Surfactant-free synthesis of biodegradable, biocompatible, and stimuli-responsive cationic nanogel particles

Nanogels have attracted much attention lately because of their many potential applications, including as nanocarriers for drug and gene delivery. Most nanogels reported previously, however, are not biodegradable, and their synthesis often requires the use of surfactants. Herein we report a surfactant-free method for the preparation of biodegradable, biocompatible, and stimuli-responsive cationic nanogels. The nanogels were synthesized by simply coaservating linear polymer precursors in mixed solvents followed by in situ cross-linking with homobifunctional cross-linkers. The versatility of this approach has been demonstrated by employing two different polymers and various cross-linkers to prepare nanogel particles with diameters ranging from 170 to 220 nm. Specifically, disulfide-containing tetralysine (TetK)- and oligoethylenimine (OEI)-based prepolymers were prepared and the subsequent nanogels were formed by covalently cross-linking the polymer coacervate phase. Nanogel particles are responsive to pH changes, increasing in size and zeta-potential with concomitant lowering of solution pH. Furthermore, as revealed by AFM imaging, nanogel particles were degradable in the presence of glutathione at concentrations similar to those in intracellular environment (10 mM). Both the nanogel and the polymer precursors were determined to exhibit minimal cytotoxicity against fibroblast 3T3 cells by flow cytometric analyses and fluorescent imaging. This study demonstrates a new surfactant-free method for preparing biodegradable, biocompatible, and stimuli-responsive nanogels as potential nanocarriers for the delivery of drugs and genes.