A SNAKE VENOM DISINTEGRIN WITH POTENT ANTITUMOR AND ANTIANGIOGENIC ACTIVITY

Abstract

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. Contortrostatin (Mr 13,500) is a homodimeric disintegrin isolated from venom of the southern copperhead snake. Contortrostatin possesses two RGD sites, one in each chain, 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 intravenous (IV) administration of a biologically active protein with full retention of biological activity. Pharmacokinetics, biodistribution, platelet reactivity, and immunogenicity of LCN were examined and compared with similar characteristics of native, unencapsulated CN. There are several advantages to liposomal delivery of CN: (i) LCN has a significantly prolonged circulatory half-life compared to native CN; (ii) LCN is passively accumulated in the tumor; (iii) LCN has no platelet reactivity; and (iv) LCN is not recognized by the immune system. We have previously demonstrated that antiangiogenic activity is an important component of CN's mechanism of antitumor action. In the present communication we demonstrate that IV delivery of LCN leads to potent antitumor and antiangiogenic activity in the orthotopic, xenograft human mammary cancer model.

Keywords: :

• Angiogenesis
• Snake venom
• Disintegrin
• Integrin
• Breast cancer
• Liposomes.