Dennis Miller

• Ph.D.
• CPTxBio

BLZ-100 (tozuleristide) is an intraoperative fluorescent imaging agent that selectively detects malignant tissue and can be used in real time to guide tumor resection. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of BLZ-100 and to explore the pharmacodynamics of fluorescence imaging of skin tumors. In this...

TPS2575 Background: Tozuleristide (also known as BLZ-100 or Tumor Paint) is a fluorescent imaging drug designed to specifically label and accumulate in tumor tissue, thus enabling more precise surgical tumor resection intraoperatively. Tozuleristide achieves tumor targeting through the peptide portion of the molecule, a modified chlorotoxin peptide...

On-target, off-tissue toxicity limits the systemic use of drugs that would otherwise reduce symptoms or reverse the damage of arthritic diseases, leaving millions of patients in pain and with limited physical mobility. We identified cystine-dense peptides (CDPs) that rapidly accumulate in cartilage of the knees, ankles, hips, shoulders, and interve...

Background: Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate molecule for FGS of glioma and other tumor types. Objective: To perform a phase 1 dose-escalation st...

Context.—: Resection of breast carcinoma with adequate margins reduces the risk of local recurrence and reoperation. Tozuleristide (BLZ-100) is an investigational peptide-fluorophore agent that may aid in intraoperative tumor detection and margin assessment. In this study, fluorescence imaging was conducted ex vivo on gross breast pathology specim...

Maximal safe surgical resection is a critical component of pediatric brain tumor treatment. Tozuleristide (BLZ-100) is an investigational imaging agent given 1-36 hours prior to surgery to facilitate fluorescence-guided tumor resection. We evaluated one commercially available device (Fluobeam) and two investigational imaging devices in a pediatric...

INTRODUCTION: Maximal safe surgical resection is an essential component of pediatric brain tumor treatment. Intraoperative fluorescence guidance may enable better tumor visualization, leading to improved surgical outcomes. BLZ-100 is a near-infrared imaging agent consisting of a tumor-binding peptide, chlorotoxin, and the fluorescent molecule, indo...

BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclini...

Real time, fluorescence-guided resection (FGS) of brain cancer may improve extent of resection while minimizing brain injury. BLZ-100 is a near-infrared (NIR) imaging agent composed of the tumor-targeting peptide, chlorotoxin and the NIR fluorescent dye, indocyanine green. It has the potential to selectively label brain and other tumors. This Phase...

Complete initial resection can give cancer patients the best opportunity for long-term survival. There is unmet need in surgical oncology for optical imaging that enables simple and precise visualization of tumors and consistent contrast with surrounding normal tissues. Near-infrared (NIR) contrast agents and camera systems that can detect them rep...

BLZ-100 is an intraoperative, fluorescent near-infrared imaging agent designed to specifically label tumor tissue and enable more complete surgical resection. The chlorotoxin (CTX) peptide portion of BLZ-100 targets the tumor, and the coupled fluorescent dye, indocyanine green, provides the fluorescent signal. CTX has been shown to target brain can...

Chronic infection with hepatitis C virus (HCV) is estimated to affect approximately 3% of the world's population and cause 350,000 deaths each year. For a number of years, the standard of care has been combination therapy with recombinant alfa interferons—originally as native proteins but more recently as polyethyleneglycol-modified derivatives—and...

Interleukin-21 (IL-21), a pleiotropic immunostimulatory type I cytokine, has anticancer effects in animal models. Preclinical studies designed to assess the safety of recombinant human IL-21 (rIL-21) for use in phase I oncology studies are described. The rIL-21 (≤3.0 mg/kg per dose) was given intravenously to cynomolgus monkeys (Macaca fascicularis...

Type III lambda interferons (IFNs) have activity similar to type I IFNs, but a more restricted receptor distribution. A pegylated human IFN lambda-1 (pegIFNλ) is under development for chronic hepatitis C. Induction of receptor signaling (STAT1 phosphorylation) and expression of interferon-stimulated genes (ISGs) by pegIFNλ were assessed in, respect...

