期刊
JOURNAL OF CONTROLLED RELEASE
卷 193, 期 -, 页码 154-161出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2014.05.016
关键词
Degradable micelles; pH-sensitive; Crosslinked micelles; Hepatocellular carcinoma; Galactose
资金
- National Natural Science Foundation of China (NSFC) [51173126, 51273139, 51103093, 51273137, 51003070, 81261120557]
- National Science Fund for Distinguished Young Scholars (NSFC) [51225302]
- Jiangsu Specially-Appointed Professor Program, Ph.D. Programs Foundation of Ministry of Education of the People's Republic of China [20133201110005]
- Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions
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(epsilon-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 mu g/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 mm(3) versus 144 mm(3) and 130 mm(3), 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. (C) 2014 Elsevier B.V. All rights reserved.
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