Simultaneous targeted delivery of doxorubicin and KRAS suppression by a hybrid molecule containing miR-143 and AS1411...

Hybrid molecules can be engineered to target tumors by merging drugs with the same or distinct mechanisms of action. The coexistence of multiple pharmacologically active entities within the cancer cell enhances the therapeutic efficacy of the hybrid molecule compared to single-target inhibitors. KRAS is considered the most common oncogenic gene in human cancers and is targeted by tumor suppressor miR-143. Therefore, an increase in miR-143 expression is a promising way to inhibit CRC cell growth. This research aims to develop a hybrid anticancer drug carrier by combining miR-143 and AS1411 aptamers through a hybridization strand (MAH) and loading doxorubicin (Dox), a chemotherapy drug. The uptake capability of MAH into the SW480 CRC cells was confirmed by detecting fluorescence intensity with a fluorescence microscope. After treatment of MAH in SW480 cells, the level of miR-143 was increased, but KRAS expression was decreased for both mRNA and protein. KRAS downstream target proteins, ERK and AKT, were downregulated as well. Furthermore, it was confirmed that DOX could be gradually released from MAH, with approximately 95% released over 72 h. Treating cells with Dox-MAH resulted in the inhibition of cell proliferation and induction of apoptosis. The protein expression of procaspase-3 and Bcl-2 was decreased, while Bax was increased, confirming that Dox-MAH triggered the cell apoptosis. The success of this research proposed a new strategy for a drug delivery system, which has multiple functions simultaneously; CRC cell-specificity, Dox carrier, and miR-143 delivery.