Interferon lambdas (IFN-lambda) are Type III interferons with biological activity, including induction of antiviral genes, similar to Type I IFNs, but signal through a distinct receptor complex. The expression pattern for the IFN-lambda receptor is more cell specific than the widely distributed IFN-alpha receptor, suggesting in vivo, IFN-lambda may...

Interferon alfacon-1 (Infergen®, CIFN, r-metIFN Con 1, hereunder interferon alfacon-1) is a type I interferon currently used to treat patients infected with the hepatitis C virus. In order to assess the embryotoxic and teratogenic effects of interferon alfacon-1, doses of 0, 1, 3 and 10 μg/kg/day were administered subcutaneously to pregnant rhesus...

Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15, yet possesses several biological properties distinct from these cytokines. IL-21 is produced mainly by activated CD4(+) T cells and natural killer T cells and mediates its activity by binding to the IL-21 receptor (IL-21R), consisting of an IL-21-specific...

Chemotherapy prolongs survival and improves quality of life (QOL) for good performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Targeted therapies may improve chemotherapy effectiveness without worsening toxicity. SGN-15 is an antibody-drug conjugate (ADC), consisting of a chimeric murine monoclonal antibody recognizin...

CD40 is a type I transmembrane protein that upon binding to CD40 ligand regulates important biologic effects in the immune system. CD40 is also highly expressed on hematologic tumors, which has raised interest in the potential for its use as a tumor target for antibody-based cancer therapy. SGN-40 is a humanized monoclonal antibody that selectively...

7039 Background: Docetaxel (Doc) remains the only FDA approved second line chemotherapy for NSCLC, but response rates and survival are low. Targeted therapies may hold more promise. NSCLC cells express a variety of tumor antigens, including the Lewis Y (Ley) antigen. SGN-15 is a novel antibody-drug conjugate that targets Ley, and delivers doxorubic...

Examination of the gastrointestinal (GI) tract has been performed for decades using barium sulfate. Although this agent has many recognized limitations including extreme radiopacity, poor intrinsic affinity for the GI mucosa, and very high density, no alternative contrast agents have emerged which produce comparable or better contrast visualization...

Examination of the gastrointestinal (GI) tract has been performed for decades using barium sulfate. Although this agent has many recognized limitations including extreme radiopacity, poor intrinsic affinity for the GI mucosa, and very high density, no alternative contrast agents have emerged which produce comparable or better contrast visualization...

Reduced porphyrins (hexahydroporphyrins, porphyrinogens) are readily oxidized in vitro by free radicals which are known to mediate oxidative stress in tissue cells. To determine if increased urinary porphyrin concentrations may reflect oxidative stress to the kidney in vivo, we measured the urinary porphyrin content of rats treated with mercury as...

Mercury exposure causes oxidative damage to the kidney, resulting in numerous biochemical changes, including the excretion of excess porphyrins in the urine (porphyrinuria). Hg(II)-induced porphyrinuria may occur, in part, by the previously reported oxidation of reduced porphyrins (porphyrinogens) by a GSH/Hg(II) complex and H2O2. To further elucid...

Studies were undertaken to investigate the principal actions underlying mercury-induced oxidative stress in the kidney. Mitochondria from kidneys of rats treated with HgCl2 (1.5 mg/kg i.p.) demonstrated a 2-fold increase in hydrogen peroxide (H2O2) formation for up to 6 hr following Hg(II) treatment using succinate as the electron transport chain s...

The effects of transition metals on nonenzymatic and ceruloplasmin catalyzed epinephrine oxidation were investigated by studying rates of epinephrine oxidation in purified buffers and in the presence of metal chelating agents. We found that epinephrine does not "autoxidize" in sodium chloride solutions prepared with deionized water that was further...

Xanthine oxidase and iron-dependent lipid peroxidation has been studied extensively in many model systems, yet several details of this process remain unclear. Because redox reactions of iron are important parameters of iron-catalyzed lipid peroxidation, we have examined the roles of superoxide and hydrogen peroxide, produced by xanthine oxidase, to...

