Chlorotoxin as a Targeting Agent for Cancer Therapies

描述(由申请人提供)：癌症治疗效果通常受到正常组织毒性的限制。在很大程度上绕过正常组织，针对癌细胞进行靶向化疗的能力，将从根本上提高癌症治疗的疗效。我们最近发现了一种蝎子衍生的多肽，氯毒素，它以近红外荧光分子Cy5.5为靶标，作用于癌细胞。这种新的分子成像结合物可以灵敏地检测到小到200个细胞的癌灶。与大多数靶向药物不同，CTX似乎针对多种类型的实体肿瘤，而不是一种特定类型的肿瘤。鉴于我们之前的工作表明CTX：Cy5.5是一种敏感的诊断试剂，目前的提议试图确定CTX结合物是否可以用作选择性治疗药物。这项研究的广泛和长期目标是了解如何安全地使用CTX将细胞毒药物输送到癌细胞，从而减少化疗的副作用。这项建议的具体目的是：1)确定CTX的分子靶点；2)识别与CTX结合的正常组织，并确定在选定的癌症中CTX结合的异质性；以及3)利用小鼠癌症模型建立CTX与一种有效的细胞毒药物的结合的有效性和毒性。这项工作的意义在于，CTX靶向有可能显著提高结合化疗的治疗指数。对于癌症患者，在保留大多数正常组织的同时，向癌细胞提供更高剂量的治疗药物，可能会提高患者的存活率和生活质量。与公共卫生相关：这项拟议工作的相关性在于，氯毒素似乎是一种具有很高潜力的分子，可以在很大程度上绕过正常组织，向癌细胞提供癌症治疗。对于癌症患者来说，这意味着可以向癌细胞提供更多的治疗，同时患者经历的副作用更少。特别有趣的是，氯毒素似乎与大多数类型的恶性实体肿瘤结合，而不仅仅是一两种类型。

DESCRIPTION (provided by applicant): Cancer therapy efficacy is often limited by toxicity in normal tissues. The ability to target chemotherapy to cancer cells, largely bypassing normal tissues, would fundamentally improve the efficacy of cancer treatment. We recently showed that a scorpion-derived peptide, chlorotoxin, targeted the near infrared fluorescent molecule, Cy5.5 to cancer cells. This new molecular imaging conjugate permitted sensitive detection of cancerous foci as small as 200 cells. Unlike most targeting agents, CTX appears to target many types of solid tumors rather than one particular type. Whereas our previous work showed that CTX:Cy5.5 is a sensitive diagnostic agent, the current proposal seeks to determine whether CTX conjugates can be used as selective therapeutic agents. The broad, long-term goal of this research is to learn how to safely use CTX to deliver cytotoxic drugs to cancer cells, thus lessening chemotherapy side effects. The specific aims of this proposal are to 1) identify the molecular target of CTX; 2) identify normal tissues that bind CTX and define CTX binding heterogeneity in selected cancers; and 3) establish the efficacy and toxicity of CTX conjugated to a potent cytotoxic drug using mouse cancer models. The significance of this work is that CTX targeting has the potential to markedly increase the therapeutic index of conjugated chemotherapy. For cancer patients, delivering higher doses of therapeutics to cancer cells while sparing most normal tissues, could result in improved survival and quality of life. PUBLIC HEALTH RELEVANCE: The relevance of the proposed work is that chlorotoxin appears to be a molecule that has high potential to specifically deliver cancer therapies to cancer cells, largely bypassing normal tissues. For cancer patients, this means more therapy could be delivered to cancer cells while the patient experiences fewer side effects. Of particular interest is that chlorotoxin appears to bind to most types of malignant solid tumors rather than just one or two types.