier-free structure and ultrahigh drug loading,is drawing more and more attentions.Homodimeric prodrugs are composed of two drug molecules and a pivotal linkage.The influence of the linkages on the self-assembly,in vivo fate and antitumor activity of homodimeric prodrugs is the focus of research.Herein,three docetaxel(DTX)homodimeric prodrugs are developed using different lengths of diselenide bond-containing linkages.Interestingly,compared with the other two linkages,the longest diselenide bond-containing linkage could facilitate the self-delivery of DTX prodrugs,thus improving the stability,circulation time and tumor targeting of prodrug nanoassemblies.Besides,the extension of linkages reduces the redox-triggered drug release and cytotoxicity of prodrug nanoassemblies in tumor cells.Although the longest diselenide bond-containing prodrug nanoassemblies possessed the lowest cytotoxicity to 4T1 cells,their stable nanostructure maintained intact during circulation and achieve the maximum accumulation of DTX in tumor cells,which finally“turned the table”.Our study illustrates the crucial role of linkages in homodimeric prodrugs,and gives valuable proposal for the development of advanced nano-DDS for cancer treatment.
文摘Novel water-soluble prodrugs of combretastatin A-4 (5-8) were synthesized and evaluated for their in vitro cytotoxicity against lung carcinoma A549. Compound 5, bearing phosphoryl choline (PC) moiety, showed 90% inhibition at 32 ktg/mL concentration after 24 h. The findings showed the PC derivative would be a promising candidate for the development of new water-soluble prodrug of cytotoxic combretastatin A-4,
基金financially Supported by National Nature Sci-ence Foundation of China(No.81773656,U1608283,81573497)Liaoning Revitalization Talents Program,No XLYC1808017,Key projects of Technology bureau in Shenyang,No18400408Key projects of Liaoning Province Department of Education,No.2017LZD03
文摘Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs.However,potential application of MCT1 to facilitate the oral delivery is still unclear.Irregular oral absorption,poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU).Herein,we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages.Interestingly,due to high MCT1 affinity and good gastrointestinal stability,5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold)and oral bioavailability(4.1-fold)compared to 5-FU.More surprisingly,stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells,which provides an ideal foundation for the improvement of oral bioavailability.In summary,good gastrointestinal stability,high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs,and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.
文摘The curcumin prodrugs, which could be selectively activated in tumor cells, were prepared to establish a basis for the targeted chemotherapy for cancer. On the basis of the molecular structure of curcumin, the N-maleoyl-L-valine-curcumin (NVC), N-maleoyl- glycine-curcumin (NGC) were chemically synthesized and identified by IR and NMR spectroscopy. After treatment with these two prodrugs for 6--24 h, the rates of growth inhibition on human bladder cancer EJ cells and renal tubular epithelial (HKC) cells were detected by MTT colorimetry. Our results showed that after the treatment with 20 μmol/L--40 μmol/L NVC and NGC for 6--24 h, the growth inhibitory effects on EJ cells were 6.71%-65.13 % (P〈0.05), 10. 96 %-73.01 % (p〈0. 05), respectively, in both dose- and time-dependent manners. When compared with the curcumin of same concentrations, the growth inhibitory effects of these two prodrugs on HKC cells were significantly decreased (P〈0.01). It is concluded that activation of curcumin prodrugs via hydrolysis functions of cellular esterase could inhibit the growth activities of tumor cells, and reduce the side effects on normal diploid cells. This provided a novel strategy for further exploration of tumor targeted chemotherapeutic drugs.
文摘A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 μmol/L and 2530 μmol/L, respectively.