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Tomas Etrych - One of the best experts on this subject based on the ideXlab platform.
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bloodstream stability predetermines the antitumor efficacy of micellar Polymer doxorubicin drug conjugates with ph triggered drug release
Molecular Pharmaceutics, 2018Co-Authors: Petr Chytil, Karel Ulbrich, Blanka řihova, Milada Sirova, Julia Kudlacova, Tomas EtrychAbstract:Herein, the biodegradable micelle-forming amphiphilic N-(2-hydroxypropyl) methacrylamide (HPMA)-based Polymer conjugates with the anticancer drug doxorubicin (Dox) designed for enhanced tumor accumulation were investigated, and the influence of their stability in the bloodstream on biodistribution, namely, tumor uptake, and in vivo antitumor efficacy were evaluated in detail. Dox was attached to the Polymer Carrier by a hydrazone bond enabling pH-controlled drug release. While the Polymer–drug conjugates were stable in a buffer at pH 7.4 (mimicking bloodstream environment), Dox was released in a buffer under mild acidic conditions modeling the tumor microenvironment or cells. The amphiphilic Polymer Carriers differed in the structure of hydrophobic cholesterol derivative moieties bound to the HPMA coPolymers via a hydrolyzable hydrazone bond, exhibiting different rates of micellar structure disintegration at various pH values. Considerable dependence of the studied Polymer–drug conjugate biodistribution o...
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high molecular weight star conjugates containing docetaxel with high anti tumor activity and low systemic toxicity in vivo
Polymer Chemistry, 2015Co-Authors: Tomas Etrych, Karel Ulbrich, J Strohalm, Blanka řihova, Milada Sirova, B Tomalova, Pavel Rossmann, Marek KovařAbstract:Here we present the Polymer conjugates where the core formed by poly(amido amine) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymers containing docetaxel (DTX) attached by a pH-sensitive hydrazone bond. DTX was derivatized with three different keto acids prior to attachment to the Polymer Carrier to introduce reactive keto groups into the drug. The therapeutic efficacy of such high-molecular-weight star conjugates is based on: (a) the enhanced permeability and retention (EPR) effect facilitating selective accumulation within solid tumors; (b) pH-controlled release of the drug, thus ensuring faster DTX release in the mildly acidic tumor microenvironment. The star DTX conjugate had a remarkably higher maximum tolerated dose in comparison with free DTX when administered as a single i.v. injection (∼160 mg kg−1vs. 40 mg kg−1 of DTX) in C57BL/6 mice. The star DTX conjugate showed significantly higher antitumor activity than free drug in the EL4 T cell lymphoma growing in syngeneic C57BL/6 mice even when given at the same dose (20 mg kg−1 of DTX eq.). Thus, the star DTX conjugates exert a much higher therapeutic activity and yet a lower systemic toxicity than free DTX.
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biodegradable star hpma Polymer drug conjugates biodegradability distribution and anti tumor efficacy
Journal of Controlled Release, 2011Co-Authors: Tomas Etrych, Lubomir Kovař, J Strohalm, Petr Chytil, Blanka řihova, Karel UlbrichAbstract:Abstract Herein, new biodegradable star Polymer–doxorubicin conjugates designed for passive tumor targeting were investigated, and their synthesis, physico-chemical characterization, drug release, biodegradation, biodistribution and in vivo anti-tumor efficacy are described. In the conjugates, the core formed by poly(amidoamine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymers bearing doxorubicin (Dox) attached by hydrazone bonds, which enabled intracellular pH-controlled drug release. The described synthesis facilitated the preparation of biodegradable Polymer conjugates in a broad range of molecular weights (200–1000 g/mol) while still maintaining low polydispersity (~ 1.7). The Polymer grafts were attached to the dendrimers through either stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high-molecular-weight Polymer Carrier to excretable products. Biodegradability tests in suspensions of EL4 T-cell lymphoma cells showed that the rate of degradation was much faster for reductively degradable conjugates (close to completion within 24 h of incubation) than for conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (slow degradation taking several days). This finding was likely due to the differences in steric hindrance in terms of the accessibility of the small molecule glutathione and the bulky enzyme cathepsin B to the Polymer substrate. Regarding drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin under mild acidic conditions that model the tumor cell microenvironment. The star Polymer–Dox conjugates exhibited significantly prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice, indicating the important role of the EPR effect in its anti-cancer activity. The star Polymer conjugates showed prominently higher in vivo anti-tumor activities than the free drug or linear Polymer conjugate when tested in mice bearing EL4 T-cell lymphoma, with a significant number of long-term surviving (LTS). Based on the results, we conclude that a Mw of HPMA coPolymers of 200,000 to 600,000 g/mol is optimal for Polymer Carriers designed for the efficient passive targeting to solid tumors. In addition, an expressive therapy-dependent stimulation of the immune system was observed.
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biodegradable star hpma Polymer conjugates of doxorubicin for passive tumor targeting
European Journal of Pharmaceutical Sciences, 2011Co-Authors: Tomas Etrych, J Strohalm, Petr Chytil, Michal Pechar, Peter Cernoch, Larisa Starovoytova, Karel UlbrichAbstract:Abstract New biodegradable star Polymer–doxorubicin (Dox) conjugates designed for passive tumor targeting were investigated and the present study described their synthesis, physico-chemical characterization, drug release and biodegradation. In the conjugates the core formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N -(2-hydroxypropyl)methacrylamide (HPMA) coPolymers bearing doxorubicin attached by hydrazone bonds, which enabled intracellular pH-controlled drug release, or by a GFLG sequence, which was susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic coPolymer precursors facilitated preparation of biodegradable Polymer conjugates in a broad range of molecular weights (110–295 kDa) while still maintaining low polydispersity (∼1.7). The Polymer grafts were attached to the dendrimers either through stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high molecular weight Polymer Carrier to products that were able to be excreted from the body by glomerular filtration. Biodegradability tests showed that the rate of degradation was much faster for reductively degradable conjugates (completed within 4 h) than the degradation of conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (within 72 h). This finding was likely due to the difference in steric hindrance for the small molecule glutathione and the enzyme cathepsin B. As for drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin either under mild acidic conditions or in the presence of lysosomal enzyme cathepsin B, both of which modeled the tumor cell microenvironment.
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n 2 hydroxypropyl methacrylamide based Polymer conjugates with ph controlled activation of doxorubicin i new synthesis physicochemical characterization and preliminary biological evaluation
Journal of Applied Polymer Science, 2008Co-Authors: Tomas Etrych, Petr Chytil, Blanka řihova, Tomas Mrkvan, Cestmir Koňak, Karel UlbrichAbstract:New method of synthesis of water-soluble Polymer-drug conjugates, exhibiting remarkable anticancer activity in mice models, has been developed. In the conjugates, an anticancer drug doxorubicin (DOX) is attached to a Polymer Carrier based on N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymer via a hydrolytically labile hydrazone bond. New methacrylamide-type comonomers, containing either hydrazide group or hydrazon of DOX, were used for coPolymerization with HPMA. In contrast to the synthetic procedure described earlier the new method is simpler, cheaper, and results in a better-defined conjugate structure. The conjugates are fairly stable in buffer at pH 7.4 (model of blood stream) but release DOX under mild acid conditions modeling the tumor microenvironment. The conjugates showed significant in vivo antitumor activity in treatment of T-cell lymphoma EL-4 bearing mice with up to 100% long-term survivors. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
Karel Ulbrich - One of the best experts on this subject based on the ideXlab platform.
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bloodstream stability predetermines the antitumor efficacy of micellar Polymer doxorubicin drug conjugates with ph triggered drug release
Molecular Pharmaceutics, 2018Co-Authors: Petr Chytil, Karel Ulbrich, Blanka řihova, Milada Sirova, Julia Kudlacova, Tomas EtrychAbstract:Herein, the biodegradable micelle-forming amphiphilic N-(2-hydroxypropyl) methacrylamide (HPMA)-based Polymer conjugates with the anticancer drug doxorubicin (Dox) designed for enhanced tumor accumulation were investigated, and the influence of their stability in the bloodstream on biodistribution, namely, tumor uptake, and in vivo antitumor efficacy were evaluated in detail. Dox was attached to the Polymer Carrier by a hydrazone bond enabling pH-controlled drug release. While the Polymer–drug conjugates were stable in a buffer at pH 7.4 (mimicking bloodstream environment), Dox was released in a buffer under mild acidic conditions modeling the tumor microenvironment or cells. The amphiphilic Polymer Carriers differed in the structure of hydrophobic cholesterol derivative moieties bound to the HPMA coPolymers via a hydrolyzable hydrazone bond, exhibiting different rates of micellar structure disintegration at various pH values. Considerable dependence of the studied Polymer–drug conjugate biodistribution o...
