PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery

• Published in: Nature communications 2016-06, Vol.7 (1), p.11822-9, Article 11822
• Main Authors: Zhao, Yi, Wang, Wei, Guo, Shutao, Wang, Yuhua, Miao, Lei, Xiong, Yang, Huang, Leaf
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/2; 13/51; 13/89; 14/63; 631/1647/2300; 631/61/51/391/3932; 631/67/1059; 631/92/436/108; 64/60; Adenylate Kinase - metabolism; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Autophagy - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Carriers - chemistry; Drug dosages; Female; Gene therapy; Gene Transfer Techniques; Humanities and Social Sciences; Humans; Hyaluronic Acid - chemistry; Kinases; Lipids - chemistry; Lung cancer; Metformin - chemistry; Metformin - pharmacology; Mice, Nude; Molecular weight; multidisciplinary; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - ultrastructure; NMR; Nuclear magnetic resonance; Pharmaceutical sciences; Pharmacy; Polyamines - chemistry; Polyelectrolytes; Polyethyleneimine - chemical synthesis; Polyethyleneimine - chemistry; Polymers; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); TOR Serine-Threonine Kinases - metabolism; Toxicity; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11822

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. The anti-diabetic drug Metformin also possesses anti-tumour activity. Here, the authors synthesize polymeric Metformin-based nanoparticles that still exert intrinsic biological activity through AMPK and mTOR regulation and can systematically deliver VEGF siRNA, significantly reducing lung cancer growth in mice.