The kinetics of iron binding by deferrioxamine B mesylate and the ramifications of this process upon iron-catalyzed lipid peroxidation were assessed. The relative rates of Fe(III) binding by deferrioxamine varied for the chelators tested as follows: ADP greater than AMP greater than citrate greater than histidine greater than EDTA. The addition of...

This study compared the effect of loading apoferritin either with ferrous ammonium sulfate in various buffers or with ceruloplasmin and chelated ferrous iron. It was shown that loading of apoferritin with ferrous ammonium sulfate was dependent on buffer and pH, and was directly related to the rate of iron autoxidation. The ceruloplasmin-dependent l...

Mercuric ion (Hg(II)) causes oxidative tissue damage in kidney cortical cells. We studied the in vitro effects of Hg(II) on hydrogen peroxide (H2O2) production by rat kidney mitochondria, a principal intracellular target of Hg(II). In mitochondria supplemented with a respiratory chain substrate (succinate or malate/glutamate) and an electron transp...

Mercuric ion, a well-known nephrotoxin, promotes oxidative tissue damage to kidney cells. One principal toxic action of Hg(II) is the disruption of mitochondrial functions, although the exact significance of this effect with regard to Hg(II) toxicity is poorly understood. In studies of the effects of Hg(II) on superoxide (O2-) and hydrogen peroxide...

Ceruloplasmin (CP) effectively inhibited superoxide and ferritin-dependent peroxidation of phospholipid liposomes, using xanthine oxidase or gamma irradiation of water as sources of superoxide. In addition, CP inhibited superoxide-dependent mobilization of iron from ferritin, suggesting that CP inhibited lipid peroxidation by decreasing the availab...

The copper binding tripeptide, glycyl-L-histidyl-L-lysine [GHK:Cu(II)] has a plethora of biological effects related to the wound healing process. The presence of iron complexes in damaged tissues is detrimental to wound healing, due to local inflammation, as well as microbial infection mediated by iron. To test if the wound healing properties of GH...

This chapter discusses iron redox reactions and lipid peroxidation. Iron-catalyzed lipid peroxidation has been studied in many in vitro model systems. While the mechanism of iron-catalyzed lipid peroxidation is not completely understood, it is well established that the redox chemistry of iron influences both the occurrence and the rate of lipid per...

Superoxide (O2-), hydrogen peroxide (H2O2), and hydroxyl radical (.OH) produced from the "autoxidation" of biomolecules, such as ascorbate, catecholamines, or thiols, have been implicated in numerous toxicities. However, the direct reaction of dioxygen with the vast majority of biomolecules, including those listed above, is spin forbidden, a condit...

We have previously observed that both Fe(II) and Fe(III) are required for lipid peroxidation to occur, with maximal rates of lipid peroxidation observed when the ratio of Fe(II) to Fe(III) is approximately one (J. R. Bucher et al. (1983) Biochem. Biophys. Res. Commun. 111, 777-784; G. Minotti and S. D. Aust (1987) J. Biol. Chem. 262, 1098-1104). Co...

The diabetogenic action of alloxan is believed to involve oxygen free radicals and iron. Incubation of glutathione (GSH) and alloxan with rat liver ferritin resulted in release of ferrous iron as assayed by spectrophotometric detection of ferrous-bathophenanthroline complex formation. Neither GSH nor alloxan alone mediated iron release from ferriti...

Ceruloplasmin (CP) was found to inhibit xanthine oxidase and ferritin-dependent peroxidation of phospholipid liposomes, as evidenced by decreased malondialdehyde formation. Ceruloplasmin was also shown to inhibit superoxide-mediated mobilization of iron from ferritin, in a concentration-dependent manner, as measured spectrophotometrically using the...

Certain chemical inducers of rat liver microsomal cytochrome P-450d are tightly bound to the cytochrome. We investigated the ability of two inducers of cytochrome P-450d, Aroclor 1254 and isosafrole, to inhibit the microsomal activation of 2-aminofluorene to a mutagen as measured in Salmonella typhimurium. Butanol treatment of microsomes from isosa...

Thesis (Ph. D.)--Utah State University. Dept. of Biochemistry, 1990. Includes bibliographical references (leaves 202-203).