The combination of paclitaxel(PTX)and doxorubicin(DOX)has been widely used in the clinic.However,it remains unsatisfied due to the generation of severe toxicity.Previously,we have successfully synthesized a prodrug PT...The combination of paclitaxel(PTX)and doxorubicin(DOX)has been widely used in the clinic.However,it remains unsatisfied due to the generation of severe toxicity.Previously,we have successfully synthesized a prodrug PTX-S-DOX(PSD).The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX.Thus,we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation.Due to the fact that copper ions(Cu2+)could coordinate with the anthracene nucleus of DOX,we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+gradient.Hence,we designed a remote loading liposomal formulation of PSD(PSD LPs)for combination chemotherapy.The prepared PSD LPs displayed extended blood circulation,improved tumor accumulation,and more significant anti-tumor efficacy compared with PSD NPs.Furthermore,PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil,indicating better safety.Therefore,this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.展开更多
Liposomes have made remarkable achievements as drug delivery vehicles in the clinic.Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs,but seem...Liposomes have made remarkable achievements as drug delivery vehicles in the clinic.Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs,but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents,thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy.In this study,a series of weak acid drug derivatives were designed by a simplistic one step synthesis,which could be remotely loaded into liposomes by p H gradient method.Cabazitaxel(CTX)weak acid derivatives were selected to evaluate regarding its safety profiles,pharmacodynamics,and pharmacokinetics.CTX weak acid derivative liposomes were superior to Jevtanaa in terms of safety profiles,including systemic toxicity,hematological toxicity,and potential central nerve toxicity.Specifically,it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons.Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.展开更多
In this paper, the analytical solution of stress field for a strained reinforcement layer bonded to a lip-shaped crack under a remote mode III uniform load and a concentrated load is obtained explicitly in the series ...In this paper, the analytical solution of stress field for a strained reinforcement layer bonded to a lip-shaped crack under a remote mode III uniform load and a concentrated load is obtained explicitly in the series form by using the technical of conformal mapping and the method of analytic continuation. The effects of material combinations, bond of interface and geometric configurations on interfaciai stresses generated by eigenstrain, remote load and concentrated load are studied. The results show that the stress concentration and interfaciai stresses can be reduced by rational material combinations and geometric configurations designs for different load forms.展开更多
Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot synd...Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine(BER) and doxorubicin(DOX), which was called Lipo Be Do. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, Lipo Be Do, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The Lipo Be Do significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil(P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.展开更多
To evaluate the controlling factors for coastline change of the Changjiang（Yangtze River） Estuary since 1974,we extracted the mean high tide line from multi-temporal remote sensing images that span from 1974 to 2014...To evaluate the controlling factors for coastline change of the Changjiang（Yangtze River） Estuary since 1974,we extracted the mean high tide line from multi-temporal remote sensing images that span from 1974 to 2014 at 2-year intervals.We chose 42 scenes to constrain the changing pattern of the Changjiang Estuary coastline,and implemented GIS technology to analyze the area change of the Changjiang（Yangtze） Subaerial Delta.Runoff,sediment discharge and coastal engineering were withal considered in the analysis of the coastline changes.The coastline has transgressed seaward since 1974,and a part of it presents inter-annual variations.The area of the Changjiang Subaerial Delta increased by 871 km2,with a net accretion rate of 21.8 km2/a.Based on the change of sediment discharge due to the major projects in the Changjiang River Basin,we divided the changing pattern of the coastline into three stages：the slow accretion stage（1974–1986）,the moderate accretion stage（1987–2002）,and the rapid accretion stage（2003–2014）.Liner regression analysis illustrated that there is a significantly positive correlation between the area changes and sediment discharge in the Chongming Eastern Shoal and Jiuduansha.This suggested that sediment load has a fundamental effect on the evolution of the Changjiang Estuary.Construction of Deep Waterway in the North Passage of the Changjiang River（1998–2010） led to a rapid accretion in the Hengsha Eastern Shoal and Jiuduansha by influencing the hydrodynamics in North Passage.Coastal engineering such as reclamation and harbor construction can also change the morphology of the Changjiang Estuary.We defined a contribution rate of area change to assess the impact of reclamation on the evolution of Changjiang Estuary.It turned out that more than 45.3% of area increment of the Changjiang Estuary was attributed to reclamation.展开更多
