Design of polyphosphoester-based drug delivery systems by efficient thiol-ene reaction

Thanks to their biocompatibility, biodegradability and their structure similar to natural biomacromolecules, polyphosphoesters (PPE) are appealing polymers for biomedical applications. In contrast to polyesters, PPE properties and functionality are easily tuned via the chemical nature of the lateral chains. To enhance the drug loading capacity of PPE-based micelles used as carriers for the delivery of poorly soluble drugs, an efficient strategy to increase the lipophilicity of the PPE block of polyethylene oxide (PEO)-b-PPE amphiphilic copolymers has been investigated. A PEO-b-PPE copolymer bearing pendant vinyl groups along the PPE block was synthesized and then modified by thiol-ene click reaction with thiols bearing either a long linear alkyl chain (dodecyl) or a tocopherol moiety. Ketoconazole was used as model for hydrophobic drugs. Comparison of the loading contents and release profiles with PEO-b-PPE bearing shorter pendant groups is presented evidencing the key role of the structure of the pendant group on the PPE backbone. Finally, the low cytotoxicity of these novel PEO-b-PPE copolymers was also demonstrated. The tocopherol derivative was evidenced as particularly promising for drug delivery systems.