Amphotericin B (AmB) and clofazimine are potent drugs hindered by their low water solubilities an... more Amphotericin B (AmB) and clofazimine are potent drugs hindered by their low water solubilities and their toxicities. Carriers able to increase their apparent water solubilities are needed for these drugs and for other molecules with similar properties. Random amphiphilic copolymers derived from poly(dimethylmalic acid) were obtained using different hydrophobization ratios and side group sizes. Apparent water solubilities of pyrene, clofazimine, and AmB were increased up to 10 000, 20 000 and 1000 times, respectively, in aqueous solutions containing these polymers. The presence of sodium chloride in polymer solution increased pyrene solubility but decreased the solubilities of clofazimine and AmB, compared to the salt-free solutions. Synergy between hydrophobic and electrostatic interactions was observed for polar and cationic molecules. Degradation studies showed that the examined polymers were degradable, but none of them were totally degraded in 28 days. These polymers could be used as a new tool for drug solubilization.
Ischemia and denervation of EDL muscle of adult rat induce a large central zone of degeneration s... more Ischemia and denervation of EDL muscle of adult rat induce a large central zone of degeneration surrounded by a thin zone of periph- eral surviving muscle fibers. Muscle regeneration is a complex phenomenon in which many agents inter- act, such as growth factors and heparan sulfate components of the extracellular matrix. We have shown that synthetic polymers, called RGTA (as
ABSTRACT The preparation of α,α,β-trisubstituted β-lactones has opened the route to living anioni... more ABSTRACT The preparation of α,α,β-trisubstituted β-lactones has opened the route to living anionic ring-opening polymerization of these monomers. Therefore, transfer reactions due to hydrogen abstraction were limited and it is now possible to strickly control sample molecular weight. Moreover, living end-groups lead to the preparation of block co-polymers with block controlled lenghts. In the same way, high-molecular-weight statistical co-polymers have been synthesized. Hydrolyzable micelles and nanoparticles will be prepared from these co-polymers after chemical modifications to adjust the hydrophilic/hydrophobic balance.
Comptes Rendus De L Academie Des Sciences Serie Ii Fascicule C-chimie, 1999
A water soluble and hydrolysable polyester derived from malic acid has been synthesized by copoly... more A water soluble and hydrolysable polyester derived from malic acid has been synthesized by copolymerization of three different malolactonic acid esters. Functional pendant groups have been selected to interact with and protect heparin binding growth factors (HBGF). Three β-substituted β-lactones have been synthesized by using aspartic acid as a chiral precursor and benzyl, allyl and butyl alcohols in the formation
Journal of Biomaterials Science-polymer Edition, 2000
A bioactive poly(β-hydroxyalkanoate) derived from malic acid was prepared and tested on bone repa... more A bioactive poly(β-hydroxyalkanoate) derived from malic acid was prepared and tested on bone repair and muscle regeneration. This functionalized and hydrolyzable polymer was obtained after several steps, the first one being the anionic copolymerization of three malolactonic acid esters. Chemical modifications were carried out on the terpolymer to turn benzyl-protecting groups into carboxyl groups and allyl groups into sulfonate groups.
We have synthesized dextran derivatives called RGTAs (for regenerating agents) that were designed... more We have synthesized dextran derivatives called RGTAs (for regenerating agents) that were designed to mimic some of the properties of heparin or heparan sulfate to interact with and protect heparin binding growth factors. Some of these growth factors have been described to be involved in myogenesis control. In previous studies, we have shown that muscle regeneration in adults could be
A concise and efficient synthesis of α,α′,β-trisubstituted β-lactones is presented. These novel l... more A concise and efficient synthesis of α,α′,β-trisubstituted β-lactones is presented. These novel lactones are easily obtained in five steps and will be dedicated to anionic ring opening polymerization.
We developed regenerating agents (RGTAs) corresponding to polysaccharides derived from dextran an... more We developed regenerating agents (RGTAs) corresponding to polysaccharides derived from dextran and containing defined amounts of carboxymethyl (CM), carboxymethyl sulfate (CMS), carboxymethyl benzylamide (CMB), or carboxymethyl benzylamide sulfate (CMBS) groups with varying degrees of substitution. These compounds mimicked some effects of heparin on smooth muscle cell (SMC) proliferation and promoted in vivo tissue remodeling. We demonstrated that only RGTAs containing both CM and sulfate groups decreased SMC proliferation, in correlation with increased sulfation level. This effect was amplified by the presence of benzylamide. Independent of this activity on cell proliferation (i.e., with postconfluent cells), RGTAs modulated collagen biosynthesis by SMCs. On the one hand, CMBS more than CMS RGTAs induced a decrease of collagen III synthesis at the level of mRNA steady state and protein production. On the other hand, CMS to a greater extent than CMBS RGTAs increased both collagen V mRNA and protein production. In addition, only benzylamide-containing RGTAs increased accumulation of collagen I and III in the cell layer. In conclusion, RGTA bioactivities required the presence of CM functions, increased with the sulfation level, and varied with benzylamide substitution. RGTAs that modulate cell proliferation and collagen biosynthesis by differential mechanisms may represent potential antifibrotic agents.
