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 ß-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.

Facile construction of bioreducible crosslinked polypeptide micelles for enhanced cancer combination therapy.

In this study, we developed pH and redox-responsive crosslinked polypeptide-based combination micelles for enhanced chemotherapeutic efficacy and minimized side effects. The stability and drug release properties of the polypeptide micelles were efficiency balanced by the corona-crosslinking of the triblock copolymer, poly(ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine) (PEG-b-pAsp-b-pTyr) with coordinated redox and pH dual-sensitivity by introducing disulfide crosslinkages. Because of the crosslinking of the middle shell of the triblock polypeptide micelles, their robust structure was maintained in strong destabilization conditions and exhibited excellent stability. GSH concentrations were significantly higher in tumor tissue than in normal tissue, which formed the basis for our design. Drug release was elevated under redox and low acidic conditions. Furthermore, crosslinked micelles showed a superior anticancer effect compared to that of non-crosslinked micelles. Incorporation of docetaxel (DTX) and lonidamine (LND) in crosslinked polypeptide micelles increased the intracellular reactive oxygen species (ROS) level and oxidative stress and caused damage to intracellular components that resulted in greater apoptosis of cancer cells than when DTX or LND was used alone. The combination of DTX and LND in crosslinked micelles exhibited efficacious inhibition of tumor growth with an excellent safety profile compared to that reported for drug cocktail combinations and non-crosslinked micelles. Overall, redox/pH-responsive polypeptide micelles could be an interesting platform for efficient chemotherapy. STATEMENT OF SIGNIFICANCE: We have synthesized a biodegradable polypeptide block copolymer to construct a facile pH and redox-responsive polymeric micelle asan advanced therapeutic system for cancer therapy. We have designed a corona-crosslinked triblock copolymer (poly (ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine) (PEG-b-pAsp-b-pTyr)) micelles co-loaded with docetaxel and lonidamine (cl-M/DL). The corona of triblock polymer was crosslinked to maintain its structural integrity in the physiological environment. The mitochondrial targeting LND is expected to generate ROS, oxidative stress and thereby synergize the chemotherapeutic efficacy of DTX in killing cancer cells. Consistently, cl-M/DL exhibited excellent antitumor efficacy in xenograft tumor model with remarkable tumor regression. Overall, we demonstrated the construction of bioreducible nanosystem for the effective synergistic delivery of DTX/LND in tumor tissues towards cancer treatment.