Tumor-Specific Targeting of Folate-Derivatized Drugs

描述(申请人提供)：叶酸受体是一种 已建立的肿瘤标记物，在许多上皮组织中表达升高 癌症，包括卵巢癌、子宫颈癌、子宫内膜癌、肾癌、脑癌和 头和脖子。当叶酸共价连接到另一个分子或 颗粒，它仍可能与叶酸高亲和力(KD-1 0-9M)结合 受体(FR)，但将失去与还原叶酸载体(A)的所有亲和力 介导许多非恶性细胞摄取叶酸的运输蛋白)。 因此，叶酸结合物只有通过FR表达才能结合和内化 细胞。由于癌细胞上FR的上调，叶酸结扎已被 假设将维生素转化为一种分子“特洛伊木马” 促进所附治疗剂或显像剂的靶向和递送 转化为恶性细胞。虽然细胞培养研究的结果是非常 令人鼓舞的是，几乎没有量化数据可以用来评估 叶酸介体药物靶向在人类患者中的治疗潜力。在……里面 我们的前两个目标，我们建议首先获得这个定量信息。 在后两个目标中，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在体内的回收率 几个相关的癌症模型。连同已公布的关于以下水平的数据 FR在各种人类癌症中的表达，这种回收信息应该 实现对总吸收和交付能力的更定量的估计 叶酸介导的靶向途径。第二，我们将解决大小如何 叶酸结合物的浓度影响其在体内对癌细胞的可及性。近期 数据表明，叶酸结合物结合和修饰的能力 整个肿瘤中的细胞可能受到分子大小的限制。量化 将需要这方面的数据来指导叶酸连接的设计 治疗学。第三，我们将合成并检测叶酸偶联的细胞毒性。 用于体内治疗效果的药物。最后，我们将定义 一种新型叶酸靶向免疫疗法的分子和细胞基础 已经证明可以在不损害小鼠的情况下根除已建立的肿瘤 正常组织。

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.