School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.
Bioorg Chem. 2018 Aug;78:372-380. doi: 10.1016/j.bioorg.2018.03.020. Epub 2018 Mar 30.
Treatment of cancer cells by clinically approved hexyl ester of 5-aminolevulinic acid (ALA-Hex) induces accumulation of fluorescent porphyrins in tumors. This allows fluorescence photodiagnosis (PD) of bladder cancer by blue light illumination. However, PD of other cancers is hampered by acute toxicity of the compound limiting its use to local applications. We have designed and synthesized a new prodrug of ALA-Hex that tackles the stability-activity paradox of amino-modified 5-ALA prodrugs. The glucuronide prodrug Glu-ALA-Hex demonstrates excellent stability under physiological conditions and activation in the presence of the target enzyme. β-glucuronidase-triggered release of 5-ALA is programmed to yield fluorescence in tumor environment with elevated β-glucuronidase activity, a characteristic of many solid tumors. Glu-ALA-Hex produces similar levels of fluorescence as ALA-Hex in breast cancer MCF7 cells in vitro but with much lower non-specific cell toxicity.
临床批准的 5-氨基酮戊酸己酯（ALA-Hex）处理癌细胞会导致肿瘤中荧光卟啉的积累。这使得膀胱癌可以通过蓝光照射进行荧光光诊断（PD）。然而，由于化合物的急性毒性限制了其在局部应用中的使用，其他癌症的 PD 受到阻碍。我们设计并合成了一种新的 ALA-Hex 前药，解决了氨基修饰的 5-ALA 前药的稳定性-活性矛盾。在生理条件下，葡萄糖醛酸苷前药 Glu-ALA-Hex 表现出优异的稳定性，并且在存在靶酶的情况下能够被激活。β-葡萄糖醛酸酶触发的 5-ALA 释放被编程为在β-葡萄糖醛酸酶活性升高的肿瘤环境中产生荧光，这是许多实体瘤的特征。Glu-ALA-Hex 在体外乳腺癌 MCF7 细胞中产生与 ALA-Hex 相似水平的荧光，但细胞毒性要低得多。
