In last few hours of maturation, the mouse oocyte takes up over twenty billion zinc atoms and arrests after the first meiotic division, until fertilization or pharmacological intervention stimulates cell cycle progression towards a new embryo. Using chemical and physical probes, we show that fertilization of the mature, zinc-enriched egg triggers the ejection of zinc into the extracellular milieu in a series of coordinated events termed zinc sparks. These events immediately follow the well-established series of calcium oscillations within the activated egg and are evolutionarily conserved in several mammalian species, including rodents and non-human primates. Functionally, the zinc sparks mediate a decrease in intracellular zinc content that is necessary for continued cell cycle progression, as increasing zinc levels within the activated egg results in the reestablishment of cell cycle arrest at metaphase. The mammalian egg thus uses a zinc-dependent switch mechanism to toggle between metaphase arrest and resumption of the meiotic cell cycle at the initiation of embryonic development.

Arsenic trioxide (As2O3) is a frontline drug for treatment of acute promyelocytic leukemia and is in clinical trials for treatment of other malignancies, including multiple myeloma; however, efforts to expand clinical utility to solid tumors have been limited by toxicity. Nanoparticulate forms of As2O3 encapsulated in 100-nm-scale, folate-targeted liposomes have been developed to lower systematic toxicity and provide a platform for targeting this agent. The resultant arsenic “nanobins” are stable under physiologic conditions but undergo triggered drug release when the pH is lowered to endosomal/lysosomal levels. Cellular uptake and antitumor efficacy of these arsenic liposomes have been evaluated in folate receptor (FR)–positive human nasopharyngeal (KB) and cervix (HeLa) cells, as well as FR-negative human breast (MCF-7) tumor cells through confocal microscopy, inductively coupled plasma mass spectroscopy, and cytotoxicity studies. Uptake of folate-targeted liposomal arsenic by KB cells was three to six times higher than that of free As2O3 or nontargeted liposomal arsenic; the enhanced uptake occurs through folate-mediated endocytosis, leading to a 28-fold increase in cytotoxicity. In contrast, tumor cells with lower FR density on the surface (HeLa and MCF-7) showed much less uptake of the folate-targeted drug and lower efficacy. In cocultures of KB and MCF-7 cells, the folate-targeted arsenic liposomes were exclusively internalized by KB cells, showing high targeting specificity. Our studies further indicate that folate-targeted delivery of As2O3 with coencapsulated nickel(II) ions (as a nontoxic adjuvant) potentiates the As2O3 efficacy in relatively insensitive solid tumor–derived cells and holds the promise of improving drug therapeutic index.

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 ...

VNC images derived from novel dual layer spectral detector CT demonstrate attenuation values similar to unenhanced images in all tissues evaluated except for subcutaneous fat. Further study is needed to determine if attenuation thresholds currently used clinically for common pathology should be adjusted, particularly for lesions containing fat.