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high molecular weight star conjugates containing docetaxel with high anti tumor activity and low systemic toxicity in vivo
Polymer Chemistry, 2015Co-Authors: Tomas Etrych, Karel Ulbrich, J Strohalm, Blanka řihova, Milada Sirova, B Tomalova, Pavel Rossmann, Marek KovařAbstract:Here we present the Polymer conjugates where the core formed by poly(amido amine) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymers containing docetaxel (DTX) attached by a pH-sensitive hydrazone bond. DTX was derivatized with three different keto acids prior to attachment to the Polymer Carrier to introduce reactive keto groups into the drug. The therapeutic efficacy of such high-molecular-weight star conjugates is based on: (a) the enhanced permeability and retention (EPR) effect facilitating selective accumulation within solid tumors; (b) pH-controlled release of the drug, thus ensuring faster DTX release in the mildly acidic tumor microenvironment. The star DTX conjugate had a remarkably higher maximum tolerated dose in comparison with free DTX when administered as a single i.v. injection (∼160 mg kg−1vs. 40 mg kg−1 of DTX) in C57BL/6 mice. The star DTX conjugate showed significantly higher antitumor activity than free drug in the EL4 T cell lymphoma growing in syngeneic C57BL/6 mice even when given at the same dose (20 mg kg−1 of DTX eq.). Thus, the star DTX conjugates exert a much higher therapeutic activity and yet a lower systemic toxicity than free DTX.
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biodegradable star hpma Polymer drug conjugates biodegradability distribution and anti tumor efficacy
Journal of Controlled Release, 2011Co-Authors: Tomas Etrych, Lubomir Kovař, J Strohalm, Petr Chytil, Blanka řihova, Karel UlbrichAbstract:Abstract Herein, new biodegradable star Polymer–doxorubicin conjugates designed for passive tumor targeting were investigated, and their synthesis, physico-chemical characterization, drug release, biodegradation, biodistribution and in vivo anti-tumor efficacy are described. In the conjugates, the core formed by poly(amidoamine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymers bearing doxorubicin (Dox) attached by hydrazone bonds, which enabled intracellular pH-controlled drug release. The described synthesis facilitated the preparation of biodegradable Polymer conjugates in a broad range of molecular weights (200–1000 g/mol) while still maintaining low polydispersity (~ 1.7). The Polymer grafts were attached to the dendrimers through either stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high-molecular-weight Polymer Carrier to excretable products. Biodegradability tests in suspensions of EL4 T-cell lymphoma cells showed that the rate of degradation was much faster for reductively degradable conjugates (close to completion within 24 h of incubation) than for conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (slow degradation taking several days). This finding was likely due to the differences in steric hindrance in terms of the accessibility of the small molecule glutathione and the bulky enzyme cathepsin B to the Polymer substrate. Regarding drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin under mild acidic conditions that model the tumor cell microenvironment. The star Polymer–Dox conjugates exhibited significantly prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice, indicating the important role of the EPR effect in its anti-cancer activity. The star Polymer conjugates showed prominently higher in vivo anti-tumor activities than the free drug or linear Polymer conjugate when tested in mice bearing EL4 T-cell lymphoma, with a significant number of long-term surviving (LTS). Based on the results, we conclude that a Mw of HPMA coPolymers of 200,000 to 600,000 g/mol is optimal for Polymer Carriers designed for the efficient passive targeting to solid tumors. In addition, an expressive therapy-dependent stimulation of the immune system was observed.
