期刊
INTERNATIONAL JOURNAL OF PHARMACEUTICS
卷 502, 期 1-2, 页码 98-106出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2016.02.024
关键词
Cardiac glycosides; Periplogenin; Octreotide; Target delivery; Octreotide-periplogenin conjugate
资金
- National Natural Science Foundation of China [30973677, 81373371]
- Doctoral Fund of Ministry of Education of China [20113227110012]
- Jiangsu Planned Projects for Postdoctoral Research Funds [1401023B]
- Postdoctoral Science Foundation Funded Project fo china [2014M560410]
- Special Fund for 333 project
- Special Fund for 331 project [BRA2013198]
- Industry-University-Research Institution Cooperation in Jiangsu province [JHB2012-37, GY2012049, GY2013055]
- Program for Scientific research innovation team in Colleges and Universities of Jiangsu Province
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Industry-University-Research Institution Cooperation in Zhenjiang [JHB2012-37, GY2012049, GY2013055]
Periplogenin (PPG), a cardiac glycoside prepared from Cortex periplocae, with similar structure to bufalin, has been found to induce apoptosis in many tumor cells. However, lots of cardiac glycosides possessing strong antitumor activity in vitro have still not passed phase I clinical trials, mostly due to poor tumor selectivity and systemic toxicity. To overcome this drawback, we designed octreotide-periplogenin (OCT-PPG) conjugate by coupling PPG-succinate to the amino-terminal end of octreotide. In comparison with free PPG, the conjugate exhibited significantly stronger cytotoxicity on HepG2 cells (SSTRs overexpression) but much less toxicity in L-02 cells. After intravenous injection of OCT-PPG conjugate into H-22 tumor-bearing mice, its total accumulation in tumor was 2.3 fold higher than that of free PPG, but was 0.71- and 0.84-fold lower in heart and liver, respectively, suggesting somatostatin-mediated target delivery of PPG into the tumor tissue and reduced distribution in heart and liver. In vivo studies using H-22 tumor model in mice confirmed the remarkable therapeutic effect of this conjugate. These results suggested that OCT-PPG conjugate could provide a new approach for clinical application of cardiac glycosides and as a targeting agent for cancer therapy. (C) 2016 Elsevier B.V. All rights reserved.
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