Synthesis Of Novel Amphiphilic Copolymers Based On Sugar Moieties: Development Of New Architectures And Biomedical Applications

Synthesis of novel amphiphilic copolymers based on sugar moieties: development of new architectures and biomedical applications As early as in the 50’s, amphiphilic copolymers started to attract much interest in the frame of polymer science thanks to their self-assemblies as organized nano-structures in a selective solvent. The resulting micelles or vesicles have emerged as potentially useful materials in the biomedical field such as drug delivery systems when matching the specific conditions of size, coating nature and functionalization,… Moreover, active cell-targeting increases the therapeutic effect by selectively delivering the drug to the required cells. Accordingly, carbohydrates have drawn much attention due to the cell recognition processes they can mediate. Carbohydrates are thus incorporated in polymer backbones to mimic the naturally occurring substrate for the adapted cell receptors. The originality of this thesis is based on the use of sugar moieties as potential multi-hydroxylated initiators for the polymerization of various lactones. This leads to well-defined amphiphilic polymer architectures along with the development of a more facile route for the incorporation of carbohydrates in polymer chains to promote active cell-targeting of the as-obtained nano-structures. The first part of the thesis aims at describing the synthesis of novel amphiphilic brush-like polymers via two pathways. A first approach relies upon the synthesis of polyester arms initiated from the alcohol groups of pending sugars distributed along a preformed hydrophilic polymethacrylate backbone obtained by controlled radical polymerization (via ATRP). Various metal-based and organic catalysts/activators have been studied to lead to the desired architectures using this “grafting from” technique. In another synthetic strategy, the lactone polymerization using a carbohydrate initiator has been carried out, followed by end-chain derivatization reactions yielding brush-like copolymers via a “grafting through” technique. Slight modifications of the end-chain functionalities have also afforded the possibility to synthesize amphiphilic mikto-arm copolymers which self-assemble in aqueous medium in micelles characterized by interesting size features affording promising applications as new drug delivery systems. On the other hand this thesis also focuses on the use of carbohydrate moieties in amphiphilic diblock copolymers such as poly(ε-caprolactone)-b-poly(methacrylate-graft-poly(ethylene oxide)-co-6-O-methacryloyl-D-galactopyranose) or poly(ε-caprolactone)-b-poly(methacrylate-graft-poly(ethylene oxide)-co-1-O-methacryloyl-D-mannofuranose), using the combination of lactone ring-opening polymerization with ATRP of the respective functionalized comonomers, followed by selective post-polymerization sugar deprotection. Next to these copolymers based on polylactones and polymethacrylates, fully degradable amphiphilic block copolymers composed of a polycarbonate backbone have been originally designed. To that end, a multi-step procedure involving the synthesis of sugar-substituted cyclic carbonates, block copolymerization reactions and ultimate selective sugar deprotection, has been investigated. The self-organization of the resulting copolymers, e.g. poly(trimethylene carbonate)-b-poly(3-O-(5’-methyl,5’-carboxy-1’,3’-dioxan-2’-one)-D-glucopyranose), has been studied in aqueous medium. Interestingly, the so-formed polymeric micelles proved to display remarkable living cell-targeting properties. Fabian SurianoDoctorat en science