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

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.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC4897747 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Zhao Yi Y Wang Wei W Guo Shutao S Wang Yuhua Y Miao Lei L Xiong Yang Y Huang Leaf L

Nature communications 20160606

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 ...[more]

PMID: 27264609

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Project description:Micelle-based siRNA carriers ("micelleplexes") were prepared from the A-B-C triblock copolymer poly(ethylene glycol)-poly(n-butyl acrylate)-poly(2-(dimethylamino)ethyl methacrylate) (PEG-PnBA-PDMAEMA), and their in vitro performance and in vivo biodistribution properties were compared with the benchmark PEGylated and basic polycation systems PEG-PDMAEMA and PDMAEMA, respectively. The micelle architecture, incorporating increased PEG shielding and a larger particle size (?50 nm) than polycation-based complexes (polyplexes; ?10 nm), enhances siRNA delivery performance in two important aspects: in vitro gene silencing efficiency and in vivo tumor accumulation. The in vitro gene silencing efficiency of the micelleplexes (24% in HeLa cells) was significantly better than the statistically insignificant levels observed for PDMAEMA and PEG-PDMAEMA polyplexes under identical conditions. This enhancement is linked to the different mechanisms by which micelleplexes are internalized (i.e., caveolar, etc.) compared to PDMAEMA and PEG-PDMAEMA polyplexes. Folate-functionalization significantly improved micelleplex uptake but had negligible influence on gene-silencing efficiency, suggesting that this parameter is not limited by cellular internalization. In vivo biodistribution analysis revealed that siRNA delivered by micelleplexes was more effectively accumulated and retained in tumor tissues than that delivered by PEGylated polyplexes. Overall, the micelle particle size and architecture appear to improve in vitro and in vivo delivery characteristics without significantly changing other properties, such as cytotoxicity and resistance to enzymes and dissociation. The self-assembled nature of micelleplexes is expected to enable incorporation of imaging modalities inside the hydrophobic micelle core, thus combining therapeutic and diagnostic capabilities. The findings from the present study suggest that the micelleplex-type carrier architecture is a useful platform for potential theranostic and tumor-targeting applications.

Dataset Information

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

Publications

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

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