Reactive oxygen species-sensitive release of cephalexin from hyaluronic acid-g-cephalexin dimer copolymer for treatment of inflammation and infection of oral soft tissue cells.

Since inflammation and/or infection against soft tissue cells increased oxidative stress and CD44 receptor expression, graft copolymer was synthesized using hyaluronic acid (HA) and cephalexin (CPX). To produce CPX dimer, to molecules of CPX were conjugated with carboxylic acid group of thioketal dicarboxylic acid (ThdCOOH). CPX dimer was conjugated with HA using thioketal diamine (ThdNH(2)) to synthesize HA-g-CPX copolymer (Abbreviated as HAgCPX). Nanoparticles of HAgCPX copolymer was fabricated by dialysis method. They were assembled in the aqueous solution and formed spherical nanoparticles with small dimeter less than 300 nm. Since HAgCPX copolymers have ROS-sensitive linkage such as thioketal group, they were disintegrated in the presence of H(2)O(2), particle size was also changed from monomodal to multimodal and then drug release rate was accelerated in the presence of H(2)O(2). These results indicated that HAgCPX nanoparticles have ROS-sensitivity. HAgCPX nanoparticles have anti-inflammatory efficacy and wound healing potential, i.e. they efficiently inhibited inflammatory cytokines and promoted wound healing of LPS-treated HGF-1 cells. LPS treatment against increased CD44 receptor expression on the HGF-1 cells. Fluorescence intensity of HGF-1 cells was significantly increased by treatment of HAgCPX nanoparticles in the absence of free HA pre-treatment while pre-treatment of HA suppressed the intracellular delivery of HAgCPX nanoparticles, indicating that HAgCPX nanoparticles can be delivered via CD44 receptor-mediated pathway. HAgCPX nanoparticles showed antimicrobial activity in vitro against various oral microbials as well as free CPX. We suggested that HAgCPX nanoparticles are promising candidate for ROS-specific and CD44 receptor-mediated delivery of drugs against inflammatory of oral soft tissue cells.