Fabrication of a Dual-Targeted Liposome-Coated Mesoporous Silica Core-Shell Nanoassembly for Targeted Cancer Therapy.

Nanoparticles have been suggested as drug-delivery systems for chemotherapeutic drugs to allow for controlled drug release profiles and selectivity to target cancer cells. In addition, nanoparticles can be used for the in situ generation and amplification of reactive oxygen species (ROS), which have been shown to be a promising strategy for cancer treatment. Thus, a targeted nanoscale drug-delivery platform could be used to synergistically improve cancer treatment by the action of chemotherapeutic drugs and ROS generation. Herein, we propose a promising chemotherapy strategy where the drug-loaded nanoparticles generate high doses of ROS together with the loaded ROS-generating chemotherapeutic drugs, which can damage the mitochondria and activate cell death, potentiating the therapeutic outcome in cancer therapy. In the present study, we have developed a dual-targeted drug-delivery nanoassembly consisting of a mesoporous silica core loaded with the chemotherapeutic, ROS-generating drug, paclitaxel (Px), and coated with a liposome layer for controlled drug release. Two different lung cancer-targeting ligands, folic acid and peptide GE11, were used to target the overexpressed nonsmall lung cancer receptors to create the final nanoassembly (MSN@Px) L-GF. Upon endocytosis by the cancer cells, the liposome layer was degraded by the intracellular lipases, and the drug was rapidly released at a rate of 65% within the first 20 h. In vitro studies confirmed that this nanoassembly was 8-fold more effective in cancer therapy compared to the free drug Px.

Dual Targeted Delivery of Liposomal Hybrid Gold Nano-Assembly for Enhanced Photothermal Therapy against Lung Carcinomas.

The delivery and accumulation of therapeutic drugs into cancer cells without affecting healthy cells are a major challenge for antitumor therapy. Here, we report the synthesis of a liposomal hybrid gold nano-assembly with enhanced photothermal activity for lung cancer treatment. The core components of the nano-assembly include gold nanorods coated with a mesoporous silica shell that offers an excellent drug-loading surface for encapsulation of doxorubicin. To enhance the photothermal capacity of nano-assembly, IR 780 dye was loaded inside a thermo-sensitive liposome, and then, the core nano-assembly was wrapped within the liposome, and GE-11 peptide and folic acid were conjugated onto the surface of the liposome to give the final nano-assembly [(GM@Dox) LI]-PF. The dual targeting approach of [(GM@Dox) LI]-PF leads to enhanced cellular uptake and improves the accumulation of nano-assemblies in cancer cells that overexpress the epidermal growth factor receptor and folate. The exposure of near-infrared laser irradiation can trigger photothermal-induced structural disruption of the nano-assembly, which allows for the precise and controllable release of Dox at targeted sites. Additionally, chemo-photothermal therapy was shown to be 11 times more effective in cancer cell treatment when compared to Dox alone. Our systematic study suggests that the nano-assemblies facilitate the cancer cells undergoing apoptosis via an intrinsic mitochondrial pathway that can be directly triggered by the chemo-photothermal treatment. This study offers an appealing candidate that holds great promise for synergistic cancer treatment.

Young adult male LEW.1WR1 rats have reduced beta cell area and develop glucose intolerance.

Prediabetes affects 1 in 3 American adults and is characterized by insulin resistance, insulin hypersecretion, and impaired glucose tolerance. Weanling LEW.1WR1 (1WR1) rats have increased blood insulin concentrations, so we hypothesized that young adult 1WR1 rats would develop impaired glucose tolerance due to the poor regulation of insulin. We monitored glucose tolerance, insulin tolerance, and weight gain for 10 weeks to assess if there was a decline in glucose processing over time. 1WR1 rats were significantly more glucose intolerant after 8 weeks. 1WR1 rats had increased body mass, yet abdominal fat mass was not significantly increased. Although the 1WR1 rats had increased circulating insulin and glucagon protein levels, 1WR1 rat beta cell area was significantly reduced. There may be underlying insulin resistance as evidenced by dysfunctional insulin regulation during fasting. Understanding the metabolic phenotype of this rat model can provide insight into the human pathophysiological changes that increase susceptibility to glucose intolerance and prediabetes.

The case for FAT10 as a novel target in fatty liver diseases.

Human leukocyte antigen F locus adjacent transcript 10 (FAT10) is a ubiquitin-like protein that targets proteins for degradation. TNFα and IFNγ upregulate FAT10, which increases susceptibility to inflammation-driven diseases like nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). It is well established that inflammation contributes to fatty liver disease, but how inflammation contributes to upregulation and what genes are involved is still poorly understood. New evidence shows that FAT10 plays a role in mitophagy, autophagy, insulin signaling, insulin resistance, and inflammation which may be directly associated with fatty liver disease development. This review will summarize the current literature regarding FAT10 role in developing liver diseases and potential therapeutic targets for nonalcoholic/alcoholic fatty liver disease and hepatocellular carcinoma.

Metabolite quantification: A fluorescence-based method for urine sample normalization prior to 1H-NMR analysis.

INTRODUCTION: Metabolomics is a multi-discipline approach to systems biology that provides a snapshot of the metabolic status of a cell, tissue, or organism. Metabolomics uses mass spectroscopy (MS) and nuclear magnetic resonance (NMR) to analyze biological samples for low molecular weight metabolites. OBJECTIVE: Normalize urine sample pre-acquisition to perform a targeted quantitative analysis of selected metabolites in rat urine. METHODS: Urine samples were provided from rats on a control diet (n = 10) and moderate sucrose diet (n = 8) collected in a metabolic cage during an eight hour fast. Urine from each sample was prepared by two different methods. One sample was a non-normalized sample of 1200 µL and the second sample was a variable volume-normalized to the concentration of urobilin in a standard sample of urine. The urobilin concentration in all samples was determined by fluorescence. Ten metabolites for each non-normalized and normalized urine sample were quantified by integration to an internal standard of DSS. RESULTS: Both groups showed an improvement in pH range going from non-normalized to normalized samples. In the group on the control diet, eight metabolites had significant improvement in range, while the remaining two metabolites had insignificant improvement in range comparing the non-normalized sample to the normalized sample. In the group on the moderate sucrose diet all ten metabolites showed significant improvement in range going from non-normalized to normalized samples. CONCLUSIONS: These findings describe a pre-acquisition method of urine normalization to adjust for differences in hydration state of each organism. This results in a narrower concentration range in a targeted analysis.