ngr-peptide and Prostatic-Neoplasms

Induction of selective thrombosis and infarction in tumor-feeding vessels represents an attractive strategy to combat cancer. Here we took advantage of the unique coagulation properties of staphylocoagulase and genetically engineered it to generate a new fusion protein with novel anti-cancer properties. This novel bi-functional protein consists of truncated coagulase (tCoa) and an NGR (GNGRAHA) motif that recognizes CD13 and α

Topics: Animals; CD13 Antigens; Cell Death; Cell Line, Tumor; Coagulase; Female; Human Umbilical Vein Endothelial Cells; Humans; Integrin alphaVbeta3; Male; Mammary Neoplasms, Animal; Mice; Mice, Inbred C57BL; Mice, Nude; Neovascularization, Pathologic; Oligopeptides; Prostatic Neoplasms; Xenograft Model Antitumor Assays

In this study, a peptide-based dual-targeting magnetic resonance imaging (MRI) contrast agent (S8) was designed and synthesized. Arg-Gly-Asp (RGD) and Asn-Gly-Arg (NGR) were combined in the targeting vector so as to allow binding, on the surface of tumor cells, to integrin αvβ3 and aminopeptidase N (CD13), respectively. The longitudinal relaxivity (r1) value of S8 was 8.297 mM-1sec-1 at a magnetic field of 11.7 T, which is approximately double the r1 value (4.25 mM-1sec-1) of Magnevist, a commercially available contrast agent. MDA-MB-231 human breast cancer cells (which overexpress αvβ3) and human prostate cancer cells PC-3 (which overexpress CD13) were used to investigate the tumor‑targeting behavior of S8. The results from the present study indicate that the designed contrast agent, S8, targets both MDA-MB‑231 and PC-3 cells.

Topics: Breast Neoplasms; CD13 Antigens; Cell Line, Tumor; Contrast Media; Female; Humans; Integrin alphaVbeta3; Magnetic Resonance Imaging; Male; Oligopeptides; Prostatic Neoplasms

In an effort to develop new agents and molecular targets for the treatment of cancer, aspargine-glycine-arginine (NGR)-targeted liposomal doxorubicin (TVT-DOX) is being studied. The NGR peptide on the surface of liposomal doxorubicin (DOX) targets an aminopeptidase N (CD13) isoform, specific to the tumor neovasculature, making it a promising strategy. To further understand the molecular mechanisms of action, we investigated cell binding, kinetics of internalization as well as cytotoxicity of TVT-DOX in vitro. We demonstrate the specific binding of TVT-DOX to CD13-expressing endothelial [human umbilical vein endothelial cells (HUVEC) and Kaposi sarcoma-derived endothelial cells (SLK)] and tumor (fibrosarcoma, HT-1080) cells in vitro. Following binding, the drug was shown to internalize through the endosomal pathway, eventually leading to the localization of doxorubicin in cell nuclei. TVT-DOX showed selective toxicity toward CD13-expressing HUVEC, sparing the CD13-negative colon-cancer cells, HT-29. Additionally, the nontargeted counterpart of TVT-DOX, Caelyx, was less cytotoxic to the CD13-positive HUVECs demonstrating the advantages of NGR targeting in vitro. The antitumor activity of TVT-DOX was tested in nude mice bearing human prostate-cancer xenografts (PC3). A significant growth inhibition (up to 60%) of PC3 tumors in vivo was observed. Reduction of tumor vasculature following treatment with TVT-DOX was also apparent. We further compared the efficacies of TVT-DOX and free doxorubicin in the DOX-resistant colon-cancer model, HCT-116, and observed the more pronounced antitumor effects of the TVT-DOX formulation over free DOX. The potential utility of TVT-DOX in a variety of vascularized solid tumors is promising.

Topics: Animals; Antineoplastic Agents; Biological Transport; CD13 Antigens; Cell Line, Tumor; Colonic Neoplasms; Doxorubicin; Drug Resistance, Neoplasm; Endocytosis; Endosomes; Humans; In Vitro Techniques; Liposomes; Male; Mice; Mice, Nude; Oligopeptides; Prostatic Neoplasms; Protein Binding