Nanocomplexes loaded with miR-128-3p for enhancing chemotherapy effect of colorectal cancer through dual-targeting silence the activity of PI3K/AKT and MEK/ERK pathway

Abstract

Although microRNAs (miRNAs)-based cancer therapy strategies have been proved to be efficient and superior to chemotherapeutic agents in certain extent, the unstable properties of miRNAs significantly impaired the wide application. Therefore, how to safely deliver the miRNAs to the targeted site of action is the most pivotal step to achieve the ideal treatment effect. In the present work, the miR-128-3p, which is able of inducing chromosomal instability, was loaded into the nanocomplexes developed by the PEG-PDMAEMA (PDMAEMA-NP). By this way, the miR-128-3p was shielded from exposure to various degrading enzymes in bloodstream. Additionally, the PEGylation endowed the PDMAEMA-NP with long time of circulation as demonstrated in vivo by pharmacokinetics investigation. To target and deliver the miR-128-3p to the site of action, a tumor-homing peptide CPKSNNGVC, which specifically targets the monocarboxylate transporter 1 (MCT1), was decorated on the surface of PDMAEMA-NP. Both in vitro and in vivo experiments demonstrated that more efficient delivery of miR-128-3p to cells or tumor tissues was obtained by the PDMAEMA-NP than plasmid. Additionally, modification of C peptides further enhanced the tumor accumulation of miR-128-3p, and in turn contributed to the stronger tumor growth inhibition effect. Underlying mechanisms study revealed that the miR-128-3p inhibited the growth, migration, and invasion of colorectal cancer (CRC) cells and progress of CRC tissues through silence of the activity of PI3K/AKT and MEK/ERK pathway. By this way, the chemotherapy effect of 5-Fluorouracil (5-Fu) was dramatically improved after co-treating the cells with miR-128-3p formulations.

Keywords

• micrornas
• nanocomplexes
• tumor-targeting
• signaling pathways
• 5-fluorouracil