Polypeptide Derivative of Metformin with the Combined Advantage of a Gene Carrier and Anticancer Activity.

Metformin (MET) is a common treatment for type II diabetes. Here, we demonstrate the anticancer activity of a polymeric metformin derivative. We successfully synthesized the polypeptide (poly-l-lysine [PLL]) derivative of metformin (LysMET) and demonstrated its capacity as an anticancer therapeutic and gene carrier. miRNA-320a was loaded into the cationic LysMET and enveloped in a lipid bilayer, and a MUC1-specific aptamer was conjugated to the surface (A-Lipo@mLysMET). The LysMET-containing guanidine moiety was more tolerable than the secondary amine-containing PLL. LysMET showed similar efficacy to MET in the induction of HT-29 tumor suppression, indicating the importance of the biguanide moiety. The synergistic effect of miRNA-320a and LysMET treatment significantly decreased cell viability compared with LysMET treatment alone, which was attributed to the role of miRNA in the β-catenin pathway. A-Lipo@mLysMET showed excellent antitumor efficacy and significantly reduced the tumor burden in all groups. AMPKα phosphorylation was markedly increased by LysMET compared with the control, with significant inhibition of the mTOR pathway. The TUNEL assay showed that apoptosis was the main mechanism responsible for cancer cell death and that A-Lipo@mLysMET resulted in the highest proportion of TUNEL-positive cells (∼36%). No noticeable organ damage was observed after treatment with either LysMET or A-Lipo@mLysMET, confirming the excellent safety profile of guanide-modified polymers. Overall, we demonstrated the feasibility of LysMET for the effective control of tumor progression as well as its dual role, as both a drug and a gene carrier.