SiRNA Delivery Mediated by pH and Redox Responsive P(DEAEMA-Co-HEMA-G-PEGMA) Nanogels

Small interfering RNAs (siRNA) have enabled novel, specific, and efficient treatment of diseases, including cancer. To obtain sufficient and well-controlled intracellular delivery, a drug delivery system is essential. Herein a delivery system for siRNA, composed of cationic biodegradable nanogels, is presented. p(DEAEMA-co-HEMA-g-PEGMA) nanogels with varying ratios of 2-diethyl aminoethyl methacrylate (DEAEMA) and 2-Hydroxyethyl methacrylate (HEMA), crosslinked with tetraethylene glycol dimethacrylate or disulfide-crosslinker bis(2-methacryloyloxy ethyl), are synthesized. The pH-depended nanogel swelling facilitates siRNA loading and endosomal disruption. The disulfide-crosslinker ensures siRNA release by GSH-mediated particle disassociating. The nanogels are within the sub-100nm range in their collapsed state, have a PDI & GE; 0.4, and a & zeta;-potential ranging from approximately 5-10 in the swollen state and 22-30V in the collapsed state and have a swelling ratio up to 1.6 in diameter. Furthermore, the nanogels show good serum-stability, and are capable of delivering siRNA with acceptable cytotoxicity levels. The nanogels induced >90% eGFP-silencing in lung cancer cells, and gene -silencing of the cancer target POLR2A led to siRNA-induced cell death in squamous carcinoma cells. The find-ings suggest that the nanogel-system may function as a carrier vehicle for cytoplasmic delivery of siRNA.