The Experts below are selected from a list of 3084 Experts worldwide ranked by ideXlab platform

Zhiyuan Zhong - One of the best experts on this subject based on the ideXlab platform.

  • Micelles with Sheddable Dendritic Polyglycerol Sulfate Shells Show Extraordinary Tumor Targetability and Chemotherapy in Vivo
    2016
    Co-Authors: Yinan Zhong, Fenghua Meng, Zhiyuan Zhong, Chao Deng, Mathias Dimde, Daniel Stöbener, Rainer Haag
    Abstract:

    Cancer nanomedicines are typically stealthed by a poly­(ethylene glycol) layer that is important to obtain extended blood circulation and elevated tumor accumulation. PEG stealth, however, also leads to poor tumor cell selectivity and uptake thereby reducing treatment efficacy. Here, we report that biodegradable micelles with sheddable dendritic polyglycerol sulfate (dPGS) shells show an unusual tumor targetability and chemotherapy in vivo. The self-assembly of dPGS-SS-poly­(ε-caprolactone) amphiphilic block copolymer with an Mn of 4.8–3.7 kg mol–1 affords negatively charged and small sized micelles (dPGS-SS-PCL Ms). dPGS-SS-PCL Ms reveal a low cytotoxicity, decent doxorubicin (DOX) loading, and accelerated drug release under a Reductive Condition. Notably, DOX-loaded dPGS-SS-PCL Ms exhibit a high tolerable dosage of more than 40 mg kg–1, a long plasma half-life of ca. 2.8 h, and an extraordinary tumor accumulation. Intriguingly, therapeutic results demonstrate that DOX-loaded dPGS-SS-PCL Ms induce complete tumor suppression, significantly improved survival rate, and diminishing adverse effects as compared to free drug (DOX·HCl) in MCF-7 human mammary carcinoma models. Dendritic polyglycerol sulfate with a superior tumor homing ability appears to be an attractive alternative to PEG in formulating targeted cancer nanomedicines

  • Enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s: Synthesis, cell compatibility, and intracellular anticancer drug delivery
    Biomacromolecules, 2015
    Co-Authors: Huanli Sun, Marc Hendriks, Ru Cheng, Fenghua Meng, Aylvin A. Dias, Chao Deng, Jan Feijen, Zhiyuan Zhong
    Abstract:

    A novel and versatile family of enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s (SS-PEAs) were developed from solution polycondensation of disulfide-containing di-p-toluenesulfonic acid salts of bis-L-phenylalanine diesters (SS-Phe-2TsOH) with di-p-nitrophenyl adipate (NA) in N,N-dimethyl formamide (DMF). SS-PEAs with Mn ranging from 16.6 to 23.6 kg/mol were obtained depending on NA/SS-Phe-2TsOH molar ratios. The chemical structures of SS-PEAs were confirmed by (1)H NMR and FTIR spectra. Thermal analyses showed that the obtained SS-PEAs were amorphous with glass transition temperature (Tg) in the range of 35.2-39.5 ºC. The in vitro degradation studies of SS-PEA films revealed that SS-PEAs underwent surface erosion in the presence of 0.1 mg/mL α-chymotrypsin and bulk degradation under a Reductive environment containing 10 mM dithiothreitol (DTT). The preliminary cell culture studies displayed that SS-PEA films could well support adhesion and proliferation of L929 fibroblast cells, indicating that SS-PEAs have excellent cell compatibility. The nanoparticles prepared from SS-PEA with PVA as a surfactant had an average size of 167 nm in phosphate buffer (PB, 10 mM, pH 7.4). SS-PEA nanoparticles while stable under physiological environment undergo rapid disintegration under an enzymatic or Reductive Condition. The in vitro drug release studies showed that DOX release was accelerated in the presence of 0.1 mg/mL α-chymotrypsin or 10 mM DTT. Confocal microscopy observation displayed that SS-PEA nanoparticles effectively transported DOX into both drug-sensitive and resistant MCF-7 cells. MTT assays revealed that DOX-loaded SS-PEA nanoparticles had a high antitumor activity approaching to free DOX in drug-sensitive MCF-7 cells, while more than 10 times higher than free DOX in drug-resistant MCF-7/ADR cells. These enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s have provided an appealing platform for biomedical technology in particular controlled drug delivery applications.