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biodegradable star hpma Polymer conjugates of doxorubicin for passive tumor targeting
European Journal of Pharmaceutical Sciences, 2011Co-Authors: Tomas Etrych, J Strohalm, Petr Chytil, Michal Pechar, Peter Cernoch, Larisa Starovoytova, Karel UlbrichAbstract:Abstract New biodegradable star Polymer–doxorubicin (Dox) conjugates designed for passive tumor targeting were investigated and the present study described their synthesis, physico-chemical characterization, drug release and biodegradation. In the conjugates the core formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N -(2-hydroxypropyl)methacrylamide (HPMA) coPolymers bearing doxorubicin attached by hydrazone bonds, which enabled intracellular pH-controlled drug release, or by a GFLG sequence, which was susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic coPolymer precursors facilitated preparation of biodegradable Polymer conjugates in a broad range of molecular weights (110–295 kDa) while still maintaining low polydispersity (∼1.7). The Polymer grafts were attached to the dendrimers either through stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high molecular weight Polymer Carrier to products that were able to be excreted from the body by glomerular filtration. Biodegradability tests showed that the rate of degradation was much faster for reductively degradable conjugates (completed within 4 h) than the degradation of conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (within 72 h). This finding was likely due to the difference in steric hindrance for the small molecule glutathione and the enzyme cathepsin B. As for drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin either under mild acidic conditions or in the presence of lysosomal enzyme cathepsin B, both of which modeled the tumor cell microenvironment.
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n 2 hydroxypropyl methacrylamide based Polymer conjugates with ph controlled activation of doxorubicin i new synthesis physicochemical characterization and preliminary biological evaluation
Journal of Applied Polymer Science, 2008Co-Authors: Tomas Etrych, Petr Chytil, Blanka řihova, Tomas Mrkvan, Cestmir Koňak, Karel UlbrichAbstract:New method of synthesis of water-soluble Polymer-drug conjugates, exhibiting remarkable anticancer activity in mice models, has been developed. In the conjugates, an anticancer drug doxorubicin (DOX) is attached to a Polymer Carrier based on N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymer via a hydrolytically labile hydrazone bond. New methacrylamide-type comonomers, containing either hydrazide group or hydrazon of DOX, were used for coPolymerization with HPMA. In contrast to the synthetic procedure described earlier the new method is simpler, cheaper, and results in a better-defined conjugate structure. The conjugates are fairly stable in buffer at pH 7.4 (model of blood stream) but release DOX under mild acid conditions modeling the tumor microenvironment. The conjugates showed significant in vivo antitumor activity in treatment of T-cell lymphoma EL-4 bearing mice with up to 100% long-term survivors. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
Michael N Helmus - One of the best experts on this subject based on the ideXlab platform.
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physical characterization of controlled release of paclitaxel from the taxus express2 drug eluting stent
Journal of Biomedical Materials Research Part A, 2004Co-Authors: Shrirang V Ranade, Kathleen M Miller, Robert E Richard, Ken A Chan, Michael J Allen, Michael N HelmusAbstract:The Polymer Carrier technology in the TAXUS™ drug-eluting stent consists of a thermoplastic elastomer poly(styrene-b-isobutylene-b-styrene) (SIBS) with microphase-separated morphology resulting in optimal properties for a drug-delivery stent coating. Comprehensive physical characterization of the stent coatings and cast film formulations showed that paclitaxel (PTx) exists primarily as discrete nanoparticles embedded in the SIBS matrix. Thermal and chemical analysis did not show any evidence of solubility of PTx in SIBS or of any molecular miscibility between PTx and SIBS. Atomic force microscope data images revealed for the first time three-dimensional stent coating surfaces at high spatial resolutions in air and in situ under phosphate-buffered saline as drug was released. PTx release involves the initial dissolution of drug particles from the PTx/SIBS coating surface. Morphological examination of the stent coatings in vitro supported an early burst release in most formulations because of surface PTx followed by a sustained slower release of PTx from the bulk coating. The in vitro PTx release kinetics were dependent on the formulation and correlated to the drug-to-Polymer ratio. Atomic force microscopy analysis confirmed this correlation and further supported the concept of a matrix-based drug-release coating. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 71A: 625–634, 2004
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physical characterization of controlled release of paclitaxel from the taxus express2 drug eluting stent
Journal of Biomedical Materials Research Part A, 2004Co-Authors: Shrirang V Ranade, Kathleen M Miller, Robert E Richard, Ken A Chan, Michael J Allen, Michael N HelmusAbstract:The Polymer Carrier technology in the TAXUS drug-eluting stent consists of a thermoplastic elastomer poly(styrene-b-isobutylene-b-styrene) (SIBS) with microphase-separated morphology resulting in optimal properties for a drug-delivery stent coating. Comprehensive physical characterization of the stent coatings and cast film formulations showed that paclitaxel (PTx) exists primarily as discrete nanoparticles embedded in the SIBS matrix. Thermal and chemical analysis did not show any evidence of solubility of PTx in SIBS or of any molecular miscibility between PTx and SIBS. Atomic force microscope data images revealed for the first time three-dimensional stent coating surfaces at high spatial resolutions in air and in situ under phosphate-buffered saline as drug was released. PTx release involves the initial dissolution of drug particles from the PTx/SIBS coating surface. Morphological examination of the stent coatings in vitro supported an early burst release in most formulations because of surface PTx followed by a sustained slower release of PTx from the bulk coating. The in vitro PTx release kinetics were dependent on the formulation and correlated to the drug-to-Polymer ratio. Atomic force microscopy analysis confirmed this correlation and further supported the concept of a matrix-based drug-release coating.
