5-Aminolevulinic acid (5-ALA) and its two ester derivatives (5-ALA-OMe and 5-ALA-OHex) have been approved for photodiagnosis and photodynamic therapy (PDT) of tumors in the clinical. However, their pharmacological activities are limited by their instability under physiological conditions and lack of tumor selectivity. With the aim to overcome these shortcomings, a glutathione-responsive 5-ALA derivative (SA) was designed based on the fact that many types of tumor cells have higher intracellular glutathione level than normal cells. SA was synthesized by masking the 5-amion group of 5-ALA methyl ester (5-ALA-OMe) with a self-immolative disulfide linker. Compared with 5-ALA and 5-ALA-OMe, SA exhibited higher stability under physiological conditions, and it can efficiently release the parent compound 5-ALA-OMe in response to glutathione. In tumor cells, SA displayed excellent protoporphyrin IX (PpIX) production activity at low concentrations while 5-ALA and 5-ALA-OMe were ineffective at the same concentration. The SA-induced PpIX production was positively correlated with the intracellular glutathione level, and SA exhibited enhanced phototoxicity due to its excellent PpIX generation activity. This study indicates that modification of the amino group in 5-ALA derivatives with a self-immolative disulfide linker is an effective strategy to improve their chemical stability and pharmacological activities, and SA is a potential photosensitizer for photodiagnosis and PDT of tumors.

5-氨基乙酰丙酸（5-ALA）及其两种酯衍生物（5-ALA-OMe和5-ALA-OHex）已被批准用于临床肿瘤的光诊断和光动力治疗（PDT）。然而，它们的药理活性因其在生理条件下的不稳定性和缺乏肿瘤选择性而受到限制。为了克服这些缺点，基于许多类型的肿瘤细胞的细胞内谷胱甘肽水平高于正常细胞的事实，设计了谷胱甘肽响应性5-ALA衍生物（ SA ）。 SA是通过用自毁二硫键掩蔽 5-ALA 甲酯 (5-ALA-OMe) 的 5-氨基离子基团来合成的。与5-ALA和5-ALA-OMe相比， SA在生理条件下表现出更高的稳定性，并且它可以响应谷胱甘肽有效释放母体化合物5-ALA-OMe。在肿瘤细胞中， SA在低浓度下表现出优异的原卟啉 IX (PpIX) 生产活性，而 5-ALA 和 5-ALA-OMe 在相同浓度下则无效。 SA诱导的PpIX产生与细胞内谷胱甘肽水平呈正相关，并且SA由于其优异的PpIX产生活性而表现出增强的光毒性。本研究表明，用自毁二硫键修饰5-ALA衍生物中的氨基是提高其化学稳定性和药理活性的有效策略， SA是一种潜在的用于肿瘤光诊断和PDT的光敏剂。