Small molecule additive enhances cell uptake of 5-aminolevulinic acid and conversion to protoporphyrin IX

• Published in: Photochemical & photobiological sciences Vol. 15; no. 11; pp. 148 - 1416
• Main Authors: Harmatys, Kara M, Musso, Anthony J, Clear, Kasey J, Smith, Bradley D
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 02.11.2016
• Subjects: Amines - chemistry; Amines - pharmacology; Amines - toxicity; Aminolevulinic Acid - metabolism; Animals; Biochemistry; Biomaterials; Cell Membrane - drug effects; Cell Survival - drug effects; Chemistry; CHO Cells; Cricetinae; Cricetulus; Photochemotherapy; Photosensitizing Agents - metabolism; Physical Chemistry; Picolinic Acids - chemistry; Picolinic Acids - pharmacology; Picolinic Acids - toxicity; Plant Sciences; Protoporphyrins - metabolism; Zinc - chemistry; Zinc - pharmacology; Zinc - toxicity
• ISSN: 1474-905X; 1474-9092; 1474-9092
• DOI: 10.1039/c6pp00151c

Administration of exogenous 5-aminolevulinic acid (5-ALA) to cancerous tissue leads to intracellular production of photoactive protoporphyrin IX, a biosynthetic process that enables photodynamic therapy and fluorescence-guided surgery of cancer. Cell uptake of 5-ALA is limited by its polar structure and there is a need for non-toxic chemical additives that can enhance its cell permeation. Two zinc-bis(dipicolylamine) (ZnBDPA) compounds were evaluated for their ability to promote uptake of 5-ALA into Chinese Hamster Ovary (CHO-K1) cells and produce protoporphyrin IX. One of the ZnBDPA compounds was found to be quite effective, and a systematic comparison of cells incubated with 5-ALA (100 μM) for 6 hours showed that the presence of this ZnBDPA compound (10 μM) produced 3-fold more protoporphyrin IX than cells treated with 5-ALA alone. The results of mechanistic studies suggest that the ZnBDPA compound does not interact strongly with the 5-ALA. Rather, the additive is membrane active and transiently disrupts the cell membrane, permitting 5-ALA permeation. The membrane disruption is not severe enough to induce cell toxicity or allow passage of larger macromolecules like plasmid DNA. Cells incubated with an admixture of 5-ALA (100 μM) and a zinc( ii )-bis(dipicolylamine) compound (10 μM) produced 3-fold more protoporphyrin IX than cells treated with 5-ALA alone.