The International Journal of Biochemistry & Cell Biology 38 (2006) 82–91 Investigation of a novel dendritic derivative of 5-aminolaevulinic acid for photodynamic therapy Gabriela M. Di Venosa a , Adriana G. Casas a , Sinan Battah b , Paul Dobbin c , Hayd´ ee Fukuda a , Alexander J. MacRobert b,∗ , Alcira Batlle a a Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET and Hospital de Clinicas Jos´ e de San Martin, University of Buenos Aires, Argentina b National Medical Laser Centre, Div. Surgical and Interventional Sciences, Royal Free and University College Medical School, University College London, Charles Bell House, 67-73 Riding House St., London W1W 7EJ, UK c School of Biological Sciences, University of Essex, UK Received 14 April 2005; received in revised form 26 July 2005; accepted 10 August 2005 Abstract Photodynamic therapy is a treatment for malignant and certain non-malignant lesions that involves administration of a photo- sensitising 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. © 2005 Elsevier Ltd. All rights reserved. Keywords: Photodynamic Therapy; PDT; Aminolaevulinic acid; ALA derivatives; Dendrimers Abbreviations: ALA, 5-aminolaevulinic acid; He-ALA, hexyl-ALA; 3m-ALA, aminomethane tris–methyl ALA TFA salt; Me-ALA, methyl ALA; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide; PBS, phosphate buffered saline; PDT, photodynamic therapy; PpIX, protoporphyrin IX; TFA, trifluoroacetic acid ∗ Corresponding author. Tel.: +44 207 6799384; fax: +44 207 8132828. E-mail address: a.macrobert@ucl.ac.uk (A.J. MacRobert). 1357-2725/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2005.08.001