Browsing by Subject "Epidermal growth factor receptor"
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Item Involvement of epidermal growth factor receptor (EGFR) signaling in estrogen inhibition of oocyte maturation mediated through G protein-coupled estrogen receptor 1 (GPER) in zebrafish (Danio rerio)(2010-05) Peyton, Candace Ann; Thomas, P. (Peter); Holt, Joan; Erdner, DeanaOocyte maturation (OM) in teleosts is under precise hormonal control by estrogens and progestins. We show here that estrogens activate an epidermal growth factor receptor (EGFR) signaling pathway through the G protein-coupled estrogen receptor (GPER) to maintain meiotic arrest of full-grown zebrafish (Danio rerio) oocytes in an in vitro germinal vesicle breakdown (GVBD) bioassay. A GPER- specific agonist decreased OM and a GPER-specific antagonist increased spontaneous OM, whereas specific nuclear estrogen receptor (ERα and ERβ) agonists did not affect OM, which suggests the inhibitory action of estrogens on OM are solely mediated through GPER. Furthermore, a peptide-bound estrogen, which cannot enter the oocyte, decreased GVBD, showing that these estrogen actions are mediated through a membrane receptor. Treatment of oocytes with actinomycin D, a transcription inhibitor, did not block the inhibitory effects of estrogens on OM, indicating that estrogens act via a nongenomic mechanism to maintain oocyte meiotic arrest. EGFR mRNA was detected in denuded zebrafish oocytes by reverse transcription polymerase chain reaction (RT-PCR). Therefore, the potential role of transactivation of EGFR in estrogen inhibition of OM was investigated. The matrix metalloproteinase inhibitor, ilomastat, which prevents the release of heparin-bound epidermal growth factor (HB-EGF), increased spontaneous OM. Moreover, specific EGFR1 (ErbB1) inhibitors and inhibitors of extracellular-related kinase 1 and 2 (ERK1/2) increased spontaneous OM. Previously, estrogens have been shown to increase 3’-5’-cyclic adenosine mono phosphate (cAMP) levels through GPER in zebrafish oocytes during meiotic arrest. Taken together these present results suggest that estrogens also act through GPER to maintain meiotic arrest through a second signaling pathway involving transactivation of EGFR and activation of ERK 1 and 2.Item Molecular specific photoacoustic imaging using plasmonic gold nanoparticles(2009-12) Mallidi, Srivalleesha; Emelianov, Stanislav Y.Cancer has become one of the leading causes of death today. The early detection of cancer may lead to desired therapeutic management of cancer and to decrease the mortality rate through effective therapeutic strategies. Advances in materials science have enabled the use of nanoparticles for added contrast in various imaging techniques. More recently there has been much interest in the use of gold nanoparticles as optical contrast agents because of their strong absorption and scattering properties at visible and near-infrared wavelengths. Highly proliferative cancer cells overexpress molecular markers such as epidermal growth factor receptor (EGFR). When specifically targeted gold nanoparticles bind to EGFR they tend to cluster thus leading to an optical red-shift of the plasmon resonances and an increase in absorption in the red region. These changes in optical properties provide the foundation for photoacoustic imaging technique to differentiate cancer cells from surrounding benign cells. In photoacoustic imaging, contrast mechanism is based on the optical absorption properties of the tissue constituents. Studies were performed on tissue phantoms, ex-vivo and in-vivo tumor models to evaluate molecular specific photoacoustic imaging technique. The results indicate that highly sensitive and selective detection of cancer cells can be achieved by utilizing the plasmon resonance coupling effect of EGFR targeted gold nanoparticles and photoacoustic imaging. In conclusion, the combined ultrasound and photoacoustic imaging technique has the ability to image molecular signature of cancer using bioconjugated gold nanoparticles.Item Targeted nanoparticle formulation for a poorly water soluble Gemcitabine derivative and its in vivo and in vitro anti-tumor activity(2012-08) Sandoval, Michael Anthony; Cui, Zhengrong; Williams, Robert O; Walkow, Janet CCancer is a collection of over one hundred different types of diseases and is responsible for the leading cause of death in the United States. More strikingly, cancer mortality rates have remained relatively unchanged for the past several decades, indicating significant clinical demand for improved cancer therapy. Gemcitabine, known clinically as Gemzar®, is used to treat a variety of human cancers, however, clinical efficacy is modest due to it’s brief blood circulation, rapid clearance, manifestation of tumor-drug resistance, and lack of drug specificity. This thesis sought to develop a solid lipid nanoparticle-based platform to passively and actively target a gemcitabine lipophilic derivative, 4-(N)-stearoyl gemcitabine, into tumor cells over-expressing epidermal growth factor receptor (EGFR) after intravenous injection. Considering gemcitabine is hydrophilic and the core of the nanoparticle is solid (hydrophobic), we lipophilized gemcitabine by conjugating a stearoyl group to its N-terminus to form 4-(N)-stearoyl gemcitabine. Second, we incorporated stearoyl gemcitabine into lecithin-based nanoparticles. The nanoparticle formulation was prepared from lecithin/glyceryl monostearate-in-water emulsions. Third, we grafted the gemcitabine nanoparticles with polyethylene glycol chains with reactive end groups that are capable of conjugating with a targeting moiety on the surface to actively target tumors that over-express EGFR. Taken together, the overall objective of the research presented in this thesis is to develop, characterize, and evaluate the anti-tumor performance in vitro as well as in mice against both human and mouse tumor models.