Petr Chytil - One of the best experts on this subject based on the ideXlab platform.
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bloodstream stability predetermines the antitumor efficacy of micellar Polymer doxorubicin drug conjugates with ph triggered drug release
Molecular Pharmaceutics, 2018Co-Authors: Petr Chytil, Karel Ulbrich, Blanka řihova, Milada Sirova, Julia Kudlacova, Tomas EtrychAbstract:Herein, the biodegradable micelle-forming amphiphilic N-(2-hydroxypropyl) methacrylamide (HPMA)-based Polymer conjugates with the anticancer drug doxorubicin (Dox) designed for enhanced tumor accumulation were investigated, and the influence of their stability in the bloodstream on biodistribution, namely, tumor uptake, and in vivo antitumor efficacy were evaluated in detail. Dox was attached to the Polymer Carrier by a hydrazone bond enabling pH-controlled drug release. While the Polymer–drug conjugates were stable in a buffer at pH 7.4 (mimicking bloodstream environment), Dox was released in a buffer under mild acidic conditions modeling the tumor microenvironment or cells. The amphiphilic Polymer Carriers differed in the structure of hydrophobic cholesterol derivative moieties bound to the HPMA coPolymers via a hydrolyzable hydrazone bond, exhibiting different rates of micellar structure disintegration at various pH values. Considerable dependence of the studied Polymer–drug conjugate biodistribution o...
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biodegradable star hpma Polymer drug conjugates biodegradability distribution and anti tumor efficacy
Journal of Controlled Release, 2011Co-Authors: Tomas Etrych, Lubomir Kovař, J Strohalm, Petr Chytil, Blanka řihova, Karel UlbrichAbstract:Abstract Herein, new biodegradable star Polymer–doxorubicin conjugates designed for passive tumor targeting were investigated, and their synthesis, physico-chemical characterization, drug release, biodegradation, biodistribution and in vivo anti-tumor efficacy are described. In the conjugates, the core formed by poly(amidoamine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymers bearing doxorubicin (Dox) attached by hydrazone bonds, which enabled intracellular pH-controlled drug release. The described synthesis facilitated the preparation of biodegradable Polymer conjugates in a broad range of molecular weights (200–1000 g/mol) while still maintaining low polydispersity (~ 1.7). The Polymer grafts were attached to the dendrimers through either stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high-molecular-weight Polymer Carrier to excretable products. Biodegradability tests in suspensions of EL4 T-cell lymphoma cells showed that the rate of degradation was much faster for reductively degradable conjugates (close to completion within 24 h of incubation) than for conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (slow degradation taking several days). This finding was likely due to the differences in steric hindrance in terms of the accessibility of the small molecule glutathione and the bulky enzyme cathepsin B to the Polymer substrate. Regarding drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin under mild acidic conditions that model the tumor cell microenvironment. The star Polymer–Dox conjugates exhibited significantly prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice, indicating the important role of the EPR effect in its anti-cancer activity. The star Polymer conjugates showed prominently higher in vivo anti-tumor activities than the free drug or linear Polymer conjugate when tested in mice bearing EL4 T-cell lymphoma, with a significant number of long-term surviving (LTS). Based on the results, we conclude that a Mw of HPMA coPolymers of 200,000 to 600,000 g/mol is optimal for Polymer Carriers designed for the efficient passive targeting to solid tumors. In addition, an expressive therapy-dependent stimulation of the immune system was observed.
