title: Aminolevulinic acid dendrimers in photodynamic treatment of cancer and atheromatous disease.
abstract: The use of endogenous protoporphyrin IX after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). We have previously reported that the conjugation of ALA dendrimers enhances porphyrin synthesis. The first 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. For this aim, we employed LM3 mammary carcinoma cells. In these tumour cells, at low concentrations porphyrin synthesis from dendrimers was higher compared to ALA, whereas at high concentrations, porphyrin synthesis was similar from both compounds. Topical application of ALA dendrimers on the skin overlying a subcutaneous LM3 implanted tumour showed no diffusion 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. As a second objective, we proposed the use of ALA-dendrimers in vascular PDT for the treatment of atherosclerosis. Thus, we focused our studies on ALA-dendrimer's selectivity towards macrophages in comparison with endothelial cells. For this aim we employed 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 compared to the endothelial cell line, demonstrating the high affinity of ALA dendrimers for macrophages. On the other hand, ALA employed at low concentrations was slightly selective (1.7-fold) for macrophages. Inhibition studies suggested that ALA dendrimer uptake in macrophages is mainly mediated by caveloae-mediated endocytosis. Our main conclusion is that in addition to being promising molecules in PDT of superficial cancer, ALA dendrimers may also find applications in vascular PDT, since in vitro they showed selectivity to the macrophage component of the atheromatous plaque, as compared to the vascular endothelium.
authors.affiliation: Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP). CONICET-Htal de Clínicas Gral. José de San Martín, Córdoba 2351 1er subsuelo, Ciudad de Buenos Aires, CP-1120AAF, Argentina. adriana@qb.fcen.uba.ar.
authors.forename: L
authors.initials: L
authors.lastname: Rodriguez
authors.forename: P
authors.initials: P
authors.lastname: Vallecorsa
authors.forename: S
authors.initials: S
authors.lastname: Battah
authors.forename: G
authors.initials: G
authors.lastname: Di Venosa
authors.forename: G
authors.initials: G
authors.lastname: Calvo
authors.forename: L
authors.initials: L
authors.lastname: Mamone
authors.forename: D
authors.initials: D
authors.lastname: Sáenz
authors.forename: M C
authors.initials: MC
authors.lastname: Gonzalez
authors.forename: A
authors.initials: A
authors.lastname: Batlle
authors.forename: A J
authors.initials: AJ
authors.lastname: MacRobert
authors.forename: A
authors.initials: A
authors.lastname: Casas
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000622:Aminolevulinic Acid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D011166:Porphyrins / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism
chemical_list: D050091:Dendrimers; D017319:Photosensitizing Agents; D011166:Porphyrins; D000622:Aminolevulinic Acid