A unique biomimetic drug-delivery system composed of 4T1-breast-cancer-cell membranes and paclitaxel-loaded polymeric nanoparticles (PPNs) (cell-membrane-coated PPNs), demonstrates superior interactions to its source tumor cells and elongated blood circulation, and displays highly cell-specific targeting of the homotypic primary tumor and metastases, with successful inhibition of the growth and lung metastasis of the breast cancer cells.

Chemical construction of molecularly organic-inorganic hybrid hollow mesoporous organosilica nanoparticles (HMONs) with silsesquioxane framework is expected to substantially improve their therapeutic performance and enhance the biological effects beneficial for biomedicine. In this work, we report on a simple, controllable, and versatile chemical homology principle to synthesize multiple-hybridized HMONs with varied functional organic groups homogeneously incorporated into the framework (up to quintuple hybridizations). As a paradigm, the hybridization of physiologically active thioether groups with triple distinctive disulfide bonds can endow HMONs with unique intrinsic reducing/acidic- and external high intensity focused ultrasound (HIFU)-responsive drug-releasing performances, improved biological effects (e.g., lowered hemolytic effect and improved histocompatibility), and enhanced ultrasonography behavior. The doxorubicin-loaded HMONs with concurrent thioether and phenylene hybridization exhibit drastically enhanced therapeutic efficiency against cancer growth and metastasis, as demonstrated both in vitro and in vivo.

OBJECTIVEWe have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms.RESEARCH DESIGN AND METHODSChanges in metabolic parameters and expression of genes and proteins involved in regulation of insulin sensitivity were analyzed in mice, human HepG2 cells, and mouse primary hepatocytes under leucine deprivation.RESULTSWe show that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control nonderepressible (GCN)2 and decreasing mammalian target of rapamycin/S6K1 signaling. In addition, we show that activation of AMP-activated protein kinase also contributes to leucine deprivation–increased hepatic insulin sensitivity. Finally, we show that leucine deprivation improves insulin sensitivity under insulin-resistant conditions.CONCLUSIONSThis study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation. Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity. These observations provide a rationale for short-term dietary restriction of leucine for the treatment of insulin resistance and associated metabolic diseases.