Living anionic polymerization techniques were applied to the synthesis of arborescent (dendritic) well-defined graft polymers having core-shell morphologies, with a hydrophobic core and a hydrophilic shell. Cycles of polystyrene substrate acetylation and anionic grafting yielded successive generations of arborescent polystyrenes. The anionic polymerization of styrene with sec-butyllithium provided polystyryllithium serving as side chains. These were coupled with a linear acetylated polystyrene substrate to obtain a generation zero (G0) arborescent polymer. An analogous G0 hydroxyl-functionalized polystyrene substrate with hydroxyl end groups was also obtained by a variation of the same technique, using a bifunctional organolithium initiator containing a hydroxyl functionality protected by a silyl ether group to generate the polystyrene side chains. These were coupled with the linear acetylated polystyrene substrate and subjected to a deprotection reaction to give the G0 polymer functionalized with hydroxyl groups at the chain ends. A similar procedure was used to generate a hydroxyl-functionalized arborescent G1 polymer from the corresponding G0 acetylated polystyrene substrate. The growth of polyglycidol chain segments was attempted from the hydroxyl-functionalized cores, to form a hydrophilic shell around the hydrophobic cores, but led to extensive degradation. A click reaction was also developed to synthesize the amphiphilic copolymers and was much more successful. In this case alkyne-functionalized arborescent polystyrene substrates, obtained by a modification of the hydroxyl-functionalized arborescent polystyrenes, were coupled with azide-functionalized polyglycidol side chains.

Living anionic polymerization techniques were applied to the synthesis of arborescent (dendritic) well-defined graft polymers having core-shell morphologies, with a hydrophobic core and a hydrophilic shell. Cycles of polystyrene substrate acetylation and anionic grafting yielded successive generations of arborescent polystyrenes. The anionic polymerization of styrene with sec-butyllithium provided polystyryllithium serving as side chains. These were coupled with a linear acetylated polystyrene substrate to obtain a generation zero (G0) arborescent polymer. An analogous G0 hydroxyl-functionalized polystyrene substrate with hydroxyl end groups was also obtained by a variation of the same technique, using a bifunctional organolithium initiator containing a hydroxyl functionality protected by a silyl ether group to generate the polystyrene side chains. These were coupled with the linear acetylated polystyrene substrate and subjected to a deprotection reaction to give the G0 polymer functionalized with hydroxyl groups at the chain ends. A similar procedure was used to generate a hydroxyl-functionalized arborescent G1 polymer from the corresponding G0 acetylated polystyrene substrate. The growth of polyglycidol chain segments was attempted from the hydroxyl-functionalized cores, to form a hydrophilic shell around the hydrophobic cores, but led to extensive degradation. A click reaction was also developed to synthesize the amphiphilic copolymers and was much more successful. In this case alkyne-functionalized arborescent polystyrene substrates, obtained by a modification of the hydroxyl-functionalized arborescent polystyrenes, were coupled with azide-functionalized polyglycidol side chains.

The self-assembly behavior of arborescent polystyrene-<em>graft</em>-poly(ethylene oxide) copolymers (PS-<em>g</em>-PEO) at the air-water interface and the solubilization/release properties of arborescent polystyrene-<em>graft</em>-poly(2-vinylpyridine) (PS-<em>g</em>-P2VP) copolymers were investigated. These amphiphilic dendritic molecules are covalently bonded unimolecular micelles incorporating a highly branched hydrophobic polystyrene core surrounded by a hydrophilic poly(ethylene oxide) or poly(2-vinylpyridine) shell. Molecules of PS-<em>g</em>-PEO copolymers spontaneously formed supramolecular assemblies at the air-water interface. The type of superstructures formed was found to depend upon copolymer composition, while the level of association was more directly related to the branching density of the polymers. At low surface pressures the PEO segments apparently remained adsorbed on the water subphase, but desorbed into water at very high surface pressures, in the condensed monolayer state. Controlled degradation of the PEO chains with UV light greatly enhanced molecular association, resulting in the formation of either large clusters or long ribbon-like superstructures. The PS-<em>g</em>-P2VP copolymers were found to efficiently solubilize and release hydrophobic small molecules in aqueous media. The partition coefficient and solubilization capacity of the copolymers for hydrophobic polyaromatic hydrocarbons increased with the polystyrene content of the copolymers, while the rate of solubilization decreased with increasing branching functionality of the copolymers. The release profiles for two model drugs displayed an initial burst in release followed by gradual approach to equilibrium. The diffusion coefficients of the drugs in the micelles increased with the branching functionality and the generation number of the micelles, presumably due to increased electrostatic repulsions of the protonated vinylpyridine units.