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biodegradable star hpma Polymer conjugates of doxorubicin for passive tumor targeting
European Journal of Pharmaceutical Sciences, 2011Co-Authors: Tomas Etrych, J Strohalm, Petr Chytil, Michal Pechar, Peter Cernoch, Larisa Starovoytova, Karel UlbrichAbstract:Abstract New biodegradable star Polymer–doxorubicin (Dox) conjugates designed for passive tumor targeting were investigated and the present study described their synthesis, physico-chemical characterization, drug release and biodegradation. In the conjugates the core formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N -(2-hydroxypropyl)methacrylamide (HPMA) coPolymers bearing doxorubicin attached by hydrazone bonds, which enabled intracellular pH-controlled drug release, or by a GFLG sequence, which was susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic coPolymer precursors facilitated preparation of biodegradable Polymer conjugates in a broad range of molecular weights (110–295 kDa) while still maintaining low polydispersity (∼1.7). The Polymer grafts were attached to the dendrimers either through stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high molecular weight Polymer Carrier to products that were able to be excreted from the body by glomerular filtration. Biodegradability tests showed that the rate of degradation was much faster for reductively degradable conjugates (completed within 4 h) than the degradation of conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (within 72 h). This finding was likely due to the difference in steric hindrance for the small molecule glutathione and the enzyme cathepsin B. As for drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin either under mild acidic conditions or in the presence of lysosomal enzyme cathepsin B, both of which modeled the tumor cell microenvironment.
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n 2 hydroxypropyl methacrylamide based Polymer conjugates with ph controlled activation of doxorubicin i new synthesis physicochemical characterization and preliminary biological evaluation
Journal of Applied Polymer Science, 2008Co-Authors: Tomas Etrych, Petr Chytil, Blanka řihova, Tomas Mrkvan, Cestmir Koňak, Karel UlbrichAbstract:New method of synthesis of water-soluble Polymer-drug conjugates, exhibiting remarkable anticancer activity in mice models, has been developed. In the conjugates, an anticancer drug doxorubicin (DOX) is attached to a Polymer Carrier based on N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymer via a hydrolytically labile hydrazone bond. New methacrylamide-type comonomers, containing either hydrazide group or hydrazon of DOX, were used for coPolymerization with HPMA. In contrast to the synthetic procedure described earlier the new method is simpler, cheaper, and results in a better-defined conjugate structure. The conjugates are fairly stable in buffer at pH 7.4 (model of blood stream) but release DOX under mild acid conditions modeling the tumor microenvironment. The conjugates showed significant in vivo antitumor activity in treatment of T-cell lymphoma EL-4 bearing mice with up to 100% long-term survivors. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
Blanka řihova - One of the best experts on this subject based on the ideXlab platform.
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bloodstream stability predetermines the antitumor efficacy of micellar Polymer doxorubicin drug conjugates with ph triggered drug release
Molecular Pharmaceutics, 2018Co-Authors: Petr Chytil, Karel Ulbrich, Blanka řihova, Milada Sirova, Julia Kudlacova, Tomas EtrychAbstract:Herein, the biodegradable micelle-forming amphiphilic N-(2-hydroxypropyl) methacrylamide (HPMA)-based Polymer conjugates with the anticancer drug doxorubicin (Dox) designed for enhanced tumor accumulation were investigated, and the influence of their stability in the bloodstream on biodistribution, namely, tumor uptake, and in vivo antitumor efficacy were evaluated in detail. Dox was attached to the Polymer Carrier by a hydrazone bond enabling pH-controlled drug release. While the Polymer–drug conjugates were stable in a buffer at pH 7.4 (mimicking bloodstream environment), Dox was released in a buffer under mild acidic conditions modeling the tumor microenvironment or cells. The amphiphilic Polymer Carriers differed in the structure of hydrophobic cholesterol derivative moieties bound to the HPMA coPolymers via a hydrolyzable hydrazone bond, exhibiting different rates of micellar structure disintegration at various pH values. Considerable dependence of the studied Polymer–drug conjugate biodistribution o...
