Chlorotoxin as a Targeting Agent for Cancer Therapies

作为癌症治疗靶向剂的氯毒素 摘要 癌症治疗功效通常受到正常组织中的毒性的限制。将化疗靶向于 癌细胞在很大程度上绕过正常组织，将从根本上提高癌症治疗的功效。 我们最近发现，蝎子衍生肽，氯毒素，针对近红外荧光 分子，Cy5.5到癌细胞。这种新的分子成像缀合物允许灵敏地检测 小至200个细胞的癌灶。与大多数靶向剂不同，CTX似乎靶向许多类型的固体 肿瘤，而不是一个特定的类型。而我们以前的工作表明CTX：Cy5.5是一种敏感的 诊断剂，目前的建议试图确定CTX缀合物是否可以用作选择性的 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来提供 细胞毒性药物，从而减轻化疗的副作用。本提案的具体目标 是1）鉴定CTX的分子靶标; 2）鉴定结合CTX的正常组织并定义CTX结合 在选定的癌症中的异质性;和3）建立与有效的抗肿瘤药物缀合的CTX的功效和毒性。 使用小鼠癌症模型的细胞毒性药物。这项工作的意义在于，CTX靶向具有潜力， 显著提高结合化疗的治疗指数。对于癌症患者来说， 对癌细胞的治疗剂量，同时保留大多数正常组织，可以提高生存率， 生活质量项目叙述 拟议工作的相关性是，氯毒素似乎是一种具有很高潜力的分子， 特异性地将癌症疗法递送到癌细胞，在很大程度上绕过正常组织。对于癌症患者来说，这 这意味着更多的治疗可以传递到癌细胞，而病人经历更少的副作用。的 特别令人感兴趣的是，氯毒素似乎与大多数类型的恶性实体瘤结合，而不仅仅是 一个或两个类型。

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.