Tumor Microenvironment-Regulated Redox Responsive Cationic Galactose-Based Hyperbranched Polymers for siRNA Delivery

Tumor microenvironment redox-modulated galactose-based hyperbranched polymers (HRRP) composed of 2-lactobionamidoethylmethacrylamide (LAEMA) and 2-aminoethylmethacrylamide (AEMA) with molecular weights of 10 and 20 kDa and LAEMA:AEMA ratios (L:A) of 1.5 and 1 were prepared via the reversible addition–fragmentation chain transfer (RAFT) polymerization. The remarkable capability of these polymers to respond to the glutathione (GSH) concentration in the tumor environment is the key factor that regulates their cellular internalization and enhances selective siRNA release into the cancer cell cytoplasm. HRRP with a molecular weight of 10 kDa and L:A ratio of 1.5 was capable of forming nanosized polyplexes and achieved around 85% epidermal growth factor receptor (EGFR) silencing in cervical (HeLa) cancer cells in the presence of serum protein without compromising the biocompatibility of the system (around 95% cell viability). The excellent stability of the polyplexes in serum and low cytotoxicity in normal cell lines warrants the use of this redox-responsive galactose-based cationic hyperbranched polymers in gene silencing applications at the preclinical level