The Brain Tumor Center of Excellence, Department of Neurosurgery, Wake Forest School of Medicine, Winston-Salem, NC, USA.
BioDrugs. 2012 Aug 1;26(4):235-44. doi: 10.2165/11631600-000000000-00000.
A number of anti-cancer drugs have their targets localized to particular intracellular compartments. These drugs reach the targets mainly through diffusion, dependent on biophysical and biochemical forces that allow cell penetration. This means that both cancer cells and normal cells will be subjected to such diffusion; hence many of these drugs, like chemotherapeutics, are potentially toxic and the concentration achieved at the site of their action is often suboptimal. The same relates to radiation that indiscriminately affects normal and diseased cells. However, nature-designed systems enable compounds present in the extracellular environment to end up inside the cell and even travel to more specific intracellular compartments. For example, viruses and bacterial toxins can more or less specifically recognize eukaryotic cells, enter these cells, and direct some protein portions to designated intracellular areas. These phenomena have led to creative thinking, such as employing viruses or bacterial toxins for cargo delivery to cells and, more specifically, to cancer cells. Proteins can be genetically engineered in order to not only mimic what viruses and bacterial toxins can do, but also to add new functions, extending or changing the intracellular routes. It is possible to make conjugates or, more preferably, single-chain proteins that recognize cancer cells and deliver cargo inside the cells, even to the desired subcellular compartment. These findings offer new opportunities to deliver drugs/labels only to cancer cells and only to their site of action within the cells. The development of such dual-specificity vectors for targeting cancer cells is an attractive and potentially safer and more efficacious way of delivering drugs. We provide examples of this approach for delivering brain cancer therapeutics, using a specific biomarker on glioblastoma tumor cells.
许多抗癌药物的作用靶点定位于特定的细胞内隔室。这些药物主要通过扩散到达靶点,扩散依赖于允许细胞穿透的生物物理和生化力。这意味着癌细胞和正常细胞都将受到这种扩散的影响;因此,许多这些药物,如化疗药物,都具有潜在的毒性,并且在其作用部位达到的浓度往往不理想。同样适用于不分青红皂白地影响正常和患病细胞的辐射。然而,自然界设计的系统使存在于细胞外环境中的化合物能够进入细胞内部,甚至能够到达更特定的细胞内隔室。例如,病毒和细菌毒素可以或多或少地特异性识别真核细胞,进入这些细胞,并将一些蛋白质部分导向指定的细胞内区域。这些现象引发了创造性思维,例如利用病毒或细菌毒素将货物递送到细胞中,更具体地说是递送到癌细胞中。蛋白质可以进行基因工程改造,不仅可以模拟病毒和细菌毒素的作用,还可以添加新的功能,扩展或改变细胞内的途径。可以制造缀合物,或者更优选地,单链蛋白,这些蛋白可以识别癌细胞并将货物递送到细胞内,甚至递送到所需的亚细胞隔室。这些发现为仅向癌细胞和细胞内的作用部位递送药物/标记物提供了新的机会。开发这种针对癌细胞的双特异性载体是一种有吸引力的、潜在更安全、更有效的药物传递方法。我们提供了使用神经胶质瘤肿瘤细胞上的特定生物标志物来递送脑癌治疗药物的这种方法的示例。