Effect of Side Chain Conjugation on the Cytotoxicity and siRNA Transfection Efficiency of 6-Amino-6-deoxy Curdlan

Abstract Cationic curdlan is a promising siRNA delivery platform because it protects siRNA, promotes intracellular siRNA release through charge reduction, prolongs intracellular retention, and supports sustained gene-silencing. However, its relatively high cationic charge can induce cytotoxicity and limit its therapeutic potential. In this study, to reduce toxicity while enhancing siRNA delivery efficiency, we conjugated short ethylene glycol side chains to 6-amino-6-deoxy curdlan and compared the siRNA transfection efficiency of the resulting polymers with that of the parental polymer. Conjugation of ethylene glycol side chains significantly improved both the biocompatibility and in vitro siRNA delivery efficiency, yielding polymers designated MEG1 and MEG2. Notably, conjugation of a short ethylene glycol side chain terminated with a lysine residue (designated CegK1) resulted in markedly enhanced biocompatibility and siRNA delivery efficiency in multiple human glioblastoma cell lines, including U251, U87-MG, and T98G. These findings demonstrate that short ethylene glycol side-chain modification is an effective strategy to optimize cationic curdlan as a safe and efficient siRNA delivery carrier for glioblastoma therapy.