Poly(ethylene glycol)–polyethyleneimine NanoGel™ particles: novel drug delivery systems for antisense oligonucleotides

A novel type of drug delivery system, termed NanoGel? is proposed. NanoGel? represent particles of a hydrophilic polymer network that were synthesized by cross-linking of polyethyleneimine (PEI) and carbonyldiimidazole-activated poly(ethylene glycol) (PEG) using emulsification/solvent evaporation technique. The resulting NanoGel? was fractionated by gel-permeation chromatography. A major fraction with an average particle size of 120 nm was used in further experiments. Antisense phosphorothioate oligonucleotides (SODN) specific to human mdr1 gene were incorporated in these NanoGel? particles. Loading of NanoGel? particles with SODN resulted in reduction of the particle effective diameter to 80 nm and decreased zeta-potential due to neutralization of the charge of PEI chains by SODN. Accumulation of SODN incorporated in NanoGel? particles in multidrug resistant (MDR) human oral epidermoid carcinoma cells (KBv) was significantly increased compared to the free SODN. Furthermore, efficient transport of SODN-loaded NanoGel? particles across polarized monolayers of human intestinal epithelial cells (Caco-2) was demonstrated. Finally, antisense SODNs incorporated in NanoGel? particles were found to effectively inhibit expression of P-glycoprotein (P-gp) efflux pump in MDR cell lines.