Selective tumor cell targeting using low-affinity, multivalent interactions
Selective tumor cell targeting using low-affinity, multivalent interactions
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DOI：
10.1021/cb6003788
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发表时间：
2007-02-01
影响因子：
4
通讯作者：
Kiessling, Laura L.
中科院分区：
文献类型：
--
作者：
Carlson, Coby B.;Mowery, Patricia;Kiessling, Laura L.
这份报告强调了低亲和力、多价相互作用在识别一种细胞类型方面的优势。我们的目标是设计一种策略来介导对肿瘤细胞的选择性杀伤，肿瘤细胞通常因其特定细胞表面受体水平较高而与正常细胞区分开来。为了测试多价相互作用是否可以导致高度特异性的细胞靶向，我们使用了化学合成的小分子配体，由两个不同的基序组成：(1)与α(V)β(3)整合素紧密结合(K-d约为10(9)M)的Arg-Gly-Asp(RGD)多肽；(2)人抗半乳糖抗体(anti-Gal)识别的半乳糖-α(13)半乳糖(α-Gal表位)。重要的是，抗-Gal结合需要碳水化合物残基的多价呈递；抗-Gal抗体与单价低聚糖(K-d约为10(-5)M)相互作用很弱，但与-Gal表位的多价显示紧密结合(K-d约为10(-11)M)。当双功能结合物修饰具有高水平的α(V)β(3)整合素的细胞时，就会产生这样的显示；由此产生的细胞表面，呈现多个半乳糖表位，可以招募抗半乳糖，从而触发补体介导的裂解。只有那些整合素受体水平高的细胞才会被杀死。相比之下，阿霉素与基于RGD的配体捆绑在一起会导致细胞不分青红皂白地死亡。这些结果突出了利用生理系统使用的多价识别过程类型来区分细胞的优势。这种策略的选择性优于传统的、非生物的、高亲和力的靶向方法。我们的结果对癌症和其他以有害细胞存在为特征的疾病的治疗具有指导意义。
This report highlights the advantages of low-affinity, multivalent interactions to recognize one cell type over another. Our goal was to devise a strategy to mediate selective killing of tumor cells, which are often distinguished from normal cells by their higher levels of particular cell surface receptors. To test whether multivalent interactions could lead to highly specific cell targeting, we used a chemically synthesized small-molecule ligand composed of two distinct motifs: (1) an Arg-Gly-Asp (RGD) peptidomimetic that binds tightly (K-d approximate to 10(9) M) to alpha(v)beta(3) integrins and (2) the galactosyl-alpha(13)galactose (alpha-Gal epitope), which is recognized by human anti--galactosyl antibodies (anti-Gal). Importantly, anti-Gal binding requires a multivalent presentation of carbohydrate residues; anti-Gal antibodies interact weakly with the monovalent oligosaccharide (K-d approximate to 10(-5) M) but bind tightly (K-d approximate to 10(-11) M) to multivalent displays of -Gal epitopes. Such a display is generated when the bifunctional conjugate decorates a cell possessing a high level of alpha(v)beta(3) integrin; the resulting cell surface, which presents many -Gal epitopes, can recruit anti-Gal, thereby triggering complement-mediated lysis. Only those cells with high levels of the integrin receptor are killed. In contrast, doxorubicin tethered to the RGD-based ligand affords indiscriminate cell death. These results highlight the advantages of exploiting the type of the multivalent recognition processes used by physiological systems to discriminate between cells. The selectivity of this strategy is superior to traditional, abiotic, high-affinity targeting methods. Our results have implications for the treatment of cancer and other diseases characterized by the presence of deleterious cells.