Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
ACS Nano. 2015 Jan 27;9(1):733-45. doi: 10.1021/nn5061964. Epub 2015 Jan 14.
Sialic acid sugars are overexpressed by cancer cells and contribute to the metastatic cascade at multiple levels. Therapeutic interference of sialic acids, however, has been difficult to pursue because of the absence of dedicated tools. Here we show that a rationally designed sialic acid-blocking glycomimetic (P-3F(ax)-Neu5Ac) successfully prevents cancer metastasis. Formulation of P-3F(ax)--Neu5Ac into poly(lactic-co-glycolic acid nanoparticles coated with antityrosinase-related protein-1 antibodies allowed targeted delivery of P-3F(ax)--Neu5Ac into melanoma cells, slow release, and long-term sialic acid blockade. Most importantly, intravenous injections of melanoma-targeting P-3F(ax)--Neu5Ac nanoparticles prevented metastasis formation in a murine lung metastasis model. These findings stress the importance of sialoglycans in cancer metastasis and advocate that sialic acid blockade using rationally designed glycomimetics targeted to cancer cells can effectively prevent cancer metastases. This targeting strategy to interfere with sialic acid-dependent processes is broadly applicable not only for different types of cancer but also in infection and inflammation.
唾液酸糖在癌细胞中过度表达，并在多个层面上促进转移级联。然而，由于缺乏专用工具，对唾液酸的治疗性干扰一直难以实现。在这里，我们展示了一种合理设计的唾液酸阻断糖模拟物（P-3F(ax)-Neu5Ac）可成功预防癌症转移。将 P-3F(ax)--Neu5Ac 制成聚（乳酸-共-乙醇酸）纳米粒子，并涂覆抗酪氨酸酶相关蛋白-1 抗体，可将 P-3F(ax)--Neu5Ac 靶向递送至黑色素瘤细胞，实现缓慢释放和长期的唾液酸阻断。最重要的是，静脉注射黑色素瘤靶向 P-3F(ax)--Neu5Ac 纳米粒子可防止小鼠肺转移模型中的转移形成。这些发现强调了唾液酸聚糖在癌症转移中的重要性，并主张使用针对癌细胞的合理设计的糖模拟物进行唾液酸阻断可有效预防癌症转移。这种靶向策略干扰依赖唾液酸的过程不仅适用于不同类型的癌症，也适用于感染和炎症。