Aim:Co-encapsulation of anti-cancer agents in pegylated liposomes may provide an effective tool to maximize efficacy of combined drug therapy by taking advantage of the long circulation time,passive targeting,and redu...Aim:Co-encapsulation of anti-cancer agents in pegylated liposomes may provide an effective tool to maximize efficacy of combined drug therapy by taking advantage of the long circulation time,passive targeting,and reduced toxicity of liposome formulations.Methods:We have developed several liposome formulations of co-encapsulated drugs using various permutations of three active agents:doxorubicin(Dox),mitomycin-C lipidic prodrug(MLP),and alendronate(Ald).Dox and MLP are available in single drug liposomal formulations:pegylated liposomal Dox(PLD,Doxil®),clinically approved,and pegylated liposomal MLP(PL-MLP,Promitil®),in phase 1-2 clinical testing.We have previously shown that co-encapsulation of Dox and Ald in pegylated liposomes(PLAD)results in a formulation with valuable immuno-pharmacologic properties and superior antitumor properties over PLD in immunocompetent animal models.Building on the PLAD and PL-MLP platforms,we developed a new pegylated liposomal formulation of co-entrapped Dox and MLP(PLAD-MLP),with the former localized in the liposome water phase via remote loading with an ammonium alendronate and the latter passively loaded into the liposome lipid bilayer.An alternative formulation of co-entrapped MLP and Dox in which ammonium Ald was replaced with ammonium sulfate(PLD-MLP)was also tested for comparative purposes.Results: PLAD-MLP displays high loading efficiency of Dox and MLP nearing 100%, and a mean vesicle diameter of 110 nm. Cryo-transmission electron microscopy (cryo-TEM) of PLAD-MLP reveals round vesicles with an intra-vesicle Dox-alendronate precipitate. PLAD-MLP was tested in an in vitro MLP activation assay with the reducing agent dithiothreitol and found to be significantly less susceptible to thiolytic activation than PL-MLP. Alongside thiolytic activation of MLP, a significant fraction of encapsulated Dox was released from liposomes. PLAD-MLP is stable upon in vitro incubation in human plasma with nearly 100% drug retention. In mouse pharmacokinetic studies, PLAD-MLP extended MLP half-life in circulation when compared to that of MLP delivered as PL-MLP. In addition, the MLP levels in tissues were greater than those obtained with PL-MLP, indicating that PLAD-MLP slows down the cleavage of the prodrug MLP to MMC, thus resulting in a more sustained and prolonged exposure. The circulation half-life of Dox in PLAD-MLP was similar to the PLD Dox half-life. The pattern of tissue distribution was similar for the co-encapsulated drugs, although Dox levels were generally higher than those of MLP, as expected from cleavage of MLP to its active metabolite MMC. In mouse tumor models, the therapeutic activity of PLAD-MLP was superior to PL-MLP and PLD with a convenient safety dose window. The Ald-free formulation, PLD-MLP, displayed similar pharmacokinetic properties to PLAD-MLP, but its therapeutic activity was lower. Conclusion: PLAD-MLP is a novel multi-drug liposome formulation with attractive pharmacological properties and powerful antitumor activity and is a promising therapeutic tool for combination cancer chemotherapy.展开更多
基金supported by National Science and Technology Major Projects for Major New Drugs Innovation and Development(No.2017ZX09101-001-005,Beijing,China)Science and Technology Plan Project of Shenyang(No.18-400-4-08,Z17-5-064,China)the Career Development Program for Young and Middle-aged Teachers in Shenyang Pharmaceutical University(Shenyang,China)
文摘The combination of paclitaxel(PTX)and doxorubicin(DOX)has been widely used in the clinic.However,it remains unsatisfied due to the generation of severe toxicity.Previously,we have successfully synthesized a prodrug PTX-S-DOX(PSD).The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX.Thus,we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation.Due to the fact that copper ions(Cu2+)could coordinate with the anthracene nucleus of DOX,we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+gradient.Hence,we designed a remote loading liposomal formulation of PSD(PSD LPs)for combination chemotherapy.The prepared PSD LPs displayed extended blood circulation,improved tumor accumulation,and more significant anti-tumor efficacy compared with PSD NPs.Furthermore,PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil,indicating better safety.Therefore,this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.
基金financially supported by the National Nature Science Foundation of China(U1608283)the Career Development Program for Young and Middle-aged Teachers in Shenyang Pharmaceutical University
文摘Liposomes have made remarkable achievements as drug delivery vehicles in the clinic.Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs,but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents,thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy.In this study,a series of weak acid drug derivatives were designed by a simplistic one step synthesis,which could be remotely loaded into liposomes by p H gradient method.Cabazitaxel(CTX)weak acid derivatives were selected to evaluate regarding its safety profiles,pharmacodynamics,and pharmacokinetics.CTX weak acid derivative liposomes were superior to Jevtanaa in terms of safety profiles,including systemic toxicity,hematological toxicity,and potential central nerve toxicity.Specifically,it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons.Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.
基金Project supported by the National Natural Science Foundation of China(Nos.10872065 and 50801025)the State Key Laboratory of Advanced Design and Manufacturing for Vehicle Body(No. 60870005)the Doctor Station Fund of Institutions of Higher Learning(No.200805320023)
文摘In this paper, the analytical solution of stress field for a strained reinforcement layer bonded to a lip-shaped crack under a remote mode III uniform load and a concentrated load is obtained explicitly in the series form by using the technical of conformal mapping and the method of analytic continuation. The effects of material combinations, bond of interface and geometric configurations on interfaciai stresses generated by eigenstrain, remote load and concentrated load are studied. The results show that the stress concentration and interfaciai stresses can be reduced by rational material combinations and geometric configurations designs for different load forms.