The self-assembly behavior of arborescent polystyrene-<em>graft</em>-poly(ethylene oxide) copolymers (PS-<em>g</em>-PEO) at the air-water interface and the solubilization/release properties of arborescent polystyrene-<em>graft</em>-poly(2-vinylpyridine) (PS-<em>g</em>-P2VP) copolymers were investigated. These amphiphilic dendritic molecules are covalently bonded unimolecular micelles incorporating a highly branched hydrophobic polystyrene core surrounded by a hydrophilic poly(ethylene oxide) or poly(2-vinylpyridine) shell. Molecules of PS-<em>g</em>-PEO copolymers spontaneously formed supramolecular assemblies at the air-water interface. The type of superstructures formed was found to depend upon copolymer composition, while the level of association was more directly related to the branching density of the polymers. At low surface pressures the PEO segments apparently remained adsorbed on the water subphase, but desorbed into water at very high surface pressures, in the condensed monolayer state. Controlled degradation of the PEO chains with UV light greatly enhanced molecular association, resulting in the formation of either large clusters or long ribbon-like superstructures. The PS-<em>g</em>-P2VP copolymers were found to efficiently solubilize and release hydrophobic small molecules in aqueous media. The partition coefficient and solubilization capacity of the copolymers for hydrophobic polyaromatic hydrocarbons increased with the polystyrene content of the copolymers, while the rate of solubilization decreased with increasing branching functionality of the copolymers. The release profiles for two model drugs displayed an initial burst in release followed by gradual approach to equilibrium. The diffusion coefficients of the drugs in the micelles increased with the branching functionality and the generation number of the micelles, presumably due to increased electrostatic repulsions of the protonated vinylpyridine units.

Arborescent polymers are characterized by a tree-like architecture and a high branching functionality. This type of polymer can be synthesized by different techniques, but the ‘grafting onto’ method is attractive because it provides good control over the molecular weight of the graft polymer and the side-chains used as building blocks. This method was applied to the synthesis of arborescent polybutadiene, using cycles of epoxidation and anionic grafting reactions. The research focused on optimization of the grafting yield for the synthesis of the G0 polymers, obtained by grafting side-chains onto a linear epoxidized substrate, with the ultimate goal of synthesizing successive generations of graft polymers using these optimized conditions. Two additives potentially useful as reactivity modifiers, N,N,N’,N’-tetramethylethylenediamine (TMEDA) and lithium bromide (LiBr), were investigated to increase the grafting yield. The influence of solvent polarity was also examined, and the reaction time was varied from one day to one week while monitoring the grafting yield. Optimal results (with grafting yields reaching up to 85% in one week) were obtained in cyclohexane-tetrahydrofuran mixtures, in the presence of LiBr, with only small (2-3%) yield increases observed after 24 h of reaction. These optimal conditions, when applied to the synthesis of G1 and G2 polymers, led to grafting yields of 78-80% when using a 1:1 ratio of epoxide groups to living ends. The influence of excess substrate was also examined individually for each generation, and likewise led to small (2-4%) increases in grafting yield. The results obtained showed that the grafting reaction was successful on the basis of 1H NMR spectroscopy and size exclusion chromatography analysis, and was sensitive to parameters such as the substitution level of the epoxidized substrate, the solvent composition, and the presence of additives.

Arborescent polymers are characterized by a tree-like architecture and a high branching functionality. This type of polymer can be synthesized by different techniques, but the ‘grafting onto’ method is attractive because it provides good control over the molecular weight of the graft polymer and the side-chains used as building blocks. This method was applied to the synthesis of arborescent polybutadiene, using cycles of epoxidation and anionic grafting reactions. The research focused on optimization of the grafting yield for the synthesis of the G0 polymers, obtained by grafting side-chains onto a linear epoxidized substrate, with the ultimate goal of synthesizing successive generations of graft polymers using these optimized conditions. Two additives potentially useful as reactivity modifiers, N,N,N’,N’-tetramethylethylenediamine (TMEDA) and lithium bromide (LiBr), were investigated to increase the grafting yield. The influence of solvent polarity was also examined, and the reaction time was varied from one day to one week while monitoring the grafting yield. Optimal results (with grafting yields reaching up to 85% in one week) were obtained in cyclohexane-tetrahydrofuran mixtures, in the presence of LiBr, with only small (2-3%) yield increases observed after 24 h of reaction. These optimal conditions, when applied to the synthesis of G1 and G2 polymers, led to grafting yields of 78-80% when using a 1:1 ratio of epoxide groups to living ends. The influence of excess substrate was also examined individually for each generation, and likewise led to small (2-4%) increases in grafting yield. The results obtained showed that the grafting reaction was successful on the basis of 1H NMR spectroscopy and size exclusion chromatography analysis, and was sensitive to parameters such as the substitution level of the epoxidized substrate, the solvent composition, and the presence of additives.

