Glycoside Esters of 5-Aminolevulinic Acid for Photodynamic Therapy of Cancer

• Published in: Bioconjugate chemistry 2008-04, Vol.19 (4), p.821-839
• Main Authors: Vallinayagam, Ramakrishnan, Schmitt, Frédéric, Barge, Jérome, Wagnieres, Georges, Wenger, Virginie, Neier, Reinhard, Juillerat-Jeanneret, Lucienne
• Format: Article
• Language: English
• Subjects: Aminolevulinic Acid - analogs & derivatives; Aminolevulinic Acid - pharmacology; Aminolevulinic Acid - therapeutic use; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Esterases - metabolism; Esterification; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Glycoside Hydrolases - metabolism; Glycosides - chemistry; Humans; Neoplasms - drug therapy; Photochemotherapy; Photosensitizing Agents - metabolism; Photosensitizing Agents - pharmacology; Prodrugs - chemistry; Prodrugs - pharmacology; Prodrugs - therapeutic use; Protoporphyrins - metabolism; Protoporphyrins - pharmacology; Sensitivity and Specificity
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc700324r

Aliphatic and ethylene glycol esters of 5-aminolevulinic acid (ALA) are very efficient precursors of the photosensitizer protoporphyrin IX (PpIX) for photodynamic therapy; however, they diffuse passively across the cell membrane and thus lack cell selectivity. We evaluated whether α-glucose, α-mannose, or β-galactose esters of ALA would present improved properties as precursors of PpIX. Esterification was performed either at the position O-1 or O-6 of the sugars with or without an ethylene glycol linker, and these glycoside esters of ALA were evaluated in human cells. The results demonstrated that glycoside esters of ALA are efficient precursors of PpIX in human cancer and angiogenic endothelial cells, comparable to free ALA, but not in normal human fibroblasts. PpIX production was confirmed by fluorescence microscopy and photodynamic treatment of cells. The O-1 or O-6 positions of functionalization and the nature of the sugar moiety did not influence PpIX production. The presence of the ethylene glycol linker generally resulted in decreased PpIX production. The uptake of these glycoside esters of ALA by cells was not decreased in the presence of high concentrations of the related sugars. Inhibitors of α-glucosidases or α-mannosidases did not decrease PpIX production. These results suggest the involvement of active non-glycoside-specific membrane transporter(s) for uptake and of esterases rather than glycosidases in the release of ALA from the glycoside esters of ALA.