  • intracellular release of doxorubicin from core crosslinked polypeptide micelles triggered by both ph and reduction Conditions
    Biomaterials, 2013
    Co-Authors: Yan Zou, Ru Cheng, Fenghua Meng, Chao Deng, Zhiyuan Zhong
    Abstract:

    Abstract Reduction and pH dual-sensitive reversibly core-crosslinked polypeptide micelles were developed from lipoic acid (LA) and cis-1,2-cyclohexanedicarboxylic acid (CCA) decorated poly(ethylene glycol)-b-poly( l -lysine) (PEG-P(LL-CCA/LA)) block copolymers for active loading and triggered intracellular release of doxorubicin (DOX). PEG-P(LL18-CCA4/LA14) and PEG-P(LL18-CCA8/LA10) (Mn PEG = 5.0 kg/mol) formed nano-sized micelles that were readily crosslinked in the presence of a catalytic amount of dithiothreitol (DTT) in phosphate buffer (pH 7.4, 10 m m ). PEG-P(LL18-CCA4/LA14) micelles displayed an elevated DOX loading over PEG-P(LL14-LA14) controls likely due to presence of ionic interactions between DOX and CCA. These core-crosslinked polypeptide micelles while exhibiting high stability against extensive dilution and high salt concentration were quickly dissociated into unimers in the presence of 10 m m DTT. The in vitro release studies showed that DOX release from PEG-P(LL18-CCA4/LA14) micelles at pH 7.4 and 37 °C was significantly inhibited by crosslinking (i.e. less than 20% release in 24 h). The release of DOX was, however, doubled under endosomal pH of 5.0, possibly triggered by cleavage of the acid-labile amide bonds of CCA. In particular, rapid DOX release was observed under a Reductive Condition containing 10 m m glutathione (GSH), in which 86.0% and 96.7% of DOX were released in 24 h at pH 7.4 and 5.0, respectively, under otherwise the same Conditions. MTT assays demonstrated that these core-crosslinked polypeptide micelles were practically non-toxic up to a tested concentration of 1.0 mg/mL, while DOX-loaded micelles caused pronounced cytotoxic effects to HeLa and HepG2 tumor cells with IC50 (inhibitory concentration to produce 50% cell death) of ca. 12.5 μg DOX equiv/mL following 48 h incubation. Confocal microscopy observations revealed that DOX-loaded crosslinked PEG-P(LL18-CCA4/LA14) micelles more efficiently delivered and released DOX into the nuclei of HeLa cells than PEG-P(LL14-LA14) counterparts. These dual-bioresponsive core-crosslinked polypeptide micelles have appeared as an advanced platform for targeted cancer therapy.

  • functional poly e caprolactone s via copolymerization of e caprolactone and pyridyl disulfide containing cyclic carbonate controlled synthesis and facile access to reduction sensitive biodegradable graft copolymer micelles
    Macromolecules, 2013
    Co-Authors: Wei Chen, Ru Cheng, Fenghua Meng, Chao Deng, Jan Feijen, Zhiyuan Zhong
    Abstract:

    Pyridyl disulfide-functionalized cyclic carbonate (PDSC) monomer was obtained in four straightforward steps from 3-methyl-3-oxetanemethanol and exploited for facile preparation of functional poly(e-caprolactone) (PCL) containing pendant pyridyl disulfide (PDS) groups via ring-opening copolymerization with e-caprolactone. The results showed that PDS-functionalized PCL polymers were prepared with controlled molecular weights and functionalities. The exchange reaction between PDS-functionalized PCL and thiolated poly(ethylene glycol) (PEG-SH) at a PEG-SH/PDS molar ratio of 2/1 afforded PCL-g-SS-PEG graft copolymers in high yields. The dynamic light scattering (DLS) analyses showed that PCL-g-SS-PEG copolymer self-assembled into micelles with a diameter of 110–120 nm and a low polydispersity (PDI) in phosphate buffer (pH 7.4, 10 mM). PCL-g-SS-PEG micelles while sufficiently stable under physiological Conditions were prone to rapid shell shedding and aggregation under a Reductive Condition. Doxorubicin (DOX) was loaded into PCL-g-SS-PEG micelles with a decent drug loading content of 10.1 wt %. Notably, in vitro release studies revealed that ca. 82.1% DOX was released in 12 h under a Reductive environment analogous to that of the intracellular compartments such as cytosol and the cell nucleus whereas only ca. 17.5% DOX was released in 24 h under nonReductive Conditions. Confocal microscopy observation indicated that DOX was delivered into the nuclei of HeLa cells following 8 h incubation with DOX-loaded PCL-g-SS-PEG micelles. MTT assays in HeLa cells demonstrated that DOX-loaded PCL-g-SS-PEG micelles retained high antitumor activity with low IC50 (half-maximal inhibitory concentration) of 0.82–0.95 μg DOX equiv/mL while blank PCL-g-SS-PEG micelles were nontoxic up to a tested concentration of 1.0 mg/mL. This study presents a versatile and controlled synthesis of PDS-functionalized biodegradable polymers and reduction-sensitive biodegradable graft copolymer micelles that are of particular interest for active intracellular drug release

Satoru Nakashima - One of the best experts on this subject based on the ideXlab platform.