Journal of Biomaterials Science, Polymer Edition, 2000
A bioactive poly(beta-hydroxyalkanoate) derived from malic acid was prepared and tested on bone r... more A bioactive poly(beta-hydroxyalkanoate) derived from malic acid was prepared and tested on bone repair and muscle regeneration. This functionalized and hydrolyzable polymer was obtained after several steps, the first one being the anionic copolymerization of three malolactonic acid esters. Chemical modifications were carried out on the terpolymer to turn benzyl-protecting groups into carboxyl groups and allyl groups into sulfonate groups. The resulting polymer bore carboxylate, sulfonate, and sec-butyl pendent groups in 65/25/10 molar proportions and were aimed at interacting with heparan binding growth factors. This polymer did not present any toxic effect in cell viability of HepG2 cells, over a large range of concentrations (0.01-0.25 mgl(-1)). Its ability to improve wound healing was tested in vivo and positive results are reported. Furthermore, the bioactivity of this polymer was evaluated using the regeneration model of Extensor digitorum longus (EDL) rat muscle. The study displayed a significant increase in the muscle regeneration and maturation.
Hybrid materials constituted by hydrophobic and hydrophilic biocompatible macromolecules are usef... more Hybrid materials constituted by hydrophobic and hydrophilic biocompatible macromolecules are useful for biomedical applications. In this context, a well-known acrylic monomer (methyl methacrylate) was polymerized and grafted onto the polysaccharide dextran by the use of ceric ammonium nitrate as a redox initiator in aqueous nitric acid medium. The effects of concentrations of dextran, acrylic monomer, and ceric ions on the copolymerization yields were investigated in detail. The obtained polymers were studied by solubility measurements, Fourier transform infrared spectrometry, (13)C nuclear magnetic resonance spectroscopy, and viscosimetric analysis. Interestingly, we found conditions to form transparent and homogeneous thin films or 3D structures with hybrid properties. Indeed, the copolymer, but not dextran or PMMA, could be dissolved in water/THF (20/80 v/v). The thermomechanical properties of the resulting copolymer analyzed by differential scanning calorimetry and dynamic mechanical analysis showed the occurrence of a single glass-transition temperature and a marked difference with the two homopolymers. The cytocompatibility of the copolymer with human endothelial cells was evidenced by the normal cell adhesion, proliferation, and morphology after 5 days in culture on these gels. In conclusion, this type of copolymer with hybrid properties of two biocompatible macromolecules could be of great interest as a 3D scaffold or for coating in biomedical applications.
Amphotericin B (AmB) and clofazimine are potent drugs hindered by their low water solubilities an... more Amphotericin B (AmB) and clofazimine are potent drugs hindered by their low water solubilities and their toxicities. Carriers able to increase their apparent water solubilities are needed for these drugs and for other molecules with similar properties. Random amphiphilic copolymers derived from poly(dimethylmalic acid) were obtained using different hydrophobization ratios and side group sizes. Apparent water solubilities of pyrene, clofazimine, and AmB were increased up to 10 000, 20 000 and 1000 times, respectively, in aqueous solutions containing these polymers. The presence of sodium chloride in polymer solution increased pyrene solubility but decreased the solubilities of clofazimine and AmB, compared to the salt-free solutions. Synergy between hydrophobic and electrostatic interactions was observed for polar and cationic molecules. Degradation studies showed that the examined polymers were degradable, but none of them were totally degraded in 28 days. These polymers could be used as a new tool for drug solubilization.
Ischemia and denervation of EDL muscle of adult rat induce a large central zone of degeneration s... more Ischemia and denervation of EDL muscle of adult rat induce a large central zone of degeneration surrounded by a thin zone of periph- eral surviving muscle fibers. Muscle regeneration is a complex phenomenon in which many agents inter- act, such as growth factors and heparan sulfate components of the extracellular matrix. We have shown that synthetic polymers, called RGTA (as
ABSTRACT The preparation of α,α,β-trisubstituted β-lactones has opened the route to living anioni... more ABSTRACT The preparation of α,α,β-trisubstituted β-lactones has opened the route to living anionic ring-opening polymerization of these monomers. Therefore, transfer reactions due to hydrogen abstraction were limited and it is now possible to strickly control sample molecular weight. Moreover, living end-groups lead to the preparation of block co-polymers with block controlled lenghts. In the same way, high-molecular-weight statistical co-polymers have been synthesized. Hydrolyzable micelles and nanoparticles will be prepared from these co-polymers after chemical modifications to adjust the hydrophilic/hydrophobic balance.
