Enhancement of all-trans retinoic acid-induced differentiation by pH-sensitive nanoparticles for solid tumor cells

Abstract

Cancer differentiation therapy is an attractive concept and has been clinically used to treat leukemia. However, it is limited to date for solid tumors. In this study, the pH-sensitive nanoparticles based on poly(amidoamine) (PAMAM) dendrimers are synthesized by coupling 3,4,5,6-tetrahydrophthalic anhydride with the first generation PAMAM. The modified dendrimers can self-assemble in aqueous solution to form nanoparticles with a diameter of 125-435 nm. The nanoparticles are relatively stable at physiological pH (pH 7.4) but dissociated in acidic environments (pH 5.0 or 6.0). The present studies show that the proliferation inhibition and albumin secretion of hepatoma carcinoma cells are enhanced with all-trans retinoic acid (ATRA) encapsulated in the nanoparticles. The enhancement of induced differentiation is due to the high internalization of ATRA in the cells by the nanoparticles. These experimental results demonstrate that pH-sensitive nanoparticles may be efficient for improving the differentiation therapy for solid tumor.

Keywords: all-trans-retinoic acid; dendrimers; induced differentiation; intracellular delivery; nanoparticles.