  • Study on paddy soil in Fukushima using Mössbauer spectroscopy
    Hyperfine Interactions, 2019
    Co-Authors: Hai Thanh Nguyen, Masaya Tsujimoto, Satoru Nakashima
    Abstract:

    One of the four neighboring fields tended to show slightly higher contamination of radioactive cesium in rice grain soon after Fukushima Daiichi Nuclear Power Plant accident. In order to understand the reason, the oxidative/Reductive atmosphere in the paddy field was investigated using 57Fe Mӧssbauer spectroscopy. The iron concentration variation was also investigated based on soil size distribution. It was suggested that the oxidative/Reductive Condition of iron state may reflect the features of the soils and then affect the solubility of potassium and radioactive cesium in the field. Oxidative atmosphere and in particular more abundant iron in larger size soil may affect the transfer of radioactive cesium from soil to rice grain.

Ru Cheng - One of the best experts on this subject based on the ideXlab platform.

  • Enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s: Synthesis, cell compatibility, and intracellular anticancer drug delivery
    Biomacromolecules, 2015
    Co-Authors: Huanli Sun, Marc Hendriks, Ru Cheng, Fenghua Meng, Aylvin A. Dias, Chao Deng, Jan Feijen, Zhiyuan Zhong
    Abstract:

    A novel and versatile family of enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s (SS-PEAs) were developed from solution polycondensation of disulfide-containing di-p-toluenesulfonic acid salts of bis-L-phenylalanine diesters (SS-Phe-2TsOH) with di-p-nitrophenyl adipate (NA) in N,N-dimethyl formamide (DMF). SS-PEAs with Mn ranging from 16.6 to 23.6 kg/mol were obtained depending on NA/SS-Phe-2TsOH molar ratios. The chemical structures of SS-PEAs were confirmed by (1)H NMR and FTIR spectra. Thermal analyses showed that the obtained SS-PEAs were amorphous with glass transition temperature (Tg) in the range of 35.2-39.5 ºC. The in vitro degradation studies of SS-PEA films revealed that SS-PEAs underwent surface erosion in the presence of 0.1 mg/mL α-chymotrypsin and bulk degradation under a Reductive environment containing 10 mM dithiothreitol (DTT). The preliminary cell culture studies displayed that SS-PEA films could well support adhesion and proliferation of L929 fibroblast cells, indicating that SS-PEAs have excellent cell compatibility. The nanoparticles prepared from SS-PEA with PVA as a surfactant had an average size of 167 nm in phosphate buffer (PB, 10 mM, pH 7.4). SS-PEA nanoparticles while stable under physiological environment undergo rapid disintegration under an enzymatic or Reductive Condition. The in vitro drug release studies showed that DOX release was accelerated in the presence of 0.1 mg/mL α-chymotrypsin or 10 mM DTT. Confocal microscopy observation displayed that SS-PEA nanoparticles effectively transported DOX into both drug-sensitive and resistant MCF-7 cells. MTT assays revealed that DOX-loaded SS-PEA nanoparticles had a high antitumor activity approaching to free DOX in drug-sensitive MCF-7 cells, while more than 10 times higher than free DOX in drug-resistant MCF-7/ADR cells. These enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s have provided an appealing platform for biomedical technology in particular controlled drug delivery applications.

  • intracellular release of doxorubicin from core crosslinked polypeptide micelles triggered by both ph and reduction Conditions
    Biomaterials, 2013
    Co-Authors: Yan Zou, Ru Cheng, Fenghua Meng, Chao Deng, Zhiyuan Zhong
    Abstract:

    Abstract Reduction and pH dual-sensitive reversibly core-crosslinked polypeptide micelles were developed from lipoic acid (LA) and cis-1,2-cyclohexanedicarboxylic acid (CCA) decorated poly(ethylene glycol)-b-poly( l -lysine) (PEG-P(LL-CCA/LA)) block copolymers for active loading and triggered intracellular release of doxorubicin (DOX). PEG-P(LL18-CCA4/LA14) and PEG-P(LL18-CCA8/LA10) (Mn PEG = 5.0 kg/mol) formed nano-sized micelles that were readily crosslinked in the presence of a catalytic amount of dithiothreitol (DTT) in phosphate buffer (pH 7.4, 10 m m ). PEG-P(LL18-CCA4/LA14) micelles displayed an elevated DOX loading over PEG-P(LL14-LA14) controls likely due to presence of ionic interactions between DOX and CCA. These core-crosslinked polypeptide micelles while exhibiting high stability against extensive dilution and high salt concentration were quickly dissociated into unimers in the presence of 10 m m DTT. The in vitro release studies showed that DOX release from PEG-P(LL18-CCA4/LA14) micelles at pH 7.4 and 37 °C was significantly inhibited by crosslinking (i.e. less than 20% release in 24 h). The release of DOX was, however, doubled under endosomal pH of 5.0, possibly triggered by cleavage of the acid-labile amide bonds of CCA. In particular, rapid DOX release was observed under a Reductive Condition containing 10 m m glutathione (GSH), in which 86.0% and 96.7% of DOX were released in 24 h at pH 7.4 and 5.0, respectively, under otherwise the same Conditions. MTT assays demonstrated that these core-crosslinked polypeptide micelles were practically non-toxic up to a tested concentration of 1.0 mg/mL, while DOX-loaded micelles caused pronounced cytotoxic effects to HeLa and HepG2 tumor cells with IC50 (inhibitory concentration to produce 50% cell death) of ca. 12.5 μg DOX equiv/mL following 48 h incubation. Confocal microscopy observations revealed that DOX-loaded crosslinked PEG-P(LL18-CCA4/LA14) micelles more efficiently delivered and released DOX into the nuclei of HeLa cells than PEG-P(LL14-LA14) counterparts. These dual-bioresponsive core-crosslinked polypeptide micelles have appeared as an advanced platform for targeted cancer therapy.

  • functional poly e caprolactone s via copolymerization of e caprolactone and pyridyl disulfide containing cyclic carbonate controlled synthesis and facile access to reduction sensitive biodegradable graft copolymer micelles
    Macromolecules, 2013
    Co-Authors: Wei Chen, Ru Cheng, Fenghua Meng, Chao Deng, Jan Feijen, Zhiyuan Zhong
    Abstract:

    Pyridyl disulfide-functionalized cyclic carbonate (PDSC) monomer was obtained in four straightforward steps from 3-methyl-3-oxetanemethanol and exploited for facile preparation of functional poly(e-caprolactone) (PCL) containing pendant pyridyl disulfide (PDS) groups via ring-opening copolymerization with e-caprolactone. The results showed that PDS-functionalized PCL polymers were prepared with controlled molecular weights and functionalities. The exchange reaction between PDS-functionalized PCL and thiolated poly(ethylene glycol) (PEG-SH) at a PEG-SH/PDS molar ratio of 2/1 afforded PCL-g-SS-PEG graft copolymers in high yields. The dynamic light scattering (DLS) analyses showed that PCL-g-SS-PEG copolymer self-assembled into micelles with a diameter of 110–120 nm and a low polydispersity (PDI) in phosphate buffer (pH 7.4, 10 mM). PCL-g-SS-PEG micelles while sufficiently stable under physiological Conditions were prone to rapid shell shedding and aggregation under a Reductive Condition. Doxorubicin (DOX) was loaded into PCL-g-SS-PEG micelles with a decent drug loading content of 10.1 wt %. Notably, in vitro release studies revealed that ca. 82.1% DOX was released in 12 h under a Reductive environment analogous to that of the intracellular compartments such as cytosol and the cell nucleus whereas only ca. 17.5% DOX was released in 24 h under nonReductive Conditions. Confocal microscopy observation indicated that DOX was delivered into the nuclei of HeLa cells following 8 h incubation with DOX-loaded PCL-g-SS-PEG micelles. MTT assays in HeLa cells demonstrated that DOX-loaded PCL-g-SS-PEG micelles retained high antitumor activity with low IC50 (half-maximal inhibitory concentration) of 0.82–0.95 μg DOX equiv/mL while blank PCL-g-SS-PEG micelles were nontoxic up to a tested concentration of 1.0 mg/mL. This study presents a versatile and controlled synthesis of PDS-functionalized biodegradable polymers and reduction-sensitive biodegradable graft copolymer micelles that are of particular interest for active intracellular drug release

Chao Deng - One of the best experts on this subject based on the ideXlab platform.

