Journal of Pharmaceutical Sciences 2015-06-01

Somatostatin receptor-mediated specific delivery of paclitaxel prodrugs for efficient cancer therapy.

Meirong Huo, Qinnv Zhu, Qu Wu, Tingjie Yin, Lei Wang, Lifang Yin, Jianping Zhou

Index: J. Pharm. Sci. 104 , 2018-28, (2015)

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Abstract

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 (1) H 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.© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.