INVESTIGADORES
MORILLA Maria Jose
artículos
Título:
Enhanced antimelanoma activity of methotrexate and zoledronic acid within polymeric sandwiches.
Autor/es:
PRISCILA SCHILRREFF; GABRIELA CERVINI; EDER L ROMERO; MARIA JOSE MORILLA
Revista:
COLLOIDS AND SURFACES B-BIOINTERFACES
Editorial:
ELSEVIER SCIENCE BV
Referencias:
Lugar: Amsterdam; Año: 2014 vol. 122
ISSN:
0927-7765
Resumen:
New therapies are urgently needed against melanoma, one of the most aggressive tumors. Melanoma cells are resistant to the antifolate methotrexate (MTX), since MTX is taken up by the folate receptor-(FR), sequestered in melanosomes and exported out of the cell. The bisphosphonate zoledronic acid(ZOL) is active in several non-skeletal tumors; however, its antitumoral activity is hampered by its long-term accumulation in bones and low cellular permeability. Recently, we showed that core shell tecto-dendrimers made of amine-terminated polyamidoamine generation 5 dendrimer (G5) as core and carboxyl-terminated G2.5 dendrimer as shell (G5G2.5) had selective cytotoxicity to melanoma cells. We hypothesized here that the activity of MTX and ZOL on melanoma cells could be enhanced when loaded within G5G2.5 MTX and ZOL were loaded within G5 cores, which were coated by a covalently bound shell of G2.5 dendrimers (drug-sandwiches). 12 nm mean diameter and -12 mV Z potential drug-sandwichesincorporating 6 and 31 molecules of MTX and ZOL, respectively, per G5G2.5, showed higher cytotoxicity (by MTT and apoptosis/necrosis assays) to melanoma (Sk-Mel-28) cells than free drugs and G5G2.5. Only MTX-sandwich was cytotoxic to Sk-Mel-28 cells and harmless to keratinocytes (HaCaT cells). The intracellular pathway of G5G2.5 was followed using chemical inhibitors of endocytosis. The increased cytotoxicity of MTX-sandwich could be due to its uptake by macropinocytosis instead of by FR, avoiding MTX exocytosis. The increased cytotoxicity of ZOL-sandwich could be due to anincreased intracellular accumulation of ZOL, owed by its endocytic uptake instead of diffusing as free drug.