Micellar nanocarriers assembled from doxorubicin-conjugated amphiphilic macromolecules (DOX-AM)

Amphiphilic macromolecules (AMs) have unique branched hydrophobic domains attached to linear PEG chains. AMs self-assemble in aqueous solution to form micelles that are hydrolytically stable in physiological conditions (37 degrees C, pH 7.4) over 4 weeks. Evidence of AM biodegradability was demonstrated by complete AM degradation after 6 d in the presence of lipase. Doxorubicin (DOX) was chemically conjugated to AMs via a hydrazone linker to form DOX-AM conjugates that self-assembled into micelles in aqueous solution. The conjugates were compared with DOX-loaded AM micelles (i.e., physically loaded DOX) on DOX content, micellar sizes and in vitro cytotoxicity. Physically encapsulated DOX loading was higher (12 wt.-%) than chemically bound DOX (6 wt.-%), and micellar sizes of DOX-loaded AMs (approximately 16 nm) were smaller than DOX-AMs (approximately 30 nm). In vitro DOX release from DOX-AM conjugates was faster at pH 5.0 (100%) compared to pH 7.4 (78%) after 48 h, 37 degrees C. Compared to free DOX and physically encapsulated DOX, chemically bound DOX had significantly higher cytotoxicity at 10(-7) M DOX dose against human hepatocellular carcinoma cells after 72 h. Overall, DOX-AM micelles showed promising characteristics as stable, biodegradable DOX nanocarriers.