Graft polymers with a dendritic architecture (arborescent polymers) were synthesized by ???click???, anionic, and cationic grafting. Arborescent polystyrene and polybutadiene systems were synthesized by ???click??? coupling using alkyne and azide functional groups, one of which was introduced randomly on the polymer substrate, while the other functionality was located at one end of the polymer serving as side chains. The two possible combinations of randomly and end-functionalized components were investigated for both polymer systems, but the best method for polystyrene involved side chains with an azide end group and randomly acetylenated substrates; for polybutadiene, acetylene-terminated side chains and randomly azidated substrates were preferred. The end-functionalized polymers were derived from a bifunctional initiator to introduce a protected hydroxyl group, which was converted into either an azide or an acetylene functionality. Coupling of the end-functionalized side chains with the substrate polymer serving as backbone yielded a comb-branched (or G0 arborescent) polymer. Further cycles of substrate functionalization and grafting led to the subsequent (G1 and G2) generations of arborescent polymers. Linear and branched (G0 and G1) hydroxylated polystyrene derivatives, some of which served as intermediates in the synthesis of the randomly functionalized ???click??? grafting substrates, were also explored as macroinitiators for the cationic polymerization of ethyl vinyl ether. The substrates functionalized with either secondary or tertiary alcohol groups yielded the desired arborescent polystyrene-graft-poly(ethyl vinyl ether) copolymers, without formation of linear contaminant. Arborescent polybutadiene of generations G1 and G2, with different side chain molecular weights, were also synthesized by anionic coupling of living polybutadienyllithium side chains with substrates functionalized with chlorosilane groups for comparison with the ???click??? methodology.

The synthesis of arborescent poly(gamma-benzyl L-glutamate) (PBG) molecules was achieved through successive grafting reactions of linear PBG chains. These linear PBG building blocks were obtained by the ring-opening polymerization of gamma-benzyl L-glutamic acid N-carboxyanhydride initiated with n-hexylamine. Cleavage of a fraction of the benzyl ester groups on a linear PBG substrate, followed by coupling with linear PBG side chains via standard peptide coupling techniques, yielded a comb-branched or generation zero (G0) arborescent PBG. Further cycles of partial deprotection and grafting reactions led to arborescent PBG molecules of the subsequent generations (G1-G3). Molecular weights reaching over 106 were obtained for G3 arborescent PBG, while maintaining narrow molecular weight distributions (Mw/Mn ≤ 1.06) for each generation. The arborescent PBG molecules displayed α-helix to randomly coiled chain conformation changes from N,N-dimethylformamide to dimethylsulfoxide. Amphiphilic copolymers were obtained by grafting the arborescent PBG substrates randomly with side chains of either poly(glycidol acetal), poly(ethylene oxide), or poly(γ-tert-butyl L-glutamate) via the same peptide coupling techniques used to generate arborescent PBG. Copolymers were also synthesized by a chain end grafting method, whereby the linear chain segments were coupled exclusively with the chain termini of the arborescent PBG substrates. Water-soluble species were obtained by removal of the acetal and tert-butyl protecting groups from the poly(glycidol acetal) and poly(γ-tert-butyl L-glutamate) side chains, respectively, while the copolymers with poly(ethylene oxide) side chains did not require further modifications. Dynamic light scattering (DLS) measurements on the arborescent copolymers in aqueous solutions revealed that unimolecular micelles were the dominant species for the chain end grafted arborescent copolymers, whereas the randomly grafted arborescent copolymers were either insoluble or displayed significant aggregation. The synthesis of arborescent copolymers with PBG cores was also achieved through “click” chemistry, using the copper-catalyzed azide-alkyne Huisgen cycloaddition (CuAAC) reaction. To that end, polyglycidol, poly(ethylene oxide), and poly(2-trimethylsilylethyl acrylate) chains terminally functionalized with azide groups were grafted onto either randomly or chain end alkyne-functionalized arborescent PBG substrates. DLS analysis revealed solubility trends similar to the arborescent copolymers obtained by the peptide coupling method. The CuAAC reaction enables the incorporation of a broader range of polymers into arborescent copolymer structures derived from PBG substrates.

