Comparation of liposomal formulations of ALA Undecanoyl ester for its use in photodynamic therapy.
ALA administration has been used to induce the endogenous photosensitiser Protoporphyrin IX for photodynamic therapy (PDT) of tumours. However, the hydrophilic nature of ALA limits its ability to penetrate through skin restricting the use of ALA-PDT to superficial diseases. Lipophilic derivatives of ALA such as ALA 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 efficacy we 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 in the mammary tumour LM3 cells. However, liposomal Und-ALA induced lower intracellular porphyrin content compared to free ALA, although total porphyrins content (intracellular+media) from free Und-ALA resulted 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 subcutaneously injected 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 both in vivo and in vitro, showing that release of Und-ALA from liposomes is not gradual and suggesting that liposome 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 not improve the rate of porphyrin synthesis either in vitro or in vivo, due to a massive release of extracellular porphyrins and a poor cytoplasmatic release of the liposome content. The design of new liposome compositions either favouring endocytosis or coated with natural polymers to prevent Und-ALA interaction with cellular membrane are desired to overcome intracellular porphyrin release after long-chained ALA esters treatment.
Di Venosa
Gabriela
G
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, Ciudad de Buenos Aires, Argentina.
Hermida
Laura
L
Fukuda
Haydée
H
Defain
María Victoria
MV
Rodriguez
Lorena
L
Mamone
Leandro
L
MacRobert
Alexander
A
Casas
Adriana
A
Batlle
Alcira
A
D000287:Administration, Topical; D000622:Aminolevulinic Acid / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D004987:Ethers / Q000737:chemistry*; D007279:Injections, Subcutaneous; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D051379:Mice; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry*; D011166:Porphyrins / Q000378:metabolism
D004987:Ethers; D008081:Liposomes; D017319:Photosensitizing Agents; D011166:Porphyrins; D000622:Aminolevulinic Acid