New derivatives of ALA and delivery systems

BATTAH, SINAN; CASAS, ADRIANA; EDWARDS, C.; BATLLE, ALCIRA; DOBBIN, P.; MACROBERT, ALEXANDER

Buenos Aires, Argentina

Workshop; 5th International Workshop on Photdynamic Therapy and Photodetection with Porphyrin precursosrs; 2006

Alcira Batlle, Qian Peng

Introduction: Intracellular porphyrin generation following administration of 5-aminolevulinic acid (ALA) has been widely in photodynamic therapy. However cellular uptake of 5-aminolevulinic acid 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 since they have a well-defined structure capable of incorporating a high drug payload. Materials and Methods: Dendrimer ALA conjugates were prepared which incorporated up to 18 aminolevulinic acid residues attached via ester linkages to a multipodent aromatic core, The ability of the dendrimer to deliver and released 5-aminolevulinic acid intracellularly for metabolism to the photosensitiser, protoporphyrin IX, was studied in the transformed PAM 212 murine keratinocyte and A431 human epidermoid carcinoma cell lines. Tissue porphyrin biodistributios were studied in a mouse model. Results: Up to an optimum concentration on 0.1 mM, the dendrimer conjugates were significantly more efficient compared to 5-aminolevulinic acid for porphyrin synthesis. The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure, together endocytic routes predominantly via macropinocytosis pathway. In vivo studies al CIPYP showed that ip administration of dendrimer ALA conjugates led to porphyrin generation in a range of tissues. Conclusions: Macromolecular dendritic derivatives are capable of delivering 5-aminolevulinic acid efficiently to cells for sustained porphyrin synthesis.