Third generation dendrimers as macromolecular carriers for ALA prodrug delivery: an in vivo study

BATTAH S, CASAS A, DI VENOSA G, FUKUDA H, BATLLE A, MACROBERT A

Munich, Alemania

Congreso; IPA 10th; 2005

International Photodynamic Association

Objectives: Esterification of ALA with aliphatic alcohols has been found to reduce the amount of ALA required for photosensitization. A different strategy would be to design a prodrug that can deliver several ALA molecules simultaneously into the cells. In this work we investigated novel dendritic ALA prodrugs in vivo and invetro. These relatively large macromolecular carriers can be taken up by cells via endocytosis thus releasing the ALA residues gradually by enzymatic hydrolysis with non-specific esterases. Material and Methods: A third generation hyperbranched dendrimer conjugated with 18 ALA molecules via ester linkages was synthesized. We tested this type of dendritic ALA (18mer) in vivo and in vetro and examined its ability to undergo hydrolysis and generate protoporphyrin IX (PpIX). The compound was administered i.p to mice bearing the subcutaneously implanted LM3 adenocarcinoma and the PpIX tissue kinetics and PpIX generation in PAM 212 cell line were measured using fluorescence detection. Results: Systemic administration to mice resulted in sustained production of PpIX in tumour, skin, liver, spleen, kidney and brain, up to 36 h after administration, a much longer period than with ALA adminiistration. Moreover, this dendrimer was able to induce high porphyrin levels even at relatively low prodrug concentrations in vivo and in vitro. Conclusions: These results show that the 18mer gradually releases ALA residues for porphyrin production. The slow release mechanism of ALA delivery using dendritic prodrugs may also have some therapeutic advantages.