duramycin and Neoplasms

Phosphatidylethanolamine (PE) is one of the most abundant phospholipids in mammalian plasma membranes. In healthy cells, PE resides predominantly in the inner leaflet of the cell membrane. In dead or dying cells on the other hand, PE is externalized to the outer leaflet of the plasma membrane. The exposure of PE on the cell surface has therefore become an attractive target for the molecular imaging of cell death using single-photon emission computed tomography (SPECT) and positron emission tomography (PET). This has motivated the development of PE-specific probes to measure cell death in vitro and non-invasively in vivo. In this review, we highlight the biological roles of PE on cell membranes, and PE exposure as a biomarker of cell death in disease processes, along with the use of PE-binding molecular probes to target PE for the characterization of cell death on a cellular and tissue level. We specifically emphasize the preclinical applications of radiolabeled duramycin for the non-invasive imaging of cell death in animal models of disease and in tumors after therapy. In addition, we discuss the clinical relevance, limitations and future perspectives of this imaging approach of cell death.

Topics: Animals; Apoptosis; Bacteriocins; Biomarkers; Cell Membrane; Disease Models, Animal; Humans; Mice; Molecular Imaging; Neoplasms; Peptides; Phosphatidylethanolamines; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon

Evaluation of [. Tracer specificity of Ga-68 labeled NODAGA-duramycin was determined in vitro using competitive binding experiments. Organ uptake was analyzed in untreated and doxorubicin, busulfan, and cisplatin-treated mice 2 h after intravenous injection of [

Topics: Acetates; Animals; Antineoplastic Combined Chemotherapy Protocols; Bacteriocins; Busulfan; Cisplatin; Doxorubicin; Female; Gallium Radioisotopes; Heterocyclic Compounds, 1-Ring; Kidney; Liver; Mice; Mice, Inbred BALB C; Neoplasms; Peptides; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals; Tissue Distribution

We have previously shown that oxidative stress within the tumor microenvironment causes phosphatidylserine (PS) to redistribute from the inner to the outer membrane leaflet of the endothelial cells (EC) creating a highly specific marker for the tumor vasculature. Because the distribution of phosphatidylethanolamine (PE) and PS within the membrane is coregulated, we reasoned that PE would also be localized in the outer membrane leaflet of tumor EC. To demonstrate this, the PE-binding peptide duramycin was biotinylated and used to determine the distribution of PE on EC in vitro and in vivo. Exposure of cultured EC to hypoxia, acidity, reactive oxygen species, or irradiation resulted in the formation of membrane blebs that were intensely PE-positive. When biotinylated duramycin was intravenously injected into tumor-bearing mice, it preferentially localized to the luminal surface of the vascular endothelium. Depending on tumor type, 13% to 56% of the tumor vessels stained positive for PE. PE-positive vessels were observed in and around hypoxic regions of the tumor. With the exception of intertubular vessels of the kidney, normal vessels remained unstained. To test the potential of PE as a biomarker for imaging, duramycin was conjugated to the near-infrared fluorophore 800CW and used for optical imaging of RM-9 prostate carcinomas. The near-infrared probe was easily detected within tumors in live animals. These results show that PE, like PS, becomes exposed on tumor vascular endothelium of multiple types of tumors and holds promise as a biomarker for noninvasive imaging and drug targeting.

Topics: Amino Acid Sequence; Animals; Antigens, Surface; Bacteriocins; Cattle; Cell Line, Tumor; Drug Evaluation, Preclinical; Endothelium, Vascular; Female; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, SCID; Models, Biological; Molecular Sequence Data; Neoplasms; Neovascularization, Pathologic; Peptides; Phosphatidylethanolamines; Up-Regulation