Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Nat Commun. 2016 Jun 6;7:11822. 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.
二甲双胍是一种广泛应用的抗糖尿病药物，具有很强的抗癌功效。在此，通过将线性聚乙烯亚胺（PEI）与二氰胺接枝，成功合成了二甲双胍的聚合物结构聚二甲双胍（PolyMet）。PolyMet 中环丙二酰胺基团中阳离子电荷的离域作用降低了 PEI 在体外和体内的毒性。此外，PolyMet 的聚阳离子特性允许将 siRNA 捕获到具有核-膜结构的脂质-聚阳离子-透明质酸（LPH）纳米颗粒中，用于系统基因传递。本文的进展使得 LPH-PolyMet 纳米颗粒能够促进 VEGF siRNA 的递送，从而在人肺癌异种移植模型中实现 VEGF 的下调，从而增强肿瘤抑制功效。即使没有 RNAi，LPH-PolyMet 纳米颗粒也能像二甲双胍一样发挥作用，通过激活 AMPK 和抑制 mTOR 来诱导抗肿瘤功效。本质上，PolyMet 成功地将二甲双胍的固有抗癌功效与携带 siRNA 的能力结合起来，从而增强了抗癌基因治疗的治疗活性。
