Journal
JOURNAL OF CONTROLLED RELEASE
Volume 149, Issue 3, Pages 299-306Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2010.10.027
Keywords
Targeted polymeric micelles; Doxorubicin; Combretastatin A4; Combination tumor therapy; Antivascular therapy
Funding
- The National Basic Research Program of China (973 Program) [2009CB930300]
- National Natural Science Foundation of China [30772666]
- National High-Tech R&D Program (863 Program) [2007AA021811]
- Ministry of Education
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The purpose of this study was to develop a targeted combinatorial polymeric micelle system that can sequentially kill tumor vasculature and tumor cells and increase the anticancer efficacy. Toward this goal, alpha v beta 3 integrin-targeting peptide (RGD) functionalized polymeric micelles (RFPMs) based on the use of poly (ethylene glycol)-b-poly(d.1-lactide) (PEG-PLA) was developed. Doxorubicin was conjugated to the biodegradable PEG-PLA micelle core, and combretastatin A4 was physically encapsulated into micelles (RFPMs-DOX-CA4). The RFPM5-DOX-CA4 has a particle size of 29.2 +/- 2.5 nm with spherical shape and high encapsulation efficiency for both drugs (> 95%). The micelles exhibited sequential release kinetics for both drugs. Treatment with RFPM5-DOX-CA4 resulted in the sequential killing of endothelial cells and tumor cells in vitro. RFPMs displayed prolonged circulation time and more drug accumulation in solid tumor than unfunctionalized polymeric micelles (UFPMs). In B16-F10 tumor-bearing mice, RFPMs-DOX-CA4 showed stronger tumor growth inhibition and significantly higher survival rate compared with the other treatment groups. Treatment with RFPMs-DOX-CA4 caused a dramatic destruction of tumor vasculature and reduction of tumor cell proliferation in vivo. These results suggested that the integrated strategy can be exploited as a potential treatment modality for cancer. (C) 2010 Elsevier B.V. All rights reserved.
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