Polyphosphate-based amphiphilic copolymers: synthesis and application to drug nanocarriers

Thanks to their biocompatibility and degradability properties, polyphosphates are
appealing polymers for biomedical applications, especially for drug delivery systems. In contrast to aliphatic polyesters, such as poly(?-caprolactone) and poly(lactide), the pentavalency of phosphorus atom allows the easy modification of the polyphosphate properties by simply adjusting the nature, the length and the functionality of the polyphosphate pendants groups. The goal of this thesis focused on the design of drug nanocarriers based on amphiphilic block copolymer micelles well-suited for the encapsulation of poorly soluble drugs. For that purpose, novel diblock copolymers composed of a water-soluble poly(ethylene oxide) block and a polyphosphate block bearing a variety of alkyl side-groups were synthesized. Firstly, n- butyl, i-butyl and n-heptyl cyclic phosphate monomers were synthesized and used for the organo-catalyzed ring-opening polymerization providing a range of PEO-b-polyphosphate amphiphilic copolymers varying by the architecture and length of the polyphosphate pendant group. Then, post-polymerization thiol-ene click reactions on preformed PEO-b- polybutenylphosphate copolymer was used to graft dodecyl or tocopherol side-chains on the polyphosphate block.The micellization of these amphiphilic block copolymers in aqueous medium was then investigated and a comparative study of the encapsulation and release of a poorly soluble model drug, i.e. ketoconazole, was carried out. Ultimately, the synthesis of a triblock copolymer was investigated to prepare shell- crosslinked core-shell-corona micelles to improve the nanoparticles stability.