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Inrecent years, polymeric nanoparticles have appeared as a mostviable and versatile delivery system for targeted cancer therapy.Various in vivo studies have demonstrated that virus-sized stealthparticles are able to circulate for a prolonged time and preferentiallyaccumulate in the tumor site via the enhanced permeability and retention(EPR) effect (so-called “passive tumor-targeting”).The surface decoration of stealth nanoparticles by a specific tumor-homingligand, such as antibody, antibody fragment, peptide, aptamer, polysaccharide,saccharide, folic acid, and so on, might further lead to increasedretention and accumulation of nanoparticles in the tumor vasculatureas well as selective and efficient internalization by target tumorcells (termed as “active tumor-targeting”). Notably,these active targeting nanoparticulate drug formulations have shownimproved, though to varying degrees, therapeutic performances in differenttumor models as compared to their passive targeting counterparts.In addition to type of ligands, several other factors such as in vivostability of nanoparticles, particle shape and size, and ligand densityalso play an important role in targeted cancer chemotherapy. In thisreview, concept and recent development of polymeric nanoparticlesconjugated with specific targeting ligands, ranging from proteins(e.g., antibodies, antibody fragments, growth factors, and transferrin),peptides (e.g., cyclic RGD, octreotide, AP peptide, and tLyp-1 peptide),aptamers (e.g., A10 and AS1411), polysaccharides (e.g., hyaluronicacid), to small biomolecules (e.g., folic acid, galactose, bisphosphonates,and biotin), for active tumor-targeting drug delivery in vitro andin vivo are highlighted and discussed. With promise to maximize therapeuticefficacy while minimizing systemic side effects, ligand-mediated activetumor-targeting treatment modality has become an emerging and indispensableplatform for safe and efficient cancer therapy. [ABSTRACT FROM AUTHOR]

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]