Folic acid-conjugated pH-responsive poly(methacrylic acid) nanospheres for targeted delivery of anticancer drugs to breast cancer cells

Abstract

Folic acid (FA)-conjugated poly(methacrylic acid) nanospheres were synthesized as a pH-responsive nanocarrier for entrapping doxorubicin (DOX) to target folate-receptors-overexpressing breast cancer cells. To this end, poly(methacrylic acid) nanospheres were first prepared by precipitation polymerization, and then, the FA was conjugated to the pendent hydroxyl groups on the surface of nanospheres via the Stiglich esterification method. The chemical structure of the desired product was evaluated by Fourier transform infrared (FTIR) and hydrogen-nuclear magnetic resonance (1H NMR) techniques. The optimized product had a spherical shape with an average diameter of 149.2 nm and narrow particle size distribution (PDI = 0.268). Also, the surface charge of the prepared nanospheres was measured to be −41.3 mV, indicating a high colloidal stability in physiological media. The prepared nanocarrier displayed a good entrapment efficiency for DOX (86.5%), along with a high drug loading capacity (17.3%). The drug release experiments showed that, by decreasing the pH of the release medium from 7.4 to 5.5, the cumulative release of the DOX from the nanospheres increased from 22 to 32%, indicating the pH-responsivity of the prepared nanocarrier. Moreover, FA-conjugated poly(methacrylic acid) (FA-PMAA) nanospheres showed a higher anticancer efficacy against folate receptor-breast cancer cells (MCF-7 cancer cells) compared to the bare nanospheres and free DOX. The half-maximal inhibitory concentrations (IC50) of free DOX, PMAA, and FA-PMAA nanospheres were 12.8, 11.0, and 2.7 µg/mL, respectively. The obtained results suggest that the FA-PMAA nanospheres could be a promising pH-responsive nanocarrier for the targeted delivery of anticancer drugs to folate-receptor overexpressing cancer cells.