Engineering of ph-sensitive, cross-linked micelles for drug delivery

Abstract

Drug delivery systems have been more interested in two decades because of their enormous advantages over free drugs. Especially, stimuli-responsive carrier systems such as, pH-sensitive, enzyme sensitive, temperature-sensitive, or ultrasound sensitive particles, have been the most attractive drug delivery strategy. For that purpose, I designed pH-sensitive cross-linked micelles that could be used for cancer therapy. Micelles nanoparticles were formed with triblock copolymers for this system containing of a hydrophilic PEG block, a central functionalized block, and a hydrophobic block to establish stable nano sized micelle particles. The hydrophobic block can provide room for hydrophobic drugs with the physical hydrophobic drug-hydrophobic core interaction and form stable, spherical 25-35 nm nanoparticles in the presence of the aqua system. In order to control the release rate of hydrophobic drugs (fluorescence hydrophobic dye Nile Red (NR) is preferred for the hydrophobic model drug), a pH-sensitive layer at the middle block of the micelles that embraces the hydrophobic block was constructed. Shell cross-linked (SCL) micelles are obtained upon introducing the glutaraldehyde as a cross-linker that able to react with NH2 functional groups of the middle block of the triblock copolymer. The formed cross-link shell contains acid-labile hydrazone linkages that are cleavable in response to acidic conditions such as cellular uptake mechanism, endocytosis, and bone lacuna not in physiologic pH.