title: Mechanisms of 5-aminolevulinic acid ester uptake in mammalian cells.
abstract: The porphyrin precursor 5-aminolevulinic acid (ALA) is being widely used in photodynamic therapy of cancer. Improvement in ALA delivery has been sought through the use of ALA derivatives, in particular the esterification of ALA with aliphatic alcohols, which in certain cases can improve cellular penetration and selectivity. ALA uptake systems appear to be distinctive for each cell type. The LM3 mammary adenocarcinoma cell line takes ALA up by BETA transporters. In this work, we investigated ALA derivative transport systems through the inhibition of radiolabelled ALA uptake in the LM3 cells. We also performed inhibition studies of gamma-aminobutyric acid (GABA) uptake. The more lipohilic ALA derivatives hexyl-ALA and undecanoyl-ALA inhibit ALA uptake, whereas methyl-ALA, R, S-ALA-2-(hydroxymethyl)tetrahydropyranyl ester and the dendron aminomethane tris methyl 5-ALA does not inhibit ALA uptake. A similar pattern was found for GABA, except that the dendron inhibited GABA uptake. However, hexyl-ALA and undecanoyl-ALA are not taken up by BETA transporters, but by simple diffusion, although they still inhibit ALA uptake by binding to the cell membrane. These results show that different modifications to the ALA molecule lead to different uptake mechanisms. Whereas ALA is taken up by BETA transporters, none of the ALA derivatives shares the same mechanism. Knowledge of the mechanisms of ALA derivatives entry into the cells is essential to understand and improve ALA-mediated PDT and to the design of new ALA derivatives that may be taken up at a higher rate than ALA.
authors.affiliation: Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, Córdoba 2351, 1er subsuelo, Ciudad de Buenos Aires, CP - 1120AAF, Argentina.
authors.forename: Lorena
authors.initials: L
authors.lastname: Rodriguez
authors.forename: Alcira
authors.initials: A
authors.lastname: Batlle
authors.forename: Gabriela
authors.initials: G
authors.lastname: Di Venosa
authors.forename: Sinan
authors.initials: S
authors.lastname: Battah
authors.forename: Paul
authors.initials: P
authors.lastname: Dobbin
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Macrobert
authors.forename: Adriana
authors.initials: A
authors.lastname: Casas
mesh_terms: D000622:Aminolevulinic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004058:Diffusion; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D051379:Mice; D011166:Porphyrins / Q000096:biosynthesis; D019802:Succinic Acid / Q000378:metabolism; D013696:Temperature; D013778:Tetrazolium Salts; D013844:Thiazoles; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018756:GABA Antagonists; D011166:Porphyrins; D013778:Tetrazolium Salts; D013844:Thiazoles; D005680:gamma-Aminobutyric Acid; D000622:Aminolevulinic Acid; D019802:Succinic Acid; C022616:thiazolyl blue