Abstract:
Ferulic acid (FA) has powerful antioxidant and antitumor activities, but it has low bioavailability
owing to its poor water solubility. Our aim is to formulate polymeric mixed micelles loaded with FA to
overcome its poor solubility and investigate its potential anticancer activity via miRNA-221/TP53INP1
axis-mediated autophagy in colon cancer. A D-optimal design with three factors was used for the
optimization of polymeric mixed micelles by studying the efects of each of total Pluronics mixture
(mg), Pluronic P123 percentage (%w/w), and drug amount (mg) on both entrapment efciency (EE%)
and particle size. The anticancer activity of FA and Tocopheryl polyethylene glycol 1000 succinate
(TPGS) mixed micelles formula (O2) was assessed by MTT and fow cytometry. O2 showed an EE% of
99.89%, a particle size of 13.86 nm, and a zeta potential of − 6.02 mv. In-vitro drug release studies
showed a notable increase in the release rate of FA from O2, as compared to the free FA. The (IC50)
values for FA from O2 and free FA were calculated against diferent cell lines showing a prominent
IC50 against Caco-2 (17.1 µg/ml, 191 µg/ml respectively). Flow cytometry showed that FA caused
cell cycle arrest at the G2/M phase in Caco-2. RT-PCR showed that O2 signifcantly increased the
mRNA expression level of Bax and CASP-3 (4.72 ± 0.17, 3.67 ± 0.14), respectively when compared to
free FA (2.59 ± 0.13, 2.14 ± 0.15), while miRNA 221 levels were decreased by the treatment with O2
(0.58 ± 0.02) when compared to free FA treatment (0.79 ± 0.03). The gene expression of TP53INP1 was
increased by the treatment with O2 compared to FA at P< 0.0001. FA-loaded TPGS mixed micelles
showed promising results for enhancing the anticancer efect of FA against colorectal cancer, probably
due to its enhanced solubility.Thus, FA-loaded TPGS mixed micelles could be a potential therapeutic
agent for colorectal cancer by targeting miRNA-221/TP53INP1 axis-mediated autophagy.
