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 (Mr 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.