Synthesis of Diethylamino End‐Modified Poly(Ethylene Glycol) With Imine Spacer to Form Mono‐Ion Complexes With <scp>pDNA</scp>

ABSTRACT The concept of our pDNA mono‐ion complex (MIC) to minimize cationic cytotoxicity for pDNA delivery has been established by using the monocationic poly(ethylene glycol) (PEG). In this study, the diethylamino end‐modified PEG with imine spacer (DEAP‐NC‐PEG) has been synthesized to enhance the MIC formation by the hydrophobic cation of a diethylamino group, which increase the hydrophobic environment around the site of electrostatic interaction with a phosphate anion of pDNA. Although our previous monocationic PEGs are necessary to form MICs with pDNA at large mixing positive/negative charge ratio, the synthesized monocationic DEAP‐NC‐PEG formed the MIC at a mixing charge ratio of 1. The resulting DEAP‐NC‐PEG/pDNA MIC was stable under aqueous conditions. Furthermore, the DEAP‐NC‐PEG formed the MIC with mRNA, offering a unique platform for nucleic acid delivery systems to minimize potential cationic cytotoxicity.