2. Academic Validation
  3. A new GSH-responsive prodrug of 5-aminolevulinic acid for photodiagnosis and photodynamic therapy of tumors

A new GSH-responsive prodrug of 5-aminolevulinic acid for photodiagnosis and photodynamic therapy of tumors

  • Eur J Med Chem. 2019 Nov 1:181:111582. doi: 10.1016/j.ejmech.2019.111582.
Ke Li 1,  Wenyi Dong 2,  Ling Qiu 3,  Qingzhu Liu 3,  Gaochao Lv 3,  Ying Peng 3,  Minhao Xie 4,  Jianguo Lin 5
Affiliations

Affiliations

  • 1 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, PR China; The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, 210029, PR China.
  • 2 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, PR China; School of Chemical and Material Engineering, Jiangnan University, Wuxi, 214122, PR China.
  • 3 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, PR China.
  • 4 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, PR China; The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, 210029, PR China. Electronic address: xieminhao@jsinm.org.
  • 5 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, PR China. Electronic address: linjianguo@jsinm.org.
PMID: 31398615 DOI: 10.1016/j.ejmech.2019.111582
Abstract

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.

Keywords

5-Aminolevulinic acid; GSH-Responsive; Photodiagnosis; Photodynamic therapy.

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