Dextranated poly(urethane amine)s designed for systemic gene delivery in ovarian cancer therapy

Abstract

Herein, comb-shaped polycations with neutral dextran as the main chain and folate-coupled bioreducible poly(urethane amine) (PUA) as the graft were designed and prepared as non-viral vectors for intravenous gene delivery targeting in tumor-bearing nude mice. Herein, primary amine-terminal PUAs with varied degrees of polymerization (DP) were prepared and then conjugated to dextrans with different molecular weights (5 kDa or 10 kDa), producing comb-shaped dextran-PUA polycations (denoted as Dex-PUA). The terminal group of the PUA graft could be further modified with folate, yielding folate-coupled Dex-PUA (denoted as Dex-PUA-FA). These comb-shaped polycations can condense genes into colloidal stable polyplexes under physiological conditions. However, these nano-polyplexes liberated genes in response to a reductive intracellular environment. In vitro transfection experiments showed that Dex10k-PUA40-FA, with 10 kDa dextran and a PUA oligomer with DP 40, induced the best transfection efficiency against SKOV-3 ovarian cancer cells in 10% serum. In vivo, the Dex10k-PUA40-FA polyplexes were applicable for intravenous gene delivery targeting SKOV-3 tumors in nude mice, affording a higher level of gene accumulation in the tumor as compared to Dex10k-PUA40 polyplexes lacking folate. Additionally, in vivo gene therapy showed that using a small hairpin RNA-silencing vascular endothelial growth factor, the Dex10k-PUA40-FA polyplexes exerted significant growth inhibition of SKOV-3 tumors with negligible systemic toxicity. The results of this study highlight dextranated PUA as a safe and robust gene vector for non-viral cancer gene therapy.