The Use of Styrene Maleic Acid Nanomicelles Encapsulating the Synthetic Cannabinoid Analog WIN55,212-2 for the Treatment of Cancer (original) (raw)

2015, Anticancer Research

shown a promise as an anticancer agent but causes psychoactive side-effects. In the present study, nano-micelles of styrene maleic acid (SMA)-conjugated WIN were synthesized to reduce side-effects and increase drug efficacy. SMA-WIN micelles were characterised and their in vitro cytotoxic effect was compared to that of free WIN against triple-negative breast cancer (MDA-MB-231), hormone receptor-positive breast cancer (MCF-7) and castrationresistant prostate cancer (PC3) cell lines. SMA-WIN micelles were synthesised with a ~15% loading, 132.7 nm average diameter, -0.0388 mV charge, and pH-dependent release rate. A dose-dependent inhibition of cell growth was observed in all three cell lines treated with both free and micellar WIN, with both formulations demonstrating equal cytotoxicity. Cancer is among the leading causes of death worldwide. Breast cancer is the most common cancer in women, contributing to 25% of all cancers diagnosed in 2012 (1), while prostate cancer is the second most common cancer in men, accounting for 15% of cancer diagnosed in men in 2012 (2). Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer (3), and is associated with a younger age of disease onset, larger tumor size, increased lymph node positivity, high risk of metastasis, and decreased overall survival. This particular subtype of breast cancer lacks all three receptors [oestrogen (ER), progesterone (PR) and human epidermal growth factor 2 (Her2/neu)] exploited by currently available hormonal and targeted therapies (4). Similarly in the prostate, the androgen receptor mediates cell growth. Androgen-independent prostate cancer does not respond to androgen-deprivation therapy. Hence, chemotherapy remains the mainstay of treatment for these hormone-resistant cancer types (5). Traditional chemotherapeutic agents exert their anticancer effects via inhibiting the growth of rapidly dividing cells. The non-specific nature of these drugs means that they also affect the growth of normal rapidly-dividing cells, such as those found in the bone marrow and the gastrointestinal mucosa, resulting in side-effects such as myelosuppression, hair loss, nausea and vomiting (6). Therefore, a safer and more targeted approach for the treatment of TNBC is desperately needed. Cannabinoid is a term given to a class of chemical compounds that act on cannabinoid receptors and includes the endogenous cannabinoids anandamide and 2-arachidonyl glycerol (7). Cannabinoids potentially have anticancer effects in models of breast, prostate, and pancreatic cancer, glioma, and lymphoma (8-10). The broad efficacy of cannabinoids is paired with the observation that the cannabinoid receptors CB1 and CB2 show increased expression in some types of tumor cells when compared to normal tissue, implying a selectivity of the drug for these cancer types (9, 10). Although the medicinal use of cannabis and its associated compounds have been known since antiquity, its place in modern medicine has remained controversial, due in part to the psychoactive effects of cannabinoids, mediated by CB1 receptors found in the central nervous system (CNS) (11). The incorporation of cannabinoids into a micellar system is a strategy to improve drug solubility, and reduce CNS side-effects by increasing the drug diameter sufficiently such that it is unable to pass through the blood-brain barrier ( ) to act on central CB1 receptors.