Abstract
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.
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