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high molecular weight star conjugates containing docetaxel with high anti tumor activity and low systemic toxicity in vivo
Polymer Chemistry, 2015Co-Authors: Tomas Etrych, Karel Ulbrich, J Strohalm, Blanka řihova, Milada Sirova, B Tomalova, Pavel Rossmann, Marek KovařAbstract:Here we present the Polymer conjugates where the core formed by poly(amido amine) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymers containing docetaxel (DTX) attached by a pH-sensitive hydrazone bond. DTX was derivatized with three different keto acids prior to attachment to the Polymer Carrier to introduce reactive keto groups into the drug. The therapeutic efficacy of such high-molecular-weight star conjugates is based on: (a) the enhanced permeability and retention (EPR) effect facilitating selective accumulation within solid tumors; (b) pH-controlled release of the drug, thus ensuring faster DTX release in the mildly acidic tumor microenvironment. The star DTX conjugate had a remarkably higher maximum tolerated dose in comparison with free DTX when administered as a single i.v. injection (∼160 mg kg−1vs. 40 mg kg−1 of DTX) in C57BL/6 mice. The star DTX conjugate showed significantly higher antitumor activity than free drug in the EL4 T cell lymphoma growing in syngeneic C57BL/6 mice even when given at the same dose (20 mg kg−1 of DTX eq.). Thus, the star DTX conjugates exert a much higher therapeutic activity and yet a lower systemic toxicity than free DTX.
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biodegradable star hpma Polymer drug conjugates biodegradability distribution and anti tumor efficacy
Journal of Controlled Release, 2011Co-Authors: Tomas Etrych, Lubomir Kovař, J Strohalm, Petr Chytil, Blanka řihova, Karel UlbrichAbstract:Abstract Herein, new biodegradable star Polymer–doxorubicin conjugates designed for passive tumor targeting were investigated, and their synthesis, physico-chemical characterization, drug release, biodegradation, biodistribution and in vivo anti-tumor efficacy are described. In the conjugates, the core formed by poly(amidoamine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymers bearing doxorubicin (Dox) attached by hydrazone bonds, which enabled intracellular pH-controlled drug release. The described synthesis facilitated the preparation of biodegradable Polymer conjugates in a broad range of molecular weights (200–1000 g/mol) while still maintaining low polydispersity (~ 1.7). The Polymer grafts were attached to the dendrimers through either stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high-molecular-weight Polymer Carrier to excretable products. Biodegradability tests in suspensions of EL4 T-cell lymphoma cells showed that the rate of degradation was much faster for reductively degradable conjugates (close to completion within 24 h of incubation) than for conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (slow degradation taking several days). This finding was likely due to the differences in steric hindrance in terms of the accessibility of the small molecule glutathione and the bulky enzyme cathepsin B to the Polymer substrate. Regarding drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin under mild acidic conditions that model the tumor cell microenvironment. The star Polymer–Dox conjugates exhibited significantly prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice, indicating the important role of the EPR effect in its anti-cancer activity. The star Polymer conjugates showed prominently higher in vivo anti-tumor activities than the free drug or linear Polymer conjugate when tested in mice bearing EL4 T-cell lymphoma, with a significant number of long-term surviving (LTS). Based on the results, we conclude that a Mw of HPMA coPolymers of 200,000 to 600,000 g/mol is optimal for Polymer Carriers designed for the efficient passive targeting to solid tumors. In addition, an expressive therapy-dependent stimulation of the immune system was observed.
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n 2 hydroxypropyl methacrylamide based Polymer conjugates with ph controlled activation of doxorubicin i new synthesis physicochemical characterization and preliminary biological evaluation
Journal of Applied Polymer Science, 2008Co-Authors: Tomas Etrych, Petr Chytil, Blanka řihova, Tomas Mrkvan, Cestmir Koňak, Karel UlbrichAbstract:New method of synthesis of water-soluble Polymer-drug conjugates, exhibiting remarkable anticancer activity in mice models, has been developed. In the conjugates, an anticancer drug doxorubicin (DOX) is attached to a Polymer Carrier based on N-(2-hydroxypropyl)methacrylamide (HPMA) coPolymer via a hydrolytically labile hydrazone bond. New methacrylamide-type comonomers, containing either hydrazide group or hydrazon of DOX, were used for coPolymerization with HPMA. In contrast to the synthetic procedure described earlier the new method is simpler, cheaper, and results in a better-defined conjugate structure. The conjugates are fairly stable in buffer at pH 7.4 (model of blood stream) but release DOX under mild acid conditions modeling the tumor microenvironment. The conjugates showed significant in vivo antitumor activity in treatment of T-cell lymphoma EL-4 bearing mice with up to 100% long-term survivors. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008