期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 104, 期 6, 页码 2018-2028出版社
WILEY-BLACKWELL
DOI: 10.1002/jps.24438
关键词
prodrugs; cancer chemotherapy; targeted drug delivery; peptide delivery; polymeric drugs
资金
- National Natural Science Foundation of China [81102397]
- Natural Science Foundation of Jiangsu Province [BK2012761]
- Qing Lan Project of Jiangsu Province [02432009]
- Fostering Plan of University Scientific and Technological Innovation Team of Jiangsu Qing Lan Project
- Innovative Project for Graduate Cultivation of Jiangsu Province [CXZZ11-0807]
- State Key Laboratory of Natural Medicines, China Pharmaceutical University [JKGQ201107, JKPZ2013004]
- Key New Drug Innovation Project from the Ministry of Science and Technology of China [2009ZX09310004]
- National Basic Research Program of China (973 Program) [2009CB903300]
In this study, a novel PTX prodrug, octreotide(Phe)-polyethene glycol-paclitaxel [OCT(Phe)-PEG-PTX], was successfully synthesized and used for targeted cancer therapy. A nontargeting conjugate, mPEG-PTX, was also synthesized and used as a control. Chemical structures of OCT(Phe)-PEG-PTX and mPEG-PTX were confirmed using H-1 nuclear magnetic resonance and circular dichroism. The drug contents in both the conjugates were 12.0% and 14.0%, respectively. Compared with the parent drug (PTX), OCT(Phe)-PEG-PTX, and mPEG-PTX prodrugs showed a 20,000- and 30,000-fold increase in water solubility, respectively. PTX release from mPEG-PTX and OCT(Phe)-PEG-PTX exhibited a pH-dependent profile. Moreover, compared with mPEG-PTX, OCT(Phe)-PEG-PTX exhibited significantly stronger cytotoxicity against NCI-H446 cells (SSTR overexpression) but comparable cytotoxicity against WI-38 cells (no SSTR expression). Results of confocal laser scanning microscopy revealed that the targeting prodrug labeled with fluorescence probe was selectively taken into tumor cells via SSTR-mediated endocytosis. In vivo investigation of prodrugs in nude mice bearing NCI-H446 cancer xenografts confirmed that OCT(Phe)-PEG-PTX prodrug exhibited stronger antitumor efficacy and lower systemic toxicity than mPEG-PTX and commercial Taxol. These results suggested that OCT(Phe)-PEG-PTX is a promising anticancer drug delivery system for targeted cancer therapy. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2018-2028, 2015
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