The synthesis of arborescent poly(gamma-benzyl L-glutamate) (PBG) molecules was achieved through successive grafting reactions of linear PBG chains. These linear PBG building blocks were obtained by the ring-opening polymerization of gamma-benzyl L-glutamic acid N-carboxyanhydride initiated with n-hexylamine. Cleavage of a fraction of the benzyl ester groups on a linear PBG substrate, followed by coupling with linear PBG side chains via standard peptide coupling techniques, yielded a comb-branched or generation zero (G0) arborescent PBG. Further cycles of partial deprotection and grafting reactions led to arborescent PBG molecules of the subsequent generations (G1-G3). Molecular weights reaching over 106 were obtained for G3 arborescent PBG, while maintaining narrow molecular weight distributions (Mw/Mn ≤ 1.06) for each generation. The arborescent PBG molecules displayed α-helix to randomly coiled chain conformation changes from N,N-dimethylformamide to dimethylsulfoxide. Amphiphilic copolymers were obtained by grafting the arborescent PBG substrates randomly with side chains of either poly(glycidol acetal), poly(ethylene oxide), or poly(γ-tert-butyl L-glutamate) via the same peptide coupling techniques used to generate arborescent PBG. Copolymers were also synthesized by a chain end grafting method, whereby the linear chain segments were coupled exclusively with the chain termini of the arborescent PBG substrates. Water-soluble species were obtained by removal of the acetal and tert-butyl protecting groups from the poly(glycidol acetal) and poly(γ-tert-butyl L-glutamate) side chains, respectively, while the copolymers with poly(ethylene oxide) side chains did not require further modifications. Dynamic light scattering (DLS) measurements on the arborescent copolymers in aqueous solutions revealed that unimolecular micelles were the dominant species for the chain end grafted arborescent copolymers, whereas the randomly grafted arborescent copolymers were either insoluble or displayed significant aggregation. The synthesis of arborescent copolymers with PBG cores was also achieved through “click” chemistry, using the copper-catalyzed azide-alkyne Huisgen cycloaddition (CuAAC) reaction. To that end, polyglycidol, poly(ethylene oxide), and poly(2-trimethylsilylethyl acrylate) chains terminally functionalized with azide groups were grafted onto either randomly or chain end alkyne-functionalized arborescent PBG substrates. DLS analysis revealed solubility trends similar to the arborescent copolymers obtained by the peptide coupling method. The CuAAC reaction enables the incorporation of a broader range of polymers into arborescent copolymer structures derived from PBG substrates.

Ce manuscrit de thèse présente la synthèse de nanoparticules d’oxyde de fer superparamagnétiques couramment appelées SPIONs servant d’agents de contraste pour l’imagerie par résonance magnétique (IRM) et la génération de chaleur pour la thérapie cellulaire par hyperthermie induite par champ magnétique radiofréquence (HMRF). Le contrôle des tailles et de la distribution en tailles des SPIONs et donc de leurs propriétés magnétiques a été obtenu en utilisant un copolymère arborescent G1 (substrat de polystyrène branché en peigne noté G0, greffé avec des groupements pendants poly(2-vinyle pyridine) ) comme milieu « gabarit », tandis que la stabilité colloïdale et la biocompatibilité des SPIONs ont été apportées par un procédé de poly-complexation ionique grâce à un copolymère double-hydrophile acide polyacrylique-bloc-poly(acrylate de 2-hydroxyéthyle) PAA-b-PHEA. / This Ph.D. dissertation describes the synthesis of superparamagnetic iron oxide nanoparticles (SPIONs) designed to serve as magnetic resonance imaging (MRI) contrast agents and for heat generation in cellular radiofrequency magnetic field hyperthermia (MFH) treatment. Control over the size and size distribution of the iron oxide nanoparticles (NPs), and thus over their magnetic properties, was achieved using a G1 arborescent copolymer (comb-branched (G0) polystyrene substrate grafted with poly(2-vinylpyridine) side chains, or G0PS-g-P2VP) as a template. Good colloidal stability and biocompatibility of the SPIONs were achieved via the formation of polyion complex (PIC) micelles with a poly(acrylic acid)-block-poly(2-hydroxyethyl acrylate) (PAA-b-PHEA) double-hydrophilic block copolymer.