  • Micelles with Sheddable Dendritic Polyglycerol Sulfate Shells Show Extraordinary Tumor Targetability and Chemotherapy in Vivo
    2016
    Co-Authors: Yinan Zhong, Fenghua Meng, Zhiyuan Zhong, Chao Deng, Mathias Dimde, Daniel Stöbener, Rainer Haag
    Abstract:

    Cancer nanomedicines are typically stealthed by a poly­(ethylene glycol) layer that is important to obtain extended blood circulation and elevated tumor accumulation. PEG stealth, however, also leads to poor tumor cell selectivity and uptake thereby reducing treatment efficacy. Here, we report that biodegradable micelles with sheddable dendritic polyglycerol sulfate (dPGS) shells show an unusual tumor targetability and chemotherapy in vivo. The self-assembly of dPGS-SS-poly­(ε-caprolactone) amphiphilic block copolymer with an Mn of 4.8–3.7 kg mol–1 affords negatively charged and small sized micelles (dPGS-SS-PCL Ms). dPGS-SS-PCL Ms reveal a low cytotoxicity, decent doxorubicin (DOX) loading, and accelerated drug release under a Reductive Condition. Notably, DOX-loaded dPGS-SS-PCL Ms exhibit a high tolerable dosage of more than 40 mg kg–1, a long plasma half-life of ca. 2.8 h, and an extraordinary tumor accumulation. Intriguingly, therapeutic results demonstrate that DOX-loaded dPGS-SS-PCL Ms induce complete tumor suppression, significantly improved survival rate, and diminishing adverse effects as compared to free drug (DOX·HCl) in MCF-7 human mammary carcinoma models. Dendritic polyglycerol sulfate with a superior tumor homing ability appears to be an attractive alternative to PEG in formulating targeted cancer nanomedicines

  • Enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s: Synthesis, cell compatibility, and intracellular anticancer drug delivery
    Biomacromolecules, 2015
    Co-Authors: Huanli Sun, Marc Hendriks, Ru Cheng, Fenghua Meng, Aylvin A. Dias, Chao Deng, Jan Feijen, Zhiyuan Zhong
    Abstract:

    A novel and versatile family of enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s (SS-PEAs) were developed from solution polycondensation of disulfide-containing di-p-toluenesulfonic acid salts of bis-L-phenylalanine diesters (SS-Phe-2TsOH) with di-p-nitrophenyl adipate (NA) in N,N-dimethyl formamide (DMF). SS-PEAs with Mn ranging from 16.6 to 23.6 kg/mol were obtained depending on NA/SS-Phe-2TsOH molar ratios. The chemical structures of SS-PEAs were confirmed by (1)H NMR and FTIR spectra. Thermal analyses showed that the obtained SS-PEAs were amorphous with glass transition temperature (Tg) in the range of 35.2-39.5 ºC. The in vitro degradation studies of SS-PEA films revealed that SS-PEAs underwent surface erosion in the presence of 0.1 mg/mL α-chymotrypsin and bulk degradation under a Reductive environment containing 10 mM dithiothreitol (DTT). The preliminary cell culture studies displayed that SS-PEA films could well support adhesion and proliferation of L929 fibroblast cells, indicating that SS-PEAs have excellent cell compatibility. The nanoparticles prepared from SS-PEA with PVA as a surfactant had an average size of 167 nm in phosphate buffer (PB, 10 mM, pH 7.4). SS-PEA nanoparticles while stable under physiological environment undergo rapid disintegration under an enzymatic or Reductive Condition. The in vitro drug release studies showed that DOX release was accelerated in the presence of 0.1 mg/mL α-chymotrypsin or 10 mM DTT. Confocal microscopy observation displayed that SS-PEA nanoparticles effectively transported DOX into both drug-sensitive and resistant MCF-7 cells. MTT assays revealed that DOX-loaded SS-PEA nanoparticles had a high antitumor activity approaching to free DOX in drug-sensitive MCF-7 cells, while more than 10 times higher than free DOX in drug-resistant MCF-7/ADR cells. These enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s have provided an appealing platform for biomedical technology in particular controlled drug delivery applications.

  • intracellular release of doxorubicin from core crosslinked polypeptide micelles triggered by both ph and reduction Conditions
    Biomaterials, 2013
    Co-Authors: Yan Zou, Ru Cheng, Fenghua Meng, Chao Deng, Zhiyuan Zhong
    Abstract:

