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

Abstract

<div>Abstract<p><b>Purpose:</b> The clinical success of arsenic trioxide (As<sub>2</sub>O<sub>3</sub>) 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<sub>2</sub>O<sub>3</sub> encapsulated in liposomal vesicles or “nanobins” [(NB(Ni,As)] to overcome these hurdles. We postulated that nanobin encapsulation of As<sub>2</sub>O<sub>3</sub> would improve its therapeutic index against clinically aggressive solid tumors, such as triple-negative breast carcinomas.</p><p><b>Experimental Design:</b> The cytotoxicity of NB(Ni,As), the empty nanobin, and free As<sub>2</sub>O<sub>3</sub> was evaluated against a panel of human breast cancer cell lines. The plasma pharmacokinetics of NB(Ni,As) and free As<sub>2</sub>O<sub>3</sub> 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.</p><p><b>Results:</b> The NB(Ni,As) agent was much less cytotoxic <i>in vitro</i> than free As<sub>2</sub>O<sub>3</sub> against a panel of human breast cancer cell lines. In contrast, NB(Ni,As) dramatically potentiated the therapeutic efficacy of As<sub>2</sub>O<sub>3</sub> <i>in vivo</i> 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).</p><p><b>Conclusions:</b> Nanobin encapsulation of As<sub>2</sub>O<sub>3</sub> improves the pharmacokinetics and antitumor efficacy of this cytotoxic agent <i>in vivo</i>. 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.</p></div>