Chlorotoxin as a Targeting Agent for Cancer Therapies

氯毒素作为癌症治疗的靶向剂 摘要 癌症的治疗效果往往受到正常组织毒性的限制。靶向化疗的能力 癌细胞在很大程度上绕过了正常组织，将从根本上提高癌症治疗的效果。 我们最近发现了一种蝎子衍生的多肽，氯毒素，以近红外荧光为靶标。 分子，Cy5.5对癌细胞的作用。这种新的分子成像偶联物可以灵敏地检测到 癌灶小至200个细胞。与大多数靶向制剂不同，CTX似乎针对许多类型的固体 肿瘤，而不是一种特定的类型。鉴于我们之前的工作表明CTX：Cy5.5是一种敏感的 诊断试剂，目前的建议试图确定环磷酰胺结合物是否可以用作选择性 治疗剂。这项研究的广泛、长期目标是学习如何安全地使用CTX递送 对癌细胞有细胞毒性的药物，从而减轻化疗的副作用。这项建议的具体目的 1)确定CTX的分子靶点；2)识别与CTX结合的正常组织并确定CTX结合 在选定的癌症中的异质性；以及3)确定CTX与有效的 使用细胞毒性药物建立小鼠肿瘤模型。这项工作的意义在于CTX靶向具有潜在的 显著提高结合化疗的治疗指数。对于癌症患者，提供更高的 在保留大多数正常组织的同时，对癌细胞进行剂量治疗，可以提高存活率和 生活质量。项目叙事 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 专门为癌细胞提供癌症治疗，基本上绕过了正常组织。对于癌症患者来说，这是 这意味着更多的治疗可以提供给癌细胞，而患者经历的副作用更少。的 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 一到两种类型。

Chlorotoxin as a targeting agent for cancer therapies Abstract 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. Project Narrative 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.