    Abstract Reduction and pH dual-sensitive reversibly core-crosslinked polypeptide micelles were developed from lipoic acid (LA) and cis-1,2-cyclohexanedicarboxylic acid (CCA) decorated poly(ethylene glycol)-b-poly( l -lysine) (PEG-P(LL-CCA/LA)) block copolymers for active loading and triggered intracellular release of doxorubicin (DOX). PEG-P(LL18-CCA4/LA14) and PEG-P(LL18-CCA8/LA10) (Mn PEG = 5.0 kg/mol) formed nano-sized micelles that were readily crosslinked in the presence of a catalytic amount of dithiothreitol (DTT) in phosphate buffer (pH 7.4, 10 m m ). PEG-P(LL18-CCA4/LA14) micelles displayed an elevated DOX loading over PEG-P(LL14-LA14) controls likely due to presence of ionic interactions between DOX and CCA. These core-crosslinked polypeptide micelles while exhibiting high stability against extensive dilution and high salt concentration were quickly dissociated into unimers in the presence of 10 m m DTT. The in vitro release studies showed that DOX release from PEG-P(LL18-CCA4/LA14) micelles at pH 7.4 and 37 °C was significantly inhibited by crosslinking (i.e. less than 20% release in 24 h). The release of DOX was, however, doubled under endosomal pH of 5.0, possibly triggered by cleavage of the acid-labile amide bonds of CCA. In particular, rapid DOX release was observed under a Reductive Condition containing 10 m m glutathione (GSH), in which 86.0% and 96.7% of DOX were released in 24 h at pH 7.4 and 5.0, respectively, under otherwise the same Conditions. MTT assays demonstrated that these core-crosslinked polypeptide micelles were practically non-toxic up to a tested concentration of 1.0 mg/mL, while DOX-loaded micelles caused pronounced cytotoxic effects to HeLa and HepG2 tumor cells with IC50 (inhibitory concentration to produce 50% cell death) of ca. 12.5 μg DOX equiv/mL following 48 h incubation. Confocal microscopy observations revealed that DOX-loaded crosslinked PEG-P(LL18-CCA4/LA14) micelles more efficiently delivered and released DOX into the nuclei of HeLa cells than PEG-P(LL14-LA14) counterparts. These dual-bioresponsive core-crosslinked polypeptide micelles have appeared as an advanced platform for targeted cancer therapy.

  • functional poly e caprolactone s via copolymerization of e caprolactone and pyridyl disulfide containing cyclic carbonate controlled synthesis and facile access to reduction sensitive biodegradable graft copolymer micelles
    Macromolecules, 2013
    Co-Authors: Wei Chen, Ru Cheng, Fenghua Meng, Chao Deng, Jan Feijen, Zhiyuan Zhong
    Abstract:

    Pyridyl disulfide-functionalized cyclic carbonate (PDSC) monomer was obtained in four straightforward steps from 3-methyl-3-oxetanemethanol and exploited for facile preparation of functional poly(e-caprolactone) (PCL) containing pendant pyridyl disulfide (PDS) groups via ring-opening copolymerization with e-caprolactone. The results showed that PDS-functionalized PCL polymers were prepared with controlled molecular weights and functionalities. The exchange reaction between PDS-functionalized PCL and thiolated poly(ethylene glycol) (PEG-SH) at a PEG-SH/PDS molar ratio of 2/1 afforded PCL-g-SS-PEG graft copolymers in high yields. The dynamic light scattering (DLS) analyses showed that PCL-g-SS-PEG copolymer self-assembled into micelles with a diameter of 110–120 nm and a low polydispersity (PDI) in phosphate buffer (pH 7.4, 10 mM). PCL-g-SS-PEG micelles while sufficiently stable under physiological Conditions were prone to rapid shell shedding and aggregation under a Reductive Condition. Doxorubicin (DOX) was loaded into PCL-g-SS-PEG micelles with a decent drug loading content of 10.1 wt %. Notably, in vitro release studies revealed that ca. 82.1% DOX was released in 12 h under a Reductive environment analogous to that of the intracellular compartments such as cytosol and the cell nucleus whereas only ca. 17.5% DOX was released in 24 h under nonReductive Conditions. Confocal microscopy observation indicated that DOX was delivered into the nuclei of HeLa cells following 8 h incubation with DOX-loaded PCL-g-SS-PEG micelles. MTT assays in HeLa cells demonstrated that DOX-loaded PCL-g-SS-PEG micelles retained high antitumor activity with low IC50 (half-maximal inhibitory concentration) of 0.82–0.95 μg DOX equiv/mL while blank PCL-g-SS-PEG micelles were nontoxic up to a tested concentration of 1.0 mg/mL. This study presents a versatile and controlled synthesis of PDS-functionalized biodegradable polymers and reduction-sensitive biodegradable graft copolymer micelles that are of particular interest for active intracellular drug release

Fenghua Meng - One of the best experts on this subject based on the ideXlab platform.

