Aminolevulinic acid dendrimers in photodynamic treatment of cancer and atheromatous disease

CASAS A

Congreso; 16th International Congress on Photobiology; 2014

International Union of Photobiology,

    Photodynamic therapy (PDT) is a new concept in the therapy of neoplastic disease. In addition, recent advances in endovascular light delivery systems have broadened the scope of PDT to include atherosclerotic treatment, so called Photoangioplasty.   The use of endogenous Protoporphyrin IX after administration of 5-aminolaevulinic acid (ALA) has led to many applications in PDT. We have previously reported that the conjugation of ALA to second-generation dendrimers enhances porphyrin synthesis.   The aim of this work was to evaluate the ability of ALA dendrimers carrying 6 and 9 ALA residues (6m-ALA and 9m-ALA) to photosensitise cancer cells and macrophages. We proposed the use of ALA-dendrimers in Photoangioplasty, and we focused our studies on selectivity, since the main aim of this therapy is to damage the macrophage component of the atheromatous plaque while leaving intact the vasculature structures.   We employed the LM3 mammary carcinoma, the Raw 264.7 macrophages and HMEC-1 microvasculature cells. Porphyrins synthesised from the three cell lines were evaluated fluorimetrically.   Porphyrin synthesis induced in macrophages by 6m-ALA and 9m-ALA, was 7 and 9 times higher respectively as compared to the endothelial cell line, demonstrating high selectivity of ALA dendrimers for macrophages. On the other hand, ALA employed at low concentrations was slightly selective (2-fold) for macrophages. Under the same conditions, porphyrin synthesis from dendrimers was higher in tumour LM3 cells as compared to ALA, showing that the dendrimers are much efficient than ALA in PDT of cancer.   Inhibition studies employing caveloae-mediated and clathrin-dependent endocytosis inhibitors, as well as macropinocytosis inhibitors, suggested that ALA dendrimers uptake is mainly mediated by caveloae-mediated endocytosis.   Our main conclusion is that, in addition to being promising molecules in PDT of cancer, ALA dendrimers are also encouraging in Photoangioplasty, since in vitro they showed selectivity for the macrophage component of the atheromatous plaque, as compared to the vascular endothelium.