A Nanoemulsion Formulation of Tamoxifen Increases Its Efficacy in a Breast Cancer Cell Line Jean-Bosco Tagne, †,‡ Srikanth Kakumanu, †,‡ Daniela Ortiz, § Thomas Shea, § and Robert J. Nicolosi* ,†,§ Center for Health and Disease Research, Biomedical Engineering/Biotechnology program, and Center for Cellular Neurobiology & Neurodegeneration Research, UniVersity of Massachusetts-Lowell, Lowell, Massachusetts 01854 Received July 6, 2007; Revised Manuscript Received September 18, 2007; Accepted November 25, 2007 Abstract: This paper reports on the preparation of a water-soluble nanoemulsion of the highly lipid-soluble drug tamoxifen (TAM). In addition, relative to a suspension of TAM, the nanoemulsion preparation demonstrated a greater  potential (increased negative charge) which has previously been associated with increasing drug/membrane permeability. This study also reports that relative to suspensions of TAM with particle sizes greater than 6000 nm, nanoemulsions of TAM, having mean particle sizes of 47 nm, inhibited cell proliferation 20-fold greater and increased cell apoptosis 4-fold greater in the HTB-20 breast cancer cell line. Thus, this work suggests that a nanoemulsion compared to a suspension preparation of TAM increases its anticancer properties relative to breast cancer. Keywords: Nano-emulsion; tamoxifen; breast cancer; cell proliferation; apoptosis Introduction Breast cancer is a malignant growth that begins in the tissues of the breast which over the course of a lifetime results in one in eight women being diagnosed with one of several types of breast cancer. For example, ductal carci- noma, which begins in the cells lining the ducts that bring milk to the nipple, accounts for more than 75% of breast cancers. Another breast cancer type, lobular carcinoma, begins in the milk-secreting glands of the breast but is otherwise similar in its behavior to ductal carcinoma. Alternatively, other varieties of breast cancer can arise from the skin, fat, connective tissues, and other cells present in the breast. Breast cancer is the most common nonskin cancer in women and the second most common cause of cancer- related deaths in U.S. women. An estimated 215 000 new breast cancer diagnoses and 40 000 breast cancer deaths occurred in 2004. Greater than 570 000 deaths were expected in the United States in 2005, with currently one in four deaths in the United States due to cancer 1 with an estimate of more than 1 000 000 new cases and 370 000 deaths annually worldwide. 2 Tamoxifen (TAM), a widely used lipid-soluble drug considered as first choice in chemotherapy and prevention of estrogen receptor-positive breast cancer, 3 inhibits prolif- eration and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression. 4 TAM is a nonsteroidal agent with potent antiestrogenic effects in animal and in vitro models. 5 The drug’s pharma- cologic properties are related to its ability to compete with estrogen for estrogen receptors in breast tissue and to inhibit the stimulatory effect of estrogen for tumor growth. However, * Corresponding author. Mailing address: 3 Solomont Way, Center for Health and Disease Research, University of Massachusetts- Lowell, Lowell, MA 01854. Tel: 978-934-4501. Fax: 978- 934-2034. E mail: robert_nicolosi@uml.edu. † Center for Health and Disease Research. ‡ Biomedical Engineering/Biotechnology program. § Center for Cellular Neurobiology & Neurodegeneration Research. (1) Jemal, A.; et al. Cancer statistics, 2005. CA Cancer J. Clin. 2005, 55 (1), 10–30. (2) Guarneri, V.; Conte, P. F. The curability of breast cancer and the treatment of advanced disease. Eur. J. Nucl. Med. Mol. Imaging 2004, 31 (1), S149–61. (3) Murphy, M. J., Jr. Molecular Action and Clinical Relevance of Aromatase Inhibitors. Oncologist 1998, 3 (2), 129–130. (4) Kallio, A. Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells. Apoptosis 2005, 10 (6), 1395–410. articles 280 MOLECULAR PHARMACEUTICS VOL. 5, NO. 2, 280–286 10.1021/mp700091j CCC: $40.75  2008 American Chemical Society Published on Web 01/03/2008