Thiol-ene Reaction: An Efficient Tool to Design Lipophilic Polyphosphoesters for Drug Delivery Systems.

Poly(ethylene glycol)--polyphosphoester (PEG--PPE) block copolymer nanoparticles are promising carriers for poorly water soluble drugs. To enhance the drug loading capacity and efficiency of such micelles, a strategy was investigated for increasing the lipophilicity of the PPE block of these PEG--PPE amphiphilic copolymers. A PEG--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 drug loading with PEG--PPE bearing shorter pendant groups is reported evidencing the key role of the structure of the pendant group on the PPE backbone. Finally, a first evidence of the biocompatibility of these novel PEG--PPE copolymers was achieved by performing cytotoxicity tests. The PEG--PPE derived by tocopherol was evidenced as particularly promising as delivery system of poorly water-soluble drugs.