Somatostatin Receptor-Mediated Specific Delivery of Paclitaxel Prodrugs for Efficient Cancer Therapy.

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, m PEG- PTX, was also synthesized and used as a control. Chemical structures of OCT( Phe)- PEG- PTX and m PEG- 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 m PEG- PTX prodrugs showed a 20,000- and 30,000-fold increase in water solubility, respectively. PTX release from m PEG- PTX and OCT( Phe)- PEG- PTX exhibited a p H-dependent profile. Moreover, compared with m PEG- 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 m PEG- 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 J Pharm Sci 104:2018-2028, 2015 [ABSTRACT FROM AUTHOR]