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 °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 (≈16 nm) were smaller than DOX–AMs (≈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 °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. Micelles from amphiphilic macromolecules (AMs) have unique branched hydrophobic domain and show potential as doxorubicin (DOX) nanocarriers. DOX–AM conjugates were designed with lysosomal pH‐sensitive hydrazone linkers for endo‐lysosomal drug delivery. Chemical conjugation and physical encapsulation of DOX in AM micelles were compared—an area not well investigated in the polymeric micelle field.