Mechanism of ALA derivatives transport used for Photodynamic Therapy

RODRÍGUEZ L, DI VENOSA G, BATTAH S, DANIEL H, MACROBERT A, CASAS A, BATLLE A

Newport, USA

Conferencia; Chemistry and Biology of Tetrapirroles Gordon Reseach Conference; 2006

Gordon Reseach Conferences

Accumulation of endogenous porphyrins produced after administration of 5-aminolevulinic acid (ALA) is applied in Photodynamic Therapy  (PDT). Due to its low membrane permeability, esterified ALA- derivatives which are less hydrophilic than ALA are under current investigation as possible alternatives to ALA. In this work it was assessed the interaction of ALA derivatives with the mammalian peptide transport system through inhibition studies employing radiolabelled ALA in Pichia pastoris cells expressing the intestinal PEPT1 and renal transporter PEPT2.  It was found that all the ALA derivatives, namely Undecanoyl-ALA (Und-ALA), Hexyl-ALA (He-ALA), R, S-ALA-2-(hydroxymethyl)tetrahydropyranyl ester (THP-ALA), Methyl-ALA (Me-ALA) and the dendron 3m-ALA inhibited 14C-ALA uptake by PEPT2.  However, only the more lipophlilic derivative Und-ALA inhibited ALA uptake by PEPT1. Direct colorimetric quantification of intracellular ALA and ALA derivatives showed that the increasing rates of affinity for PEPT2 were: THP-ALA>He-ALA>ALA=3m-ALA>Me-ALA>Und-ALA; and for PEPT1: ALA>3m-ALA>He-ALA>THP-ALA>Me-ALA=Und-ALA. Und-ALA binds with high affinity to the membranes of PEPT2 and PEPT1-expressing yeasts.  Our results suggest that the derivatives THP-ALA and He-ALA could improve ALA-PDT outcome when applied in tissues expressing PEPT2 such as kidney, mammary gland, brain, lung but not in tissues like intestine, expressing PEPT1.