Aminolevulinic acid dendrimers in photodynamic treatment of cancer and atheromatous disease

RODRIGUEZ L; VALLECORSA P; BATTAH S; DI VENOSA G; CALVO G; MAMONE L; SAENZ D; GONZALEZ MC; BATLLE A; MACROBERT AJ; CASAS A

Photochemical and Photobiological Sciences

ROYAL SOC CHEMISTRY

Lugar: CAMBRIDGE; Año: 2015 vol. 14 p. 1617 - 1627

1474-905X

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. 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 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 vascular PDT, 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 intima layer. We employed LM3 mammary carcinoma, Raw 264.7 macrophages and HMEC-1 microvasculature cells. Porphyrin synthesis induced in macrophages by 6m-ALA and 9m-ALA (3 h, 0.025 mM), was 6 and 4.6 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 (1.7-fold) for macrophages. At low concentrations, porphyrin synthesis from dendrimers was higher in LM3 and macrophages but not in HMEC-1 cells as compared to ALA.  Inhibition studies suggested that ALA dendrimers uptake is mainly mediated by caveloae-mediated endocytosis. Topical application of ALA dendrimers on the skin overlying a subcutaneous LM3 tumour showed no difusion of the molecules either to distant skin sites or to the adjacent tumour, suggesting a promising use of the ALA macromolecules in superficial cancer models. Our main conclusion is that, in addition to being promising molecules in PDT of cancer, ALA dendrimers are also encouraging in vascular PDT, since in vitro they showed selectivity for the macrophage component of the atheromatous plaque, as compared to the vascular endothelium.