Degradable micelles based on hydrolytically degradable amphiphilic graft copolymers for doxorubicin delivery

Micelles based on a low-toxic and hydrolytically degradable poly(β-amino ester)-g-octadecyl acrylate (PAE-g-ODA) amphiphilic copolymer were developed for doxorubicin (DOX) delivery. A two-step reaction pathway was used to synthesize PAE-g-ODA copolymers with poly(ethylene glycol) segments in the backbone via Michael-type addition reaction. Copolymers with various grafting degrees were obtained by tuning the feeding molar ratios of acrylate/formed secondary amine and the grafting reaction time. Among this series of copolymers, PAE-g-ODA-2 (PAE-g-ODA with 45% ODA side chains) were found to form spherical micelles with an average size of 72.5 nm, as determined by dynamic light scattering (DLS) and transmission electron microscope (TEM), whereas the other PAE-g-ODA copolymers fail to form stable micelles with a narrow size distribution in an aqueous solution. The titration curve illustrated that PAE-g-ODA-2 has a high buffer capacity in the pH range of 7.5-5. The hydrolytic degradation of PAE-g-ODA-2 copolymer in PBS buffer (pH 7.4, 37 °C) was monitored by 1H NMR. It was found that up to 70% ester groups in the backbones were hydrolyzed in 48 h. The DOX-loaded micelles release about 70% trapped DOX within 48 h in physiological condition. Cytotoxicity assay showed a low cytotoxicity of PAE-g-ODA-2 micelles as well as a higher inhibition against HepG2 tumor cells of DOX-loaded micelles than free DOX.