Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer (PaCa) is a fatal human cancer due to its exceptional resistance to all current anticancer therapies. The cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly overexpressed in PaCa and seems to play an important role in cancer resistance to anticancer treatment. The inhibition of HO-1 sensitized PaCa cells to chemo- and radiotherapy <it>in vitro</it>.</p> <p>Therefore, we investigated the effects of HO-1 and its metabolites biliverdin, carbon monoxide and iron on PaCa cells.</p> <p>PaCa cell lines with divergent HO-1 expression patterns were used in a murine orthotopic cancer model. HO-1 expression and activity was regulated by zinc (inhibition) and cobalt (induction) protoporphyrin. Furthermore, the influence of cellular HO-1 levels and its metabolites on effects of standard chemotherapy with gemcitabine was tested <it>in vivo </it>and <it>in vitro</it>.</p> <p>Results</p> <p>High HO-1 expression in PaCa cell lines was associated with increased chemoresistance <it>in vitro</it>. Chemoresistance to gemcitabine was increased during HO-1 induction in PaCa cells expressing low levels of HO-1. The inhibition of HO-1 activity in pancreatic tumors with high HO-1 boosted chemotherapeutic effects <it>in vivo </it>significantly. Furthermore, biliverdin and iron promoted PaCa resistance to chemotherapy. Consequently, specific iron chelation by desferrioxamine revealed profound anticancerous effects.</p> <p>Conclusion</p> <p>In summary, the inhibition of HO-1 and the chelation of iron in PaCa cells were associated with increased sensitivity and susceptibility of pancreatic tumors to chemotherapy <it>in vivo</it>. The metabolites biliverdin and iron seem to be involved in HO-1-mediated resistance to anticancer treatment. Therefore, HO-1 inhibition or direct interference with its metabolites may evolve new PaCa treatment strategies.</p

Shining light on polymeric drug nanocarriers with fluorescence correlation spectroscopy

The use of nanoparticles as carriers is an extremely promising way for administration of therapeutic agents, such as drug molecules, proteins, and nucleic acids. Such nanocarriers (NCs) can increase the solubility of hydrophobic compounds, protect their cargo from the environment, and if properly functionalized, deliver it to specific target cells and tissues. Polymer-based NCs are especially promising, because they offer high degree of versatility and tunability. However, in order to get a full advantage of this therapeutic approach and develop efficient delivery systems, a careful characterization of the NCs is needed. This review highlights the fluorescence correlation spectroscopy (FCS) technique as a powerful and versatile tool for NCs characterization at all stages of the drug delivery process. In particular, FCS can monitor and quantify the size of the NCs and the drug loading efficiency after preparation, the NCs stability and possible interactions with, e.g., plasma proteins in the blood stream and the kinetic of drug release in the cytoplasm of the target cells.Drug Delivery Technolog