Aminolevulinic acid dendrimers in the treatment of cancer and atheromatous disease

VAINMAN M, RODRÍGUEZ L, DI VENOSA G, MAMONE L, GÁNDARA L, VALLECORSA P, ROSSETTI MV, BATLLE A, BATTAH S, CASAS A.

Lucerna

Congreso; Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias & International Meeting of Porphyria Patients.; 2013

Swiss Society of Clinical Chemistry

Photodynamic therapy (PDT) is an anticancer treatment that involves administration of a tumour-localising photosensitizer and its subsequent activation by visible light to result primarily in singlet oxygen?induced photodamage to the tumour. The photosensitizer absorbs light and in the presence of oxygen transfers energy, producing short-lived cytotoxic oxygen species such as singlet oxygen or other oxygen radicals. The use of endogenous protoporphyrin IX (PpIX) after administration of 5-aminolaevulinic acid (ALA) has led to many applications in PDT. However the efficacy of ALA-PDT is sub-optimal for thicker tumours and improved ALA delivery and therapeutic response are required. We have investigated the conjugation of ALA to a second-generation dendrimer for enhancing porphyrin synthesis in vitro. Recent advances in laser technology, and endovascular light delivery systems have broadened the scope of PDT to include atherosclerotic applications, so called Photoangioplasty. The aim of this work was to evaluate in vitro the ability of ALA dendrimers 6m-ALA and 9m-ALA to photosensitize cancer cells and macrophages. We have focused on selectivity, since the main aim is to damage macrophage component of the atheromatous plaque while leaving intact the vasculature structures. We have employed the LM3 mammary carcinoma, the Raw 264.7 macrophage and HMEC-1 microvasculature cell lines. Porphyrins synthesised from the three cell lines were evaluated fluorimetrically. LM3, HMEC-1 and Raw 264.7 cell lines exposed to both 6m-ALA and 9m-ALA reached complete ALA release from the nanocarriers 24 hr after incubation. On the other hand, porphyrin synthesis is higher at 3 hr in macrophages (6m-ALA= 52 ± 6 µg porphyrins/105 cells, 9m-ALA= 59 ± 7 µg porph./105 cells) as compared to the endothelial cell line (6m-ALA= 28 ± 3 µg porph./105 cells, 9m-ALA= 27 ± 2 µg porph/105 ccells) employing 0.2 mM concentrations (p< 0,01), thus demonstrating selectivity of dendrimers for macrophages. In tumour LM3 cells, PpIX from dendrimers is much higher as compared to ALA (ALA= 48 ± 6 µg porph./105 cells, 6m-ALA= 168 ± 19 µg porph/105 cells, 9m-ALA= 176 ± 20 µg porph/105 cells) at 3 hr employing 0.025 mM concentrations, showing the that dendrimers  are much efficient than ALA for use in PDT of cancer.