Dual-targeted 5-aminolevulinic acid derivatives with glutathione depletion function for enhanced photodynamic therapy.

Abstract

Photodynamic therapy (PDT) is a promising tumor therapy which utilizes reactive oxygen species (ROSs) to cause tumor cells death. 5-aminolevulinic acid (ALA) and two of its esters are FDA-approved photosensitizers. However, their clinical application suffers from their instability and lack of tumor selectivity. In addition, the overexpression of glutathione (GSH) in some tumor cells reduces the PDT efficiency due to the ROS-scavenging ability of GSH. In this work, we present three multifunctional ALA derivates with the characteristics of dual-targeting and GSH depletion to improve the therapeutic effect of ALA-based PDT. The general structure of these compounds consists of an ALA methyl ester (ALA-OMe) moiety that can metabolize to photosensitive protoporphyin IX (PpIX) inside the cells, a biotin group for targeting biotin receptor-positive tumor cells and a disulfide bond-based self-immolative linker which can be activated by GSH to liberate ALA-OMe. Simultaneously, the reaction between the disulfide bond and GSH also depletes intracellular GSH, causing tumor cells more vulnerable to ROSs. All three compounds exhibited high stability under physiological conditions. In vitro experiments demonstrated that the more lipophilic compounds 1 and 2 were much more efficient in inducing PpIX production in biotin receptor-overexpressed HeLa cells as compared with their parent compound (ALA-OMe). And the PpIX generation induced by compounds 1 and 2 was positively correlated with the overexpression of biotin receptor and GSH level in tumor cells. More importantly, the GSH depletion ability of them significantly increased their phototoxicity. Furthermore, in comparison with ALA-OMe, compound 2 showed much higher in vivo efficiency in PpIX production. All the results demonstrate that the combination strategy of dual-targeting and GSH depletion can be used to concurrently enhance the tumor-specificity and anti-tumor efficiency of ALA-based PDT. And this strategy may be used for designing other ALA-based photosensitizers with higher tumor-specificity and better therapeutic effects.

• Authors: Ke Li, Wenyi Dong, Yinxing Miao, Qingzhu Liu, Ling Qiu, Jianguo Lin
• Journal: Journal of photochemistry and photobiology. B, Biology (J Photochem Photobiol B) Vol. 215 Pg. 112107 (Feb 2021) ISSN: 1873-2682 [Electronic] Switzerland
• PMID: 33401190 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

• Receptors, Growth Factor
• biotin receptor
• Aminolevulinic Acid
• Glutathione

Topics

• Aminolevulinic Acid (analogs & derivatives, pharmacology)
• Glutathione (metabolism)
• HeLa Cells
• Humans
• Intracellular Space (drug effects, metabolism, radiation effects)
• Photochemotherapy
• Receptors, Growth Factor (metabolism)