Micelles of poly(ethylene oxide)-b-poly(e-caprolactone) as vehicles for the solubilization, stabilization, and controlled delivery of curcumin Zengshuan Ma, 1 Azita Haddadi, 1 Ommoleila Molavi, 1 Afsaneh Lavasanifar, 1 Raymond Lai, 2 John Samuel 1y 1 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8 2 Department of Laboratory Medicine and Pathology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2B7 Received 20 December 2006; revised 11 April 2007; accepted 30 May 2007 Published online 23 October 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.31584 Abstract: Curcumin is recognized as a potential chemo- therapeutic agent against a variety of tumors. However, the clinical application of curcumin is hindered due to its poor water solubility and fast degradation. The objective of this study was to investigate amphiphilic block copoly- mer micelles of poly(ethylene oxide)-b-poly(e-caprolactone) (PEO-PCL) as vehicles for the solubilization, stabilization, and controlled delivery of curcumin. Curcumin-loaded PEO-PCL micelles were prepared by a cosolvent evapora- tion technique. PEO-PCL micelles were able to solubilize curcumin effectively, protect the encapsulated curcumin from hydrolytical degradation in physiological matrix, and control the release of curcumin over a few days. The char- acteristics of resultant micelles were found to depend on the polymerization degrees of e-caprolactone. Among dif- ferent PEO-PCL micelles, PEO 5000 -PCL 24500 was the most efficient in solubilizing curcumin while PEO 5000 -PCL 13000 was the best carrier in reducing its release rate. PEO-PCL micelle-encapsulated curcumin retained its cytotoxicity in B16-F10, a mouse melanoma cell line, and SP-53, Mino, and JeKo-1 human mantle cell lymphoma cell lines. These results demonstrated the potential of PEO-PCL micelles as an injectable formulation for efficient solubilization, stabili- zation, and controlled delivery of curcumin. Ó 2007 Wiley Periodicals, Inc. J Biomed Mater Res 86A: 300–310, 2008 Key words: curcumin; poly(ethylene oxide)-b-poly(e-capro- lactone); polymeric micelle; solubility; controlled release INTRODUCTION Curcumin is a polyphenol derived from the root of turmeric (Curcuma longa L., Zingeberaceae), which has been extensively used in south and southeast tropical Asia as a dietary spice, a source of coloring agent, and a treatment for a wide variety of ailments including biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusi- tis. 1 Recent studies show that curcumin, either alone or in combination with other anticancer agents, has potent anticancer effects. This was evidenced by its inhibitory effects on the growth of a number of tumor cell lines in vitro and in vivo, including mela- noma, mantle cell lymphoma (MCL), hepatic, prostatic, ovarian, and pancreatic carcinomas. 2–7 Curcumin has been reported to have diverse effects on signaling mol- ecules, such as downregulation of the expression of angiogenesis-associated genes, 4 activation of the apo- ptotic mechanisms, 5 and induction of the cell cycle arrest. 6 Importantly, curcumin is a potent inhibitor of nuclear factor-kappaB (NF-jB) signaling pathway. 3,5 NF-jB is a sequence-specific transcription factor regu- lating the expression of a variety of proteins that in- hibit apoptosis and promote cell proliferation and migration. A number of studies have established a causal link between constitutive activation of NF-jB and carcinogenesis of liver, colon, lung, leukemia, and prostate tumors. 8,9 In addition, upregulation of NF-jB is a major reason for failure of chemotherapy with a number of drugs and an important reason for metasta- sis. 10,11 Chemopreventive agents suppressing NF-jB will sensitize tumor cells to chemotherapies. Curcumin has been reported to augment chemotherapeutic responses of cancer cells to a variety of antitumor { Deceased Correspondence to: A. Lavasanifar; e-mail: alavasanifar@ pharmacy.ualberta.ca Contract grant sponsor: Natural Sciences and Engineer- ing Research Council of Canada; contract grant numbers: STPGP 336986, G121210926, and G121220086 Contract grant sponsor: Canadian Institute of Health Research; contract grant number: MOP 42407 ' 2007 Wiley Periodicals, Inc.