Optimising Photodynamic Therapy: In vitro and in vivo use of ALA derivatives

BATLLE A, CASAS A, PEROTTI C, DI VENOSA G, FUKUDA H, MACROBERT A

Bressanone, Italia

Simposio; International Symposium on Photodynamic Diagnosis and Therapy in clinical practice; 2003

5-Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) has been shown to be clinically beneficial for the treatment of certain tumours, including several skin cancers, however optimal tissue localisation is yet a problem.  The use of more lipophilic ALA derivatives instead of ALA, to enhance protoporphyrin IX (PPIX) bioavailability is being examined. The aim of this work, has been therefore to test, using both in vitro and in vivo systems, the efficiency of different ALA derivatives: Hexyl-ALA (He-ALA), Undecanoyl-ALA and R,S-ALA-2-(Hydroxymethyl) tetrahydropyranyl-ALA (THP-ALA), compared with ALA. These compounds were assayed in vitro, employing a cell line derived from a murine mammary tumour and tumour explants, and in vivo, after injection of the cells into mice. In cells, PPIX synthesis from He-ALA was more efficient than from ALA. Instead, Undecanoyl-ALA and THP-ALA did not enhance ALA response. Kinetics of porphyrin synthesis from the different derivatives suggests different uptake mechanisms. I.p. injection of ALA derivatives to mice, resulted in a tumoural porphyrin concentration 4-times lower when compared with equimolar amounts of ALA. In tumour explants, porphyrin synthesis from He-ALA and ALA was similar, but it was 3.3-times lower from THP-ALA as compared to ALA. Undecanoyl-ALA produced nearly basal PPIX levels, these results were showing a good correlation between both in vitro models. ALA levels measured in the unperfused  tumour, after ALA or ALA derivatives injection, did not correlate with porphyrin synthesis. Both in vitro and in vivo data, are suggesting that capillaries are playing an important role in the cellular uptake of ALA esters.