title: Small molecule additive enhances cell uptake of 5-aminolevulinic acid and conversion to protoporphyrin IX.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, 236 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA. smith.115@nd.edu.
authors.forename: Kara M
authors.initials: KM
authors.lastname: Harmatys
authors.affiliation: Department of Chemistry and Biochemistry, 236 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA. smith.115@nd.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Musso
authors.affiliation: Department of Chemistry and Biochemistry, 236 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA. smith.115@nd.edu.
authors.forename: Kasey J
authors.initials: KJ
authors.lastname: Clear
authors.affiliation: Department of Chemistry and Biochemistry, 236 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, USA. smith.115@nd.edu.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Smith
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000622:Aminolevulinic Acid / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000378:metabolism; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011524:Protoporphyrins / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: C501847:2,2'-dipicolylamine; D000588:Amines; D017319:Photosensitizing Agents; D010848:Picolinic Acids; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; D015032:Zinc