This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Battah, S. Articles by MacRobert, A. J. Search for Related Content PubMed PubMed Citation Articles by Battah, S. Articles by MacRobert, A. J.

Research Articles: Therapeutics, Targets, and Development

Macromolecular delivery of 5-aminolaevulinic acid for photodynamic therapy using dendrimer conjugates

¹ National Medical Laser Centre, Division Surgical and Interventional Sciences, Royal Free and University College Medical School, University College London, United Kingdom; ² Department of Biological Sciences, University of Essex, Essex, United Kingdom; and ³ Centro de Investigaciones sobre Porfirinas y Porfirias, Consejo Nacional de Investigaciones Científicas y Técnicas, and Hospital de Clínicas José de San Martín, University of Buenos Aires, Buenos Aires, Argentina

Requests for reprints: Alexander J. MacRobert, National Medical Laser Centre, University College London, Charles Bell House, 67-73 Riding House Street, London W1W 7EJ, United Kingdom. Phone: 0207-6799060; Fax: 0207-8132828. E-mail: a.macrobert{at}ucl.ac.uk

Abstract

Intracellular porphyrin generation following administration of 5-aminolaevulinic acid (5-ALA) has been widely used in photodynamic therapy. However, cellular uptake of 5-ALA is limited by its hydrophilicity, and improved means of delivery are therefore being sought. Highly branched polymeric drug carriers known as dendrimers present a promising new approach to drug delivery because they have a well-defined structure capable of incorporating a high drug payload. In this work, a dendrimer conjugate was investigated, which incorporated 18 aminolaevulinic acid residues attached via ester linkages to a multipodent aromatic core. The ability of the dendrimer to deliver and release 5-ALA intracellularly for metabolism to the photosensitizer, protoporphyrin IX, was studied in the transformed PAM 212 murine keratinocyte and A431 human epidermoid carcinoma cell lines. Up to an optimum concentration of 0.1 mmol/L, the dendrimer was significantly more efficient compared with 5-ALA for porphyrin synthesis. The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure, together with minimal dark toxicity. Cellular uptake of the dendrimer occurs through endocytic routes predominantly via a macropinocytosis pathway. In conclusion, macromolecular dendritic derivatives are capable of delivering 5-ALA efficiently to cells for sustained porphyrin synthesis. [Mol Cancer Ther 2007;6(3):876–85]

Grant support: Biotechnology and Biological Sciences Research Council grant (S. Battah).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Unpublished data.

Received 6/21/06; revised 11/30/06; accepted 1/24/07.

This article has been cited by other articles:

				L. Bourre, F. Giuntini, I. M. Eggleston, M. Wilson, and A. J. MacRobert 5-Aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy Mol. Cancer Ther., June 1, 2008; 7(6): 1720 - 1729. [Abstract] [Full Text] [PDF]