Comparison of liposomal formulations of ALA Undecanoyl ester for its use in photodynamic therapy

DI VENOSA G; HERMIDA L; FUKUDA H; DEFAIN MV; RODRIGUEZ L; MAMONE L; MACROBERT A; CASAS A; BATLLE A

JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY

Elsevier Sequoia

Año: 2009 vol. 96 p. 152 - 158

1011-1344

ALA administration has been used to induce the endogenous photosensitiser Protoporphyrin IX for photodynamictherapy (PDT) of tumours. However, the hydrophilic nature of ALA limits its ability to penetratethrough skin restricting the use of ALA-PDT to superficial diseases. Lipophilic derivatives of ALA such asALA Undecanoyl ester (Und-ALA) were designed to have better diffusing properties. However, Und-ALA,applied topically on the skin over the tumour, induced low porphyrin content. To improve Und-ALA efficacywe tested the efficacy of Und-ALA as porphyrin inducer, delivered in phosphatidylcholine and phosphatidylglycerol(PC–PG) or phosphatidylcholine and phosphatidic acid (PC–PA) liposomal formulations.Entrapment of Und-ALA into PC–PA or PC–PG liposomes resulted in a dramatic impairment of toxicity inthe mammary tumour LM3 cells. However, liposomal Und-ALA induced lower intracellular porphyrin contentcompared to free ALA, although total porphyrins content (intracellular + media) from free Und-ALAresulted equal compared to liposomal Und-ALA, due to induction of porphyrins release induced by the latter.Topical administration of Und-ALA in PC–PG or PC–PA liposomes over the skin of LM3 subcutaneouslyinjected mice, induced equal amount of tumour porphyrins as compared to free Und-ALA.The kinetics of porphyrins synthesis from Und-ALA is similar for free and liposomal formulations bothin vivo and in vitro, showing that release of Und-ALA from liposomes is not gradual and suggesting thatliposome membranes either fuses or binds to the cell membranes.To sum up, the incorporation of Und-ALA into liposomes of PC–PA or PC–PG composition does notimprove the rate of porphyrin synthesis either in vitro or in vivo, due to a massive release of extracellularporphyrins and a poor cytoplasmatic release of the liposome content. The design of new liposome compositionseither favouring endocytosis or coated with natural polymers to prevent Und-ALA interaction withcellular membrane are desired to overcome intracellular porphyrin release after long-chained ALA esterstreatment.