Tumor-Specific Targeting of Folate-Derivatized Drugs

叶酸衍生药物的肿瘤特异性靶向

• 批准号: 6622784
• 负责人: PHILIP Stewart LOW
• 金额: $ 24.94万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6622784
• 关键词: autoradiography; chemical conjugate; clinical research; cytotoxicity; drug delivery systems; drug design /synthesis /production; fluoresceins; fluorescence microscopy; folate; human subject; immunotherapy; laboratory mouse; molecular size; neoplasm /cancer chemotherapy; paclitaxel; receptor binding; receptor expression; transport proteins

DESCRIPTION (provided by applicant): The receptor for folic acid is an established tumor marker, showing elevated expression in many epithelial cancers, including cancers of the ovary, cervix, endometrium, kidney, brain and head and neck. When folic acid is covalently linked to another molecule or particle, it may still bind with high affinity (KD -1 0-9M) to the folate receptor (FR), but will lose all affinity for the reduced folate carrier (a transport protein that mediates folate uptake by many nonmalignant cells). Folate conjugates are, therefore, bound and internalized only by FR-expressing cells. Because of FR upregulation on cancer cells, folate ligation has been hypothesized to convert the vitamin into a molecular "Trojan Horse" that can facilitate targeting and delivery of attached therapeutic or imaging agents into malignant cells. While results from cell culture studies have been very encouraging, few quantitative data are available to permit an assessment of the therapeutic potential of folatemediated drug targeting in human patients. In our first two aims, we propose to first obtain this quantitative information. In the last two aims, we will test the therapeutic potential of the strategy in mouse tumor models. First, we will measure the in vivo recycling rate of FR in several relevant cancer models. Together with published data on the levels of FR expression in various human cancers, this recycling information should enable a more quantitative estimate of the total uptake and delivery capacity of the folate-mediated targeting pathway. Second, we will address how the size of a folate conjugate impacts its accessibility to cancer cells in vivo. Recent data indicate that the ability of folate conjugates to bind to and decorate cells throughout a tumor mass may be limited by molecular size. Quantitative data on this matter will be required to guide the design of folate-linked therapeutics. Third, we will synthesize and test folate-conjugated cytotoxic drugs for therapeutic efficacy in vivo. And finally, we will define the molecular and cellular bases of a novel folate-targeted immunotherapy that we have already shown can eradicate established tumors in mice without damaging normal tissues.

描述（由申请人提供）：叶酸受体是一种 已建立的肿瘤标志物，显示在许多上皮细胞中表达升高， 癌症，包括卵巢癌、子宫颈癌、子宫内膜癌、肾癌、脑癌和 头和颈当叶酸与另一个分子共价连接时， 尽管叶酸颗粒被破坏，但它仍然可以以高亲和力（KD-10 - 9 M）与叶酸结合 受体（FR），但将失去对还原叶酸载体（a 介导许多非恶性细胞摄取叶酸的转运蛋白）。 因此，叶酸缀合物仅通过表达FR的细胞结合和内化。 细胞由于癌细胞上的FR上调，叶酸连接已经被证实是一种有效的方法。 假设将维生素转化为分子“特洛伊木马”， 促进附着的治疗剂或成像剂的靶向和递送 转化成恶性细胞虽然细胞培养研究的结果非常 令人鼓舞的是，很少有定量数据可以用来评估 叶酸介导的药物靶向治疗人类患者的潜力。在 我们的前两个目标，我们建议首先获得这种定量信息。 在最后两个目标中，我们将测试该策略的治疗潜力， 小鼠肿瘤模型。首先，我们将测量FR的体内再循环率， 几种相关的癌症模型。加上已公布的关于 FR在各种人类癌症中的表达，这种循环信息应该 能够更定量地估计总吸收和输送能力 叶酸介导的靶向通路的一部分。第二，我们将讨论规模如何 叶酸缀合物的量影响其在体内对癌细胞的可及性。最近 数据表明叶酸缀合物结合并修饰 整个肿瘤块中的细胞可能受到分子大小的限制。定量 关于这一问题的数据将被要求指导叶酸相关的设计。 治疗学第三，我们将合成和测试叶酸结合的细胞毒， 用于体内治疗功效的药物。最后，我们将定义 一种新的叶酸靶向免疫疗法的分子和细胞基础， 已经证明可以根除小鼠体内已形成的肿瘤， 正常组织