A Novel Nanoparticulate Formulation of Arsenic Trioxide with Enhanced Therapeutic Efficacy in a Murine Model of Breast Cancer

Abstract

Purpose: The clinical success of arsenic trioxide (As 2 O 3 ) in hematologic malignancies has not been replicated in solid tumors due to poor pharmacokinetics and dose-limiting toxicity. We have developed a novel nanoparticulate formulation of As 2 O 3 encapsulated in liposomal vesicles or "nanobins" [(NB(Ni, As)] to overcome these hurdles. We postulated that nanobin encapsulation of As 2 O 3 would improve its therapeutic index against clinically aggressive solid tumors, such as triple-negative breast carcinomas.Experimental Design: The cytotoxicity of NB(Ni,As), the empty nanobin, and free As 2 O 3 was evaluated against a panel of human breast cancer cell lines. The plasma pharmacokinetics of NB(Ni,As) and free As 2 O 3 were compared in rats to measure drug exposure. In addition, the antitumor activity of these agents was evaluated in an orthotopic model of human triple-negative breast cancer.Results: The NB(Ni,As) agent was much less cytotoxic in vitro than free As 2 O 3 against a panel of human breast cancer cell lines. In contrast, NB(Ni,As) dramatically potentiated the therapeutic efficacy of As 2 O 3 in vivo in an orthotopic model of triple-negative breast cancer. Reduced plasma clearance, enhanced tumor uptake, and induction of tumor cell apoptosis were observed for NB(Ni,As).Conclusions: Nanobin encapsulation of As 2 O 3 improves the pharmacokinetics and antitumor efficacy of this cytotoxic agent in vivo. Our findings demonstrate the therapeutic potential of this nanoscale agent and provide a foundation for future clinical studies in breast cancer and other solid tumors. Clin Cancer Res; 16(14); 3607-17. ©2010 AACR.Breast cancer is the second leading cause of cancer mortality for women in the United States (1). Although preventive agents and targeted therapies directed at the estrogen receptor, progesterone receptor, and human epidermal growth factor 2 receptor (HER2/neu) have resulted in improved clinical outcomes for many women with breast cancer, formidable challenges remain in treating tumors that do not express these molecular targets. These "triple-negative" breast carcinomas represent 15% of newly diagnosed breast cancer cases and often exhibit a basal epithelial or basal-like gene expression profile that is associated with poor survival (2-4). Consistent with its aggressive nature, triple-negative breast cancer is characterized by high rates of distant recurrence, particularly in the lung and brain, within the first five years after diagnosis despite adjuvant chemotherapy (5, 6). Hence, development of new therapeutic agents for these clinically intractable tumors is highly desirable.Arsenic trioxide (As 2 O 3 ) is a Food and Drug Administration-approved treatment for refractory acute promyelocytic leukemia (APL) and has shown preliminary activity in patients with relapsed/refractory multiple myeloma (7-10). Several mechanisms of action have been proposed for As 2 O 3 activity, including induction of apoptosis mediated by reactive oxygen species, promotion of cellular differentiation, and ...

Enhanced Metastasis Suppression by Targeting TRAIL Receptor 2 in a Murine Model of Triple-Negative Breast Cancer

“…Triple-negative MDA-MB-231-mCherry breast cancer cells (1 Â 10 6 ) in 100% Matrigel (BD Bioscience) were injected into the ducts of both 4th mammary glands of 4-to 5-week-old female athymic nu/nu mice (Harlan Laboratories) as described (33). To characterize the metastatic phenotype of this orthotopic model, mice were euthanized at 2-week intervals from 2 to 10 weeks after tumor inoculation (6-8 mice/time point).…”

Fangchinoline Inhibits Breast Tumor Proliferation and Induces Apoptosis in MDA-MB-231 Cell Line in Vivo

“…Previously, Choi HSC et al [4,5] reported that Fan has Anti-inflammatory effects. Zhang YH et al [8,9] also reported that Fan inhibited rat aortic vascular smooth muscle cell proliferation and cell cycle progression through inhibition of ERK1/2 activation and c-fos expression. However, this is the first report to demonstrate that Fan induced apoptosis in breast cancer xenograft and Fan could be consider as a potential drug for future breast tumor therapy.…”

“…Nerve growth factor has been used as a target in curing breast cancer in the form of anti-NGF antibodies or small interfering RNA against NGF displaying inhibition of tumor growth and metastasis [7]. Nanobin encapsulation of As 2 O 3 improves the pharmacokinetics and antitumor efficacy in breast cancer in vivo [8,9]. Based on the progress of anti-tumor therapeutics, we selected Fan, an efficient component of Stephaniae tetrandrine to test its potential effect on breast cancer.…”

Multidrug resistance protein 1 (ABCC1) confers resistance to arsenic compounds in human myeloid leukemic HL-60 cells

“…It has been shown that arsenic directly binds to PML-RARa fusion proteins and then induces its protein degradation, resulting in induced cell differentiation and apoptosis (Zhang et al 2010). Moreover, As 2 O 3 is also being newly applied for other forms of tumor and diseases for clinical treatment (Bobe et al 2006;Ahn et al 2010). However, little is known about the mechanisms underlying arsenic-induced anticancer effects in patients, because As 2 O 3 can be quickly transformed into mono-and dimethylated forms in human and animals after the injection (Vahter and Marafante 1983;Wang et al 2004;Drobna et al 2009).…”