PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery.

Yi Zhao,Shutao Guo,Lei Miao,Yang Xiong,Yuhua Wang,Wei Wang,Leaf Huang

doi:10.1038/ncomms11822

Abstract

Metformin, a widely implemented anti-diabetic drug, exhibits potent anticancer efficacies. Herein a polymeric construction of Metformin, PolyMetformin (PolyMet) is successfully synthesized through conjugation of linear polyethylenimine (PEI) with dicyandiamide. The delocalization of cationic charges in the biguanide groups of PolyMet reduces the toxicity of PEI both in vitro and in vivo. Furthermore, the polycationic properties of PolyMet permits capture of siRNA into a core-membrane structured lipid-polycation-hyaluronic acid (LPH) nanoparticle for systemic gene delivery. Advances herein permit LPH-PolyMet nanoparticles to facilitate VEGF siRNA delivery for VEGF knockdown in a human lung cancer xenograft, leading to enhanced tumour suppressive efficacy. Even in the absence of RNAi, LPH-PolyMet nanoparticles act similarly to Metformin and induce antitumour efficacy through activation of the AMPK and inhibition of the mTOR. In essence, PolyMet successfully combines the intrinsic anticancer efficacy of Metformin with the capacity to carry siRNA to enhance the therapeutic activity of an anticancer gene therapy.

Highlights

Metformin, a widely implemented anti-diabetic drug, exhibits potent anticancer efficacies
PolyMet successfully combines the intrinsic anticancer efficacy of Metformin with the capacity to carry short interfering RNA (siRNA) to enhance the therapeutic activity of an anticancer gene therapy
Inspired by the fact that Metformin can be synthesized through a one-step reaction of dimethylamine hydrochloride and 2-cyanoguanidine, with heating (Supplementary Fig. 1), the Metformin polymer was designed using a similar method

Summary

Introduction

A widely implemented anti-diabetic drug, exhibits potent anticancer efficacies. PolyMet successfully combines the intrinsic anticancer efficacy of Metformin with the capacity to carry siRNA to enhance the therapeutic activity of an anticancer gene therapy. A polycationic bi-guanidine composed of the anticancer therapeutic, Metformin (dimethyl-biguanide), has been developed for in vivo siRNA delivery. The anticancer efficacy of Metformin can be primarily attributed to the activation of AMP-activated protein kinase (AMPK)[26,27] and inhibition of the mammalian target of rapamycin (mTOR)[28,29] This cationic small molecular drug shows excellent tolerability and can be dosed at up to 2 g per day due to low toxicity.

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Results

Conclusion