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Abstrakt
Selective Antitumoral Effect of Sorafenib Loaded PLGA Nanoparticles Conjugated with Cetuximab on Undifferentiated/Anaplastic Thyroid Carcinoma Cells
Mato E, Puras G, Bell O, Agirre M, Hernández RM, Igartua M, Moreno R, Gonzalez G, Alberto de Leiva Hidalgo and Jose Luis Pedraz
Drug targeting represents a challenging approach with promising potential to circumvent some problems associated with many toxic effects of antineoplastics drugs. The objective of the present study was to develop PLGA nanoparticles surface modified with cetuximab to deliver in a targeted fashion sorafenib into undifferentiated/anaplastic thyroid carcinoma cell line as an efficient in vitro model
Sorafenib loaded nanoparticles were obtained by the single emulsion evaporation method and characterized in terms of size (252 nm), charge (-14.6 mV), morphology (spherical), drug entrapment efficiency (58%) and in vitro drug release. Resulted nanoparticles were surface conjugated with monoclonal antibody cetuximab by EDC/Sulfo-NHS cross linking chemistry, without affecting significantly to their physicochemical properties. 51% of the cetuximab was incorporated into the surface of PLGA nanoparticles. Cellular uptake studies were performed with fluorescent (6-coumarin) PLGA nanoparticles and cetuximab conjugated fluorescent PLGA nanoparticles in both thyroid anaplastic (CAL-62) and normal thyroid cells (Nthy-ori 3-1). Confocal microscopy assays revealed that the capture of immunonanoparticles over the time showed a different pattern depending on the cell and the nanoparticles studies. In vitro antiproliferation assay based on MTT showed that sorafenib incorporated nanoparticles had a more cytotoxic effect on normal thyroid Nthy-ori 3-1 cells than on anaplastic thyroid CAL-62 cells. However, cetuximab conjugated nanoparticles reverted the cytotoxicity profile, showing a lower cytotoxic effect on normal thyroid Nthy-ori 3-1 cells when compared with anaplastic thyroid CAL-62 cells. These data suggest that sorafenib-PLGA nanoparticles surface modified with cetuximab represent a new and promising targeting approach for the treatment of epithelial thyroid cancer.