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 已确定的肿瘤标志物，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 头部和颈部。当叶酸与另一个分子共价连接或 颗粒，它仍可能以高亲和力 (KD -1 0-9M) 与叶酸结合 受体（FR），但会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 FR 表达来结合和内化 细胞。由于 FR 对癌细胞的上调，叶酸结扎已被 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显像剂的靶向和递送 进入恶性细胞。虽然细胞培养研究的结果非常好 令人鼓舞的是，很少有定量数据可供评估 叶酸介导的药物靶向对人类患者的治疗潜力。在 我们的前两个目标是，我们建议首先获得这些定量信息。 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 的体内回收率 一些相关的癌症模型。连同已发布的水平数据 FR 在各种人类癌症中的表达，此回收信息应该 能够更定量地估计总吸收和输送能力 叶酸介导的靶向途径。其次，我们将讨论如何确定尺寸 叶酸结合物的含量影响其在体内对癌细胞的可及性。最近的 数据表明，叶酸缀合物结合和修饰的能力 整个肿瘤块中的细胞可能受到分子大小的限制。定量 需要有关此事的数据来指导叶酸相关药物的设计 疗法。第三，我们将合成并测试叶酸结合的细胞毒性 具有体内治疗功效的药物。最后，我们将定义 我们研究了一种新型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而不损伤 正常组织。