TY - JOUR
T1 - A novel nanoparticulate formulation of arsenic trioxide with enhanced therapeutic efficacy in a murine model of breast cancer
AU - Ahn, Richard W.
AU - Chen, Feng
AU - Chen, Haimei
AU - Stern, Stephan T.
AU - Clogston, Jeffrey D.
AU - Patri, Anil K.
AU - Raja, Meera R.
AU - Swindell, Elden P.
AU - Parimi, Vamsi
AU - Cryns, Vincent L.
AU - O'Halloran, Thomas V.
PY - 2010/7/15
Y1 - 2010/7/15
N2 - Purpose: The clinical success of arsenic trioxide (As2O 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 As2O3 encapsulated in liposomal vesicles or "nanobins" [(NB(Ni, As)] to overcome these hurdles. We postulated that nanobin encapsulation of As 2O3 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 As2O3 was evaluated against a panel of human breast cancer cell lines. The plasma pharmacokinetics of NB(Ni,As) and free As 2O3 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 As2O3 against a panel of human breast cancer cell lines. In contrast, NB(Ni,As) dramatically potentiated the therapeutic efficacy of As2O3 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 As2O3 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.
AB - Purpose: The clinical success of arsenic trioxide (As2O 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 As2O3 encapsulated in liposomal vesicles or "nanobins" [(NB(Ni, As)] to overcome these hurdles. We postulated that nanobin encapsulation of As 2O3 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 As2O3 was evaluated against a panel of human breast cancer cell lines. The plasma pharmacokinetics of NB(Ni,As) and free As 2O3 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 As2O3 against a panel of human breast cancer cell lines. In contrast, NB(Ni,As) dramatically potentiated the therapeutic efficacy of As2O3 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 As2O3 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.
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U2 - 10.1158/1078-0432.CCR-10-0068
DO - 10.1158/1078-0432.CCR-10-0068
M3 - Article
C2 - 20519360
AN - SCOPUS:77954735171
SN - 1078-0432
VL - 16
SP - 3607
EP - 3617
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -