Galactose-installed photo-crosslinked pH-sensitive degradable micelles for active targeting chemotherapy of hepatocellular carcinoma in mice

In this study, we designed and developed galactose-installed photo-crosslinked pH-sensitive degradable micelles (Gal-CLMs) for active targeting chemotherapy of hepatocellular carcinoma in mice. Gal-CLMs were readily obtained from co-self-assembly of poly(ethylene glycol)-b-poly(mono-2,4,6-trimethoxy benzylidene-pentaerythritol carbonate-co-acryloyl carbonate) (PEG-b-P(TMBPEC-co-AC)) and Gal-PEG-b-poly(ε-caprolactone) (Gal-PEG-b-PCL) copolymers followed by photo-crosslinking. Notably, paclitaxel (PTX)-loaded Gal-CLMs (Gal-PTX-CLMs) showed a narrow distribution (PDI = 0.08–0.12) with average sizes ranging from 92.1 to 136.3 nm depending on the Gal contents. The release of PTX from Gal-CLMs while inhibited at physiological pH was enhanced under endosomal pH conditions. MTT assays in asialoglycoprotein receptor (ASGP-R) over-expressing HepG2 cells demonstrated that half-maximal inhibitory concentration (IC50) values of Gal-PTX-CLMs decreased from 11.7 to 2.9 to 1.1 μg/mL with increasing Gal contents from 10% to 20% to 30%, supporting receptor-mediated endocytosis mechanism. The in vivo biodistribution studies in human hepatoma SMMC-7721 tumor-bearing nude mice displayed that Gal20-PTX-CLMs resulted in significantly enhanced drug accumulation in the tumors over non-targeting PTX-CLM counterpart. In accordance, Gal20-PTX-CLMs caused much greater tumor growth inhibition than non-targeting PTX-CLMs as well as non-crosslinking Gal20-PTX-NCLM controls (average tumor volume: ca. 35 mm3versus 144 mm3 and 130 mm3, respectively). Histological analysis showed that Gal20-PTX-CLMs induced more extensive apoptosis of tumor cells while less damage to normal liver and kidney compared to Taxol. Ligand-installed photo-crosslinked pH-responsive degradable micelles have a great potential for targeted cancer chemotherapy.

Ligand-directed photo-crosslinked pH-sensitive degradable micelles simultaneously resolve dilemmas of stability versus intracellular drug release and stealth versus efficient internalization by target tumor cells, resulting in potent inhibition of tumor growth in vivo as well as alleviation of systemic side effects.Figure optionsDownload high-quality image (241 K)Download as PowerPoint slide