Branched Glycerol-Based Copolymer with Ultrahigh p65 siRNA Delivery Efficiency for Enhanced Cancer Therapy.

The small interfering RNA (siRNA) is emerging as a potential therapeutic for the treatment of various diseases because of the targeted gene silencing capability. The suppression of p65 expression has shown great potential in various cancer treatments. However, various substantial obstacles limit its clinical applications, including low cellular uptake, instability, and cytotoxicity of delivery vehicles. We show a highly branched and biocompatible glycerol-based copolymer (HBGC) to effectively deliver siRNA for excellent p65 gene silencing and safe lung cancer treatment in vitro and in vivo. HBGCs could be synthesized through a facile and modular one-spot Michael addition. HBGCs effectively protect siRNA in serum, enhance cellular uptake of siRNA, and show negligible cytotoxicity in various cells (A549, HeLa, HepG2, and C2C12). Additionally, the HBGC-siRNA complex potently downregulates the p65 expression in A549 cancer cells (almost the highest value of 96% in reported references) and enhances the cellular apoptosis compared to that of commercial transfection agents polyethyleneimine 25 kDa and Lipofectamine 2000. The HBGC-siRNA complex demonstrated significantly increased accumulation in the tumor sites and enhanced downregulation of p65 gene and cancer cell apoptosis. Furthermore, the tumor growth could be significantly inhibited in a subcutaneous lung tumor model with negligible adverse effects.