基金the Career Development Program for Yong and Middle-aged Teachers in Shenyang Pharmaceutical University。
文摘Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine(BER) and doxorubicin(DOX), which was called Lipo Be Do. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, Lipo Be Do, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The Lipo Be Do significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil(P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.
文摘To evaluate the controlling factors for coastline change of the Changjiang（Yangtze River） Estuary since 1974,we extracted the mean high tide line from multi-temporal remote sensing images that span from 1974 to 2014 at 2-year intervals.We chose 42 scenes to constrain the changing pattern of the Changjiang Estuary coastline,and implemented GIS technology to analyze the area change of the Changjiang（Yangtze） Subaerial Delta.Runoff,sediment discharge and coastal engineering were withal considered in the analysis of the coastline changes.The coastline has transgressed seaward since 1974,and a part of it presents inter-annual variations.The area of the Changjiang Subaerial Delta increased by 871 km2,with a net accretion rate of 21.8 km2/a.Based on the change of sediment discharge due to the major projects in the Changjiang River Basin,we divided the changing pattern of the coastline into three stages：the slow accretion stage（1974–1986）,the moderate accretion stage（1987–2002）,and the rapid accretion stage（2003–2014）.Liner regression analysis illustrated that there is a significantly positive correlation between the area changes and sediment discharge in the Chongming Eastern Shoal and Jiuduansha.This suggested that sediment load has a fundamental effect on the evolution of the Changjiang Estuary.Construction of Deep Waterway in the North Passage of the Changjiang River（1998–2010） led to a rapid accretion in the Hengsha Eastern Shoal and Jiuduansha by influencing the hydrodynamics in North Passage.Coastal engineering such as reclamation and harbor construction can also change the morphology of the Changjiang Estuary.We defined a contribution rate of area change to assess the impact of reclamation on the evolution of Changjiang Estuary.It turned out that more than 45.3% of area increment of the Changjiang Estuary was attributed to reclamation.
基金a research grant of Lipomedix Pharmaceuticals Ltd.
文摘Aim:Co-encapsulation of anti-cancer agents in pegylated liposomes may provide an effective tool to maximize efficacy of combined drug therapy by taking advantage of the long circulation time,passive targeting,and reduced toxicity of liposome formulations.Methods:We have developed several liposome formulations of co-encapsulated drugs using various permutations of three active agents:doxorubicin(Dox),mitomycin-C lipidic prodrug(MLP),and alendronate(Ald).Dox and MLP are available in single drug liposomal formulations:pegylated liposomal Dox(PLD,Doxil®),clinically approved,and pegylated liposomal MLP(PL-MLP,Promitil®),in phase 1-2 clinical testing.We have previously shown that co-encapsulation of Dox and Ald in pegylated liposomes(PLAD)results in a formulation with valuable immuno-pharmacologic properties and superior antitumor properties over PLD in immunocompetent animal models.Building on the PLAD and PL-MLP platforms,we developed a new pegylated liposomal formulation of co-entrapped Dox and MLP(PLAD-MLP),with the former localized in the liposome water phase via remote loading with an ammonium alendronate and the latter passively loaded into the liposome lipid bilayer.An alternative formulation of co-entrapped MLP and Dox in which ammonium Ald was replaced with ammonium sulfate(PLD-MLP)was also tested for comparative purposes.Results: PLAD-MLP displays high loading efficiency of Dox and MLP nearing 100%, and a mean vesicle diameter of 110 nm. Cryo-transmission electron microscopy (cryo-TEM) of PLAD-MLP reveals round vesicles with an intra-vesicle Dox-alendronate precipitate. PLAD-MLP was tested in an in vitro MLP activation assay with the reducing agent dithiothreitol and found to be significantly less susceptible to thiolytic activation than PL-MLP. Alongside thiolytic activation of MLP, a significant fraction of encapsulated Dox was released from liposomes. PLAD-MLP is stable upon in vitro incubation in human plasma with nearly 100% drug retention. In mouse pharmacokinetic studies, PLAD-MLP extended MLP half-life in circulation when compared to that of MLP delivered as PL-MLP. In addition, the MLP levels in tissues were greater than those obtained with PL-MLP, indicating that PLAD-MLP slows down the cleavage of the prodrug MLP to MMC, thus resulting in a more sustained and prolonged exposure. The circulation half-life of Dox in PLAD-MLP was similar to the PLD Dox half-life. The pattern of tissue distribution was similar for the co-encapsulated drugs, although Dox levels were generally higher than those of MLP, as expected from cleavage of MLP to its active metabolite MMC. In mouse tumor models, the therapeutic activity of PLAD-MLP was superior to PL-MLP and PLD with a convenient safety dose window. The Ald-free formulation, PLD-MLP, displayed similar pharmacokinetic properties to PLAD-MLP, but its therapeutic activity was lower. Conclusion: PLAD-MLP is a novel multi-drug liposome formulation with attractive pharmacological properties and powerful antitumor activity and is a promising therapeutic tool for combination cancer chemotherapy.
