Zhao Xiaobin, Li Hong, Lee Robert J
Abbott Laboratories, Global Pharmaceutics and Life Cycle Technology, Abbott Park, IL 60064, USA.
Expert Opin Drug Deliv. 2008 Mar;5(3):309-19. doi: 10.1517/17425247.5.3.309.
Targeted delivery via selective cellular markers can potentially increase the efficacy and reduce the toxicity of therapeutic agents. The folate receptor (FR) has two glycosyl phosphatidylinositol (GPI)-anchored isoforms, alpha and beta. FR-alpha expression is frequently amplified in epithelial cancers, whereas FR-beta expression is found in myeloid leukemia and activated macrophages associated with chronic inflammatory diseases. Conjugates of folic acid and anti-FR antibodies can be taken up by cancer cells via receptor-mediated endocytosis, thus providing a mechanism for targeted delivery to FR+ cells. The aim of this article is to provide a brief overview of applications of FR targeting in drug delivery, with an emphasis on the strategy of using folate as a targeting ligand. In order to do this, recent literature is surveyed on targeted delivery via both FR sub-types, as well as new findings on selective receptor upregulation in the targeted cells. A wide variety of molecules and drug carriers, including imaging agents, chemotherapeutic agents, oligonucleotides, proteins, haptens, liposomes, nanoparticles and gene transfer vectors have been conjugated to folate and evaluated for FR-targeted delivery. Substantial targeting efficacy has been found both in vitro and in vivo. In addition, mechanisms and methods for selective FR upregulation have been uncovered, which might enhance the effectiveness of the FR-targeted delivery strategy. FR-alpha serves as a useful marker for cancer, whereas FR-beta serves as a marker for myeloid leukemia and chronic inflammatory diseases. FR-targeted agents have shown promising efficacy in preclinical models and significant potential for future clinical application in a wide range of diseases.
通过选择性细胞标志物进行靶向递送有可能提高治疗药物的疗效并降低其毒性。叶酸受体（FR）有两种糖基磷脂酰肌醇（GPI）锚定的亚型，即α和β。FR-α的表达在上皮癌中经常扩增，而FR-β的表达则见于髓系白血病以及与慢性炎症性疾病相关的活化巨噬细胞中。叶酸与抗FR抗体的偶联物可通过受体介导的内吞作用被癌细胞摄取，从而为靶向递送至FR+细胞提供了一种机制。本文的目的是简要概述FR靶向在药物递送中的应用，重点是使用叶酸作为靶向配体的策略。为此，我们综述了近期关于通过两种FR亚型进行靶向递送的文献，以及靶向细胞中选择性受体上调的新发现。多种分子和药物载体，包括成像剂、化疗药物、寡核苷酸、蛋白质、半抗原、脂质体、纳米颗粒和基因转移载体，已与叶酸偶联并评估其FR靶向递送效果。在体外和体内均发现了显著的靶向疗效。此外，还发现了选择性FR上调的机制和方法，这可能会提高FR靶向递送策略的有效性。FR-α可作为癌症的有用标志物，而FR-β可作为髓系白血病和慢性炎症性疾病的标志物。FR靶向药物在临床前模型中已显示出有前景的疗效，并且在未来广泛疾病的临床应用中具有巨大潜力。
