Lu Yingjuan, Low Philip S
Department of Chemistry, 1393 Brown Building, Purdue University, West Lafayette, IN 47907, USA.
Adv Drug Deliv Rev. 2002 Sep 13;54(5):675-93. doi: 10.1016/s0169-409x(02)00042-x.
The receptor for folic acid constitutes a useful target for tumor-specific drug delivery, primarily because: (1) it is upregulated in many human cancers, including malignancies of the ovary, brain, kidney, breast, myeloid cells and lung, (2) access to the folate receptor in those normal tissues that express it can be severely limited due to its location on the apical (externally-facing) membrane of polarized epithelia, and (3) folate receptor density appears to increase as the stage/grade of the cancer worsens. Thus, cancers that are most difficult to treat by classical methods may be most easily targeted with folate-linked therapeutics. To exploit these peculiarities of folate receptor expression, folic acid has been linked to both low molecular weight drugs and macromolecular complexes as a means of targeting the attached molecules to malignant cells. Conjugation of folic acid to macromolecules has been shown to enhance their delivery to folate receptor-expressing cancer cells in vitro in almost all situations tested. Folate-mediated macromolecular targeting in vivo has, however, yielded only mixed results, largely because of problems with macromolecule penetration of solid tumors. Nevertheless, prominent examples do exist where folate targeting has significantly improved the outcome of a macromolecule-based therapy, leading to complete cures of established tumors in many cases. This review presents a brief mechanistic background of folate-targeted macromolecular therapeutics and then summarizes the successes and failures observed with each major application of the technology.
叶酸受体是肿瘤特异性药物递送的一个有用靶点，主要原因如下：（1）它在许多人类癌症中上调，包括卵巢癌、脑癌、肾癌、乳腺癌、髓样细胞癌和肺癌；（2）在那些表达叶酸受体的正常组织中，由于其位于极化上皮细胞的顶端（朝外）膜上，获取叶酸受体的途径可能会受到严重限制；（3）随着癌症分期/分级的恶化，叶酸受体密度似乎会增加。因此，那些用传统方法最难治疗的癌症，可能最容易用与叶酸相连的治疗药物来靶向治疗。为了利用叶酸受体表达的这些特性，叶酸已与低分子量药物和大分子复合物相连，作为将附着分子靶向恶性细胞的一种手段。在几乎所有测试情况下，叶酸与大分子的偶联已显示能在体外增强它们向表达叶酸受体的癌细胞的递送。然而，叶酸介导的大分子在体内的靶向作用仅产生了好坏参半的结果，主要是因为大分子穿透实体瘤存在问题。尽管如此，确实存在一些突出的例子，其中叶酸靶向显著改善了基于大分子的治疗效果，在许多情况下导致已建立的肿瘤完全治愈。本综述介绍了叶酸靶向大分子治疗的简要机制背景，然后总结了该技术在每个主要应用中观察到的成功与失败情况。