Comptes Rendus De L Academie Des Sciences Serie Ii Fascicule C-chimie, 1999
A water soluble and hydrolysable polyester derived from malic acid has been synthesized by copoly... more A water soluble and hydrolysable polyester derived from malic acid has been synthesized by copolymerization of three different malolactonic acid esters. Functional pendant groups have been selected to interact with and protect heparin binding growth factors (HBGF). Three β-substituted β-lactones have been synthesized by using aspartic acid as a chiral precursor and benzyl, allyl and butyl alcohols in the formation
Journal of Biomaterials Science-polymer Edition, 2000
A bioactive poly(β-hydroxyalkanoate) derived from malic acid was prepared and tested on bone repa... more A bioactive poly(β-hydroxyalkanoate) derived from malic acid was prepared and tested on bone repair and muscle regeneration. This functionalized and hydrolyzable polymer was obtained after several steps, the first one being the anionic copolymerization of three malolactonic acid esters. Chemical modifications were carried out on the terpolymer to turn benzyl-protecting groups into carboxyl groups and allyl groups into sulfonate groups.
We have synthesized dextran derivatives called RGTAs (for regenerating agents) that were designed... more We have synthesized dextran derivatives called RGTAs (for regenerating agents) that were designed to mimic some of the properties of heparin or heparan sulfate to interact with and protect heparin binding growth factors. Some of these growth factors have been described to be involved in myogenesis control. In previous studies, we have shown that muscle regeneration in adults could be
A concise and efficient synthesis of α,α′,β-trisubstituted β-lactones is presented. These novel l... more A concise and efficient synthesis of α,α′,β-trisubstituted β-lactones is presented. These novel lactones are easily obtained in five steps and will be dedicated to anionic ring opening polymerization.
We developed regenerating agents (RGTAs) corresponding to polysaccharides derived from dextran an... more We developed regenerating agents (RGTAs) corresponding to polysaccharides derived from dextran and containing defined amounts of carboxymethyl (CM), carboxymethyl sulfate (CMS), carboxymethyl benzylamide (CMB), or carboxymethyl benzylamide sulfate (CMBS) groups with varying degrees of substitution. These compounds mimicked some effects of heparin on smooth muscle cell (SMC) proliferation and promoted in vivo tissue remodeling. We demonstrated that only RGTAs containing both CM and sulfate groups decreased SMC proliferation, in correlation with increased sulfation level. This effect was amplified by the presence of benzylamide. Independent of this activity on cell proliferation (i.e., with postconfluent cells), RGTAs modulated collagen biosynthesis by SMCs. On the one hand, CMBS more than CMS RGTAs induced a decrease of collagen III synthesis at the level of mRNA steady state and protein production. On the other hand, CMS to a greater extent than CMBS RGTAs increased both collagen V mRNA and protein production. In addition, only benzylamide-containing RGTAs increased accumulation of collagen I and III in the cell layer. In conclusion, RGTA bioactivities required the presence of CM functions, increased with the sulfation level, and varied with benzylamide substitution. RGTAs that modulate cell proliferation and collagen biosynthesis by differential mechanisms may represent potential antifibrotic agents.
Journal of Biomaterials Science, Polymer Edition, 2000
A bioactive poly(beta-hydroxyalkanoate) derived from malic acid was prepared and tested on bone r... more A bioactive poly(beta-hydroxyalkanoate) derived from malic acid was prepared and tested on bone repair and muscle regeneration. This functionalized and hydrolyzable polymer was obtained after several steps, the first one being the anionic copolymerization of three malolactonic acid esters. Chemical modifications were carried out on the terpolymer to turn benzyl-protecting groups into carboxyl groups and allyl groups into sulfonate groups. The resulting polymer bore carboxylate, sulfonate, and sec-butyl pendent groups in 65/25/10 molar proportions and were aimed at interacting with heparan binding growth factors. This polymer did not present any toxic effect in cell viability of HepG2 cells, over a large range of concentrations (0.01-0.25 mgl(-1)). Its ability to improve wound healing was tested in vivo and positive results are reported. Furthermore, the bioactivity of this polymer was evaluated using the regeneration model of Extensor digitorum longus (EDL) rat muscle. The study displayed a significant increase in the muscle regeneration and maturation.
Hybrid materials constituted by hydrophobic and hydrophilic biocompatible macromolecules are usef... more Hybrid materials constituted by hydrophobic and hydrophilic biocompatible macromolecules are useful for biomedical applications. In this context, a well-known acrylic monomer (methyl methacrylate) was polymerized and grafted onto the polysaccharide dextran by the use of ceric ammonium nitrate as a redox initiator in aqueous nitric acid medium. The effects of concentrations of dextran, acrylic monomer, and ceric ions on the copolymerization yields were investigated in detail. The obtained polymers were studied by solubility measurements, Fourier transform infrared spectrometry, (13)C nuclear magnetic resonance spectroscopy, and viscosimetric analysis. Interestingly, we found conditions to form transparent and homogeneous thin films or 3D structures with hybrid properties. Indeed, the copolymer, but not dextran or PMMA, could be dissolved in water/THF (20/80 v/v). The thermomechanical properties of the resulting copolymer analyzed by differential scanning calorimetry and dynamic mechanical analysis showed the occurrence of a single glass-transition temperature and a marked difference with the two homopolymers. The cytocompatibility of the copolymer with human endothelial cells was evidenced by the normal cell adhesion, proliferation, and morphology after 5 days in culture on these gels. In conclusion, this type of copolymer with hybrid properties of two biocompatible macromolecules could be of great interest as a 3D scaffold or for coating in biomedical applications.
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