Investigation of a novel dendritic derivative of 5-aminolaevulinic acid for photodynamic therapy.
Photodynamic therapy is a treatment for malignant and certain non-malignant lesions that involves administration of a photosensitising drug. The use of 5-aminolaevulinic acid-induced porphyrins has become one of the most active fields of photodynamic therapy research. Since the efficacy of the treatment is somewhat limited by the hydrophilic nature of 5-aminolaevulinic acid, chemical modifications such as esterification with aliphatic alcohols have been made to induce higher porphyrin production. In an attempt to improve delivery of 5-aminolaevulinic acid to tissue, we have investigated the use of dendritic derivatives capable of bearing several drug molecules. The aim of this work was to evaluate in vivo and in vitro the efficacy of the first generation dendron, aminomethane tris-methyl 5-aminolaevulinic acid (containing three 5-aminolaevulinic acid residues) in terms of porphyrin synthesis. In LM3 cells, the dendron induced similar porphyrin levels compared to equimolar concentrations of 5-aminolaevulinic acid. Although the dendron is taken up with comparable efficiency to 5-aminolaevulinic acid, we found that there is only partial intracellular liberation of 5-aminolaevulinic acid residues. Both systemic and topical administration of the dendron to tumour-bearing mice induced higher porphyrin levels than the widely investigated hexyl ester derivative in most tissues studied, although it was not possible to surpass the levels induced by 5-aminolaevulinic acid. In conclusion, aminomethane tris-methyl 5-aminolaevulinic acid is capable of being taken up by cells efficiently, and liberating the active residues, although in vivo it was not possible to improve upon the efficacy of 5-aminolevulinic acid. Studies of accessibility and regulation of the esterases are needed to improve the design of these dendritic derivatives.
Di Venosa
Gabriela M
GM
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clinicas José de San Martin, University of Buenos Aires, Argentina.
Casas
Adriana G
AG
Battah
Sinan
S
Dobbin
Paul
P
Fukuda
Haydée
H
Macrobert
Alexander J
AJ
Batlle
Alcira
A
D000622:Aminolevulinic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000138:chemical synthesis; D000818:Animals; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010778:Photochemotherapy / Q000379:methods; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000138:chemical synthesis; D011166:Porphyrins / Q000096:biosynthesis
D017319:Photosensitizing Agents; D011166:Porphyrins; D000622:Aminolevulinic Acid