  • Micelles with Sheddable Dendritic Polyglycerol Sulfate Shells Show Extraordinary Tumor Targetability and Chemotherapy in Vivo
    2016
    Co-Authors: Yinan Zhong, Fenghua Meng, Zhiyuan Zhong, Chao Deng, Mathias Dimde, Daniel Stöbener, Rainer Haag
    Abstract:

    Cancer nanomedicines are typically stealthed by a poly­(ethylene glycol) layer that is important to obtain extended blood circulation and elevated tumor accumulation. PEG stealth, however, also leads to poor tumor cell selectivity and uptake thereby reducing treatment efficacy. Here, we report that biodegradable micelles with sheddable dendritic polyglycerol sulfate (dPGS) shells show an unusual tumor targetability and chemotherapy in vivo. The self-assembly of dPGS-SS-poly­(ε-caprolactone) amphiphilic block copolymer with an Mn of 4.8–3.7 kg mol–1 affords negatively charged and small sized micelles (dPGS-SS-PCL Ms). dPGS-SS-PCL Ms reveal a low cytotoxicity, decent doxorubicin (DOX) loading, and accelerated drug release under a Reductive Condition. Notably, DOX-loaded dPGS-SS-PCL Ms exhibit a high tolerable dosage of more than 40 mg kg–1, a long plasma half-life of ca. 2.8 h, and an extraordinary tumor accumulation. Intriguingly, therapeutic results demonstrate that DOX-loaded dPGS-SS-PCL Ms induce complete tumor suppression, significantly improved survival rate, and diminishing adverse effects as compared to free drug (DOX·HCl) in MCF-7 human mammary carcinoma models. Dendritic polyglycerol sulfate with a superior tumor homing ability appears to be an attractive alternative to PEG in formulating targeted cancer nanomedicines

  • Enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s: Synthesis, cell compatibility, and intracellular anticancer drug delivery
    Biomacromolecules, 2015
    Co-Authors: Huanli Sun, Marc Hendriks, Ru Cheng, Fenghua Meng, Aylvin A. Dias, Chao Deng, Jan Feijen, Zhiyuan Zhong
    Abstract:

    A novel and versatile family of enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s (SS-PEAs) were developed from solution polycondensation of disulfide-containing di-p-toluenesulfonic acid salts of bis-L-phenylalanine diesters (SS-Phe-2TsOH) with di-p-nitrophenyl adipate (NA) in N,N-dimethyl formamide (DMF). SS-PEAs with Mn ranging from 16.6 to 23.6 kg/mol were obtained depending on NA/SS-Phe-2TsOH molar ratios. The chemical structures of SS-PEAs were confirmed by (1)H NMR and FTIR spectra. Thermal analyses showed that the obtained SS-PEAs were amorphous with glass transition temperature (Tg) in the range of 35.2-39.5 ºC. The in vitro degradation studies of SS-PEA films revealed that SS-PEAs underwent surface erosion in the presence of 0.1 mg/mL α-chymotrypsin and bulk degradation under a Reductive environment containing 10 mM dithiothreitol (DTT). The preliminary cell culture studies displayed that SS-PEA films could well support adhesion and proliferation of L929 fibroblast cells, indicating that SS-PEAs have excellent cell compatibility. The nanoparticles prepared from SS-PEA with PVA as a surfactant had an average size of 167 nm in phosphate buffer (PB, 10 mM, pH 7.4). SS-PEA nanoparticles while stable under physiological environment undergo rapid disintegration under an enzymatic or Reductive Condition. The in vitro drug release studies showed that DOX release was accelerated in the presence of 0.1 mg/mL α-chymotrypsin or 10 mM DTT. Confocal microscopy observation displayed that SS-PEA nanoparticles effectively transported DOX into both drug-sensitive and resistant MCF-7 cells. MTT assays revealed that DOX-loaded SS-PEA nanoparticles had a high antitumor activity approaching to free DOX in drug-sensitive MCF-7 cells, while more than 10 times higher than free DOX in drug-resistant MCF-7/ADR cells. These enzymatically and Reductively degradable α-amino acid-based poly(ester amide)s have provided an appealing platform for biomedical technology in particular controlled drug delivery applications.

