Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression.
Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression.
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DOI：
10.1158/1535-7163.499.3.4
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发表时间：
2004-04
影响因子：
5.7
通讯作者：
S. Swenson;Fritz K. Costa;R. Minea;R. Sherwin;W. Ernst;G. Fujii;Dongyun Yang;F. Markland
中科院分区：
文献类型：
--
作者：
S. Swenson;Fritz K. Costa;R. Minea;R. Sherwin;W. Ernst;G. Fujii;Dongyun Yang;F. Markland
尽管在这一领域进行了大量研究，但转移性乳腺癌仍然是一种预后不良的疾病。在开发出有效的治疗方法之前，必须研究新的治疗方法。在这份报告中，我们描述了一种有效的方法，提供一种新的蛇毒去整合素，contortrostatin（CN），在原位，异种移植模型的人乳腺癌的免疫缺陷小鼠。CN（Mr 13，500）是从南方铜斑蛇毒液中分离的同型二聚体去整合素。同源二聚体具有两个Arg-Gly-Asp位点，其调节其与肿瘤细胞和血管生成血管内皮细胞上的整合素的相互作用。尽管我们的实验室先前已经描述了CN在人类乳腺癌小鼠模型中的抗肿瘤活性，但递送方法（每日瘤内注射）无法转化为临床应用。我们现在描述一种临床相关的CN给药方法，脂质体递送（LCN）。设计了一种独特的脂质体系统，用于静脉内给药生物活性蛋白，完全保留生物活性。LCN的药代动力学，生物分布，血小板反应性和免疫原性进行了测定，并与天然的，未封装CN的类似特性进行了比较。CN的脂质体递送有几个优点：（1）与天然CN相比，LCN的循环半衰期显着延长;（2）LCN在肿瘤中被动累积;（3）LCN没有血小板反应性;（4）LCN不被免疫系统识别。最后，抗血管生成活性是CN抗肿瘤作用机制的重要组成部分。我们已经证明，静脉注射给药LCN在原位异种移植人乳腺肿瘤模型中产生了有效的抗血管生成活性。
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.