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The therapeutic performance of biodegradablemicellar drugs isfar from optimal due to existing challenges like poor tumor cell uptakeand intracellular drug release. Here, we report on ligand-directedreduction-sensitive shell-sheddable biodegradable micelles based onpoly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) copolymeractively delivering doxorubicin (DOX) into the nuclei of target cancercells, inducing superb in vitro antitumor effects. The micelles wereconstructed from PEG-SS-PCL and galactose-PEG-PCL (Gal-PEG-PCL) blockcopolymers, in which Gal-PEG-PCL was designed with a longer PEG thanthat in PEG-SS-PCL (6.0 vs 5.0 kDa) to fully expose Gal ligands ontothe surface of micelles for effective targeting to hepatocellularcarcinoma cells. PEG-SS-PCL combining with 10 or 20 wt % of Gal-PEG-PCLformed uniform micelles with average sizes of 56.1 and 58.2 nm (denotedas PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20, respectively). The in vitrorelease studies showed that about 81.1 and 75.0% DOX was releasedin 12 h from PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles undera reducing condition containing 10 mM dithiothreitol (DTT). In contrast,minimal DOX release (<12%) was observed for PEG-SS-PCL/Gal10 andPEG-SS-PCL/Gal20 micelles under nonreducing conditions as well asfor reduction-insensitive Gal-PEG-PCL and PEG-PCL/Gal20 micelles inthe presence of 10 mM DTT. MTT assays in HeLa and HepG2 cells showedthat DOX-loaded PEG-SS-PCL/Gal20 micelles exhibited apparent targetabilityand significantly enhanced antitumor efficacy toward asialoglycoproteinreceptor (ASGP-R)-overexpressing HepG2 cells with a particularly lowhalf maximal inhibitory concentration (IC50) of 1.58 μgDOX equiv/mL, which was comparable to free DOX and approximately sixtimes lower than that for nontargeting PEG-SS-PCL counterparts underotherwise the same conditions. Interestingly, confocal microscopyobservations using FITC-labeled PEG-SS-PCL/Gal20 micelles showed thatDOX was efficiently delivered and released into the nuclei of HepG2cells in 8 h. Flow cytometry revealed that cellular DOX level in HepG2cells treated with DOX-loaded PEG-SS-PCL/Gal20 micelles was much greaterthan that with reduction-insensitive PEG-PCL/Gal20 and nontargetingPEG-SS-PCL controls, signifying the importance of combining shell-sheddingand active targeting. Ligand-directed, reduction-sensitive, shell-sheddable,and biodegradable micelles have emerged as a versatile and potentplatform for targeted cancer chemotherapy. [ABSTRACT FROM AUTHOR]