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 tumor microenvironment (TME) serves as an innate resistance niche for chemotherapy assault and a physiological barrier against therapeutic nanoparticles (NP) penetration. Previous studies have indicated that therapeutic NP can distribute to and deplete tumor associated fibroblasts (TAF) for improved therapeutic outcome. However, resistance develops after repeated chemotherapeutic NP exposure. In this study, we explored NP-delivered cisplatin induced resistance in the TME by investigating the effects of NP damaged TAF on neighboring naïve cells and comparing the stroma structure of single and multiple dose NP treatments. Our study suggested that although off-targeted NP damaged TAF initially inhibited tumor growth, chronic exposure of TAF to cisplatin NP led to elevated secretion of Wnt16 in a paracrine manner that supported tumor cell resistance and stroma reconstruction. Our study demonstrates that knockdown of Wnt16 in the damaged TAF could be a promising combinatory strategy to improve efficacy of NP delivered cisplatin in a stroma-rich bladder cancer model.

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