Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression

• Published in: Molecular cancer therapeutics 2004-04, Vol.3 (4), p.499-511
• Main Authors: Swenson, Stephen, Costa, Fritz, Minea, Radu, Sherwin, Russell P, Ernst, William, Fujii, Gary, Yang, Dongyun, Markland, Jr, Francis S
• Format: Article
• Language: English
• Subjects: Agkistrodon; Animals; Blood Platelets - metabolism; Breast Neoplasms - blood supply; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Division - drug effects; Cell Line, Tumor; Disease Progression; Disintegrins - administration & dosage; Disintegrins - immunology; Disintegrins - pharmacokinetics; Disintegrins - therapeutic use; Humans; Injections, Intravenous; Iodine Radioisotopes; Liposomes - administration & dosage; Mice; Mice, Nude; Neovascularization, Pathologic - drug therapy; Protein Binding; Snake Venoms - chemistry; Tissue Distribution; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.499.3.4

Despite significant research in this area, metastatic breast cancer remains a disease with a poor prognosis. Until an effective therapy is developed, it is imperative that new treatment modalities be investigated. In this report, we describe an effective method for delivery of a novel snake venom disintegrin, contortrostatin (CN), in an orthotopic, xenograft model of human mammary cancer in immunodeficient mice. CN ( M r 13,500) is a homodimeric disintegrin isolated from venom of the Southern Copperhead snake. The homodimer possesses two Arg-Gly-Asp sites, which modulate its interaction with integrins on tumor cells and angiogenic vascular endothelial cells. Although our laboratory has previously described the antitumor activity of CN in a mouse model of human mammary cancer, the method of delivery, daily intratumor injection, was not translatable to clinical application. We now describe a clinically relevant method of administering CN, liposomal delivery (LCN). A unique liposomal system has been designed for i.v. administration of a biologically active protein with full retention of biological activity. Pharmacokinetics, biodistribution, platelet reactivity, and immunogenicity of LCN were determined and compared with similar characteristics of native, unencapsulated CN. There are several advantages to liposomal delivery of CN: ( 1 ) LCN has a significantly prolonged circulatory half-life compared with native CN; ( 2 ) LCN is passively accumulated in the tumor; ( 3 ) LCN has no platelet reactivity; and ( 4 ) LCN is not recognized by the immune system. Finally, antiangiogenic activity is an important component of CN's mechanism of antitumor action. We have demonstrated that i.v. delivery of LCN leads to potent antiangiogenic activity in the orthotopic, xenograft human mammary tumor model.