  • intracellular release of doxorubicin from core crosslinked polypeptide micelles triggered by both ph and reduction Conditions
    Biomaterials, 2013
    Co-Authors: Yan Zou, Ru Cheng, Fenghua Meng, Chao Deng, Zhiyuan Zhong
    Abstract:

    Abstract Reduction and pH dual-sensitive reversibly core-crosslinked polypeptide micelles were developed from lipoic acid (LA) and cis-1,2-cyclohexanedicarboxylic acid (CCA) decorated poly(ethylene glycol)-b-poly( l -lysine) (PEG-P(LL-CCA/LA)) block copolymers for active loading and triggered intracellular release of doxorubicin (DOX). PEG-P(LL18-CCA4/LA14) and PEG-P(LL18-CCA8/LA10) (Mn PEG = 5.0 kg/mol) formed nano-sized micelles that were readily crosslinked in the presence of a catalytic amount of dithiothreitol (DTT) in phosphate buffer (pH 7.4, 10 m m ). PEG-P(LL18-CCA4/LA14) micelles displayed an elevated DOX loading over PEG-P(LL14-LA14) controls likely due to presence of ionic interactions between DOX and CCA. These core-crosslinked polypeptide micelles while exhibiting high stability against extensive dilution and high salt concentration were quickly dissociated into unimers in the presence of 10 m m DTT. The in vitro release studies showed that DOX release from PEG-P(LL18-CCA4/LA14) micelles at pH 7.4 and 37 °C was significantly inhibited by crosslinking (i.e. less than 20% release in 24 h). The release of DOX was, however, doubled under endosomal pH of 5.0, possibly triggered by cleavage of the acid-labile amide bonds of CCA. In particular, rapid DOX release was observed under a Reductive Condition containing 10 m m glutathione (GSH), in which 86.0% and 96.7% of DOX were released in 24 h at pH 7.4 and 5.0, respectively, under otherwise the same Conditions. MTT assays demonstrated that these core-crosslinked polypeptide micelles were practically non-toxic up to a tested concentration of 1.0 mg/mL, while DOX-loaded micelles caused pronounced cytotoxic effects to HeLa and HepG2 tumor cells with IC50 (inhibitory concentration to produce 50% cell death) of ca. 12.5 μg DOX equiv/mL following 48 h incubation. Confocal microscopy observations revealed that DOX-loaded crosslinked PEG-P(LL18-CCA4/LA14) micelles more efficiently delivered and released DOX into the nuclei of HeLa cells than PEG-P(LL14-LA14) counterparts. These dual-bioresponsive core-crosslinked polypeptide micelles have appeared as an advanced platform for targeted cancer therapy.

  • functional poly e caprolactone s via copolymerization of e caprolactone and pyridyl disulfide containing cyclic carbonate controlled synthesis and facile access to reduction sensitive biodegradable graft copolymer micelles
    Macromolecules, 2013
    Co-Authors: Wei Chen, Ru Cheng, Fenghua Meng, Chao Deng, Jan Feijen, Zhiyuan Zhong
    Abstract:

    Pyridyl disulfide-functionalized cyclic carbonate (PDSC) monomer was obtained in four straightforward steps from 3-methyl-3-oxetanemethanol and exploited for facile preparation of functional poly(e-caprolactone) (PCL) containing pendant pyridyl disulfide (PDS) groups via ring-opening copolymerization with e-caprolactone. The results showed that PDS-functionalized PCL polymers were prepared with controlled molecular weights and functionalities. The exchange reaction between PDS-functionalized PCL and thiolated poly(ethylene glycol) (PEG-SH) at a PEG-SH/PDS molar ratio of 2/1 afforded PCL-g-SS-PEG graft copolymers in high yields. The dynamic light scattering (DLS) analyses showed that PCL-g-SS-PEG copolymer self-assembled into micelles with a diameter of 110–120 nm and a low polydispersity (PDI) in phosphate buffer (pH 7.4, 10 mM). PCL-g-SS-PEG micelles while sufficiently stable under physiological Conditions were prone to rapid shell shedding and aggregation under a Reductive Condition. Doxorubicin (DOX) was loaded into PCL-g-SS-PEG micelles with a decent drug loading content of 10.1 wt %. Notably, in vitro release studies revealed that ca. 82.1% DOX was released in 12 h under a Reductive environment analogous to that of the intracellular compartments such as cytosol and the cell nucleus whereas only ca. 17.5% DOX was released in 24 h under nonReductive Conditions. Confocal microscopy observation indicated that DOX was delivered into the nuclei of HeLa cells following 8 h incubation with DOX-loaded PCL-g-SS-PEG micelles. MTT assays in HeLa cells demonstrated that DOX-loaded PCL-g-SS-PEG micelles retained high antitumor activity with low IC50 (half-maximal inhibitory concentration) of 0.82–0.95 μg DOX equiv/mL while blank PCL-g-SS-PEG micelles were nontoxic up to a tested concentration of 1.0 mg/mL. This study presents a versatile and controlled synthesis of PDS-functionalized biodegradable polymers and reduction-sensitive biodegradable graft copolymer micelles that are of particular interest for active intracellular drug release