The purpose of this study was to develop a gene vector electrostatically assembled with a polysaccharide capsule. We used pDNA/polyethylenimine (PEI) complexes as efficient non-viral vectors. The pDNA/PEI complex was electrostatically encapsulated with various polysaccharides such as fucoidan, λ-carrageenan, xanthan gum, alginic acid, hyaluronic acid, and chondroitin sulfate (CS). The pDNA/PEI complex was shown as nanoparticles with positive ζ-potential, although the ternary complexes encapsulated with polysaccharides were shown as nanoparticles with negative ζ-potential. The pDNA/PEI complex showed high agglutination activity and cytotoxicity, although the ternary complexes encapsulated with polysaccharides had no agglutination activities and lower cytotoxicities. The pDNA/PEI complex showed high uptake and high transgene efficiency in B16-F10 cells. On the other hand, most of the ternary complexes show little uptake and gene expression. The ternary complex encapsulated by CS, however, showed comparable transgene efficiency to the pDNA/PEI complex. The uptake and gene expression of the ternary complex encapsulated by CS were significantly inhibited by hypothermia and the addition of CS, suggesting that the ternary complex was taken by CS-specific receptor-mediated energy-dependent process.3
Inhalation of bacterial endotoxin induces pulmonary inflammation by activation of nuclear factor B (NFB), production of cytokines and chemokines, and neutrophil activation. Although glucocorticoids are the drugs of choice, administration of free drugs results in adverse effects as a result of a lack of selectivity for the inflammatory effector cells. Because alveolar macrophages play a key role in the inflammatory response in the lung, selective targeting of glucocorticoids to alveolar macrophages offers efficacious pharmacological intervention with minimal side effects. We have demonstrated previously the selective targeting of mannosylated liposomes to alveolar macrophages via mannose receptor-mediated endocytosis after intratracheal administration. In this study, the anti-inflammatory effects of dexamethasone palmitate incorporated in mannosylated liposomes (DPML) at 0.5 mg/kg via intratracheal administration were investigated in lipopolysaccharide-induced lung inflammation in rats. DPML significantly inhibited tumor necrosis factor ␣, interleukin-1, and cytokine-induced neutrophil chemoattractant-1 levels, suppressed neutrophil infiltration and myeloperoxidase activity, and inhibited NFB and p38 mitogen-activated protein kinase activation in the lung. These results prove the value of inhaled mannosylated liposomes as powerful targeting systems for the delivery of anti-inflammatory drugs to alveolar macrophages to improve their efficacy against lung inflammation. Inhalation of lipopolysaccharide (LPS), which is a component of Gram-negative bacteria presenting as an environment pollutant, contributes to inflammation in the lung. The downstream signaling pathways after LPS stimulation include the activation of alveolar macrophages, which are key effector cells to release proinflammatory cytokines including tumor necrosis factor ␣ (TNF␣), interleukin-1 (IL-1) (Ulich et al., 1991), chemokines such as cytokine-induced neutrophil chemoattractant-1 (CINC-1) (Ulich et al., 1995), and activation of nuclear factor B (NFB) and p38 mitogen-activated protein kinase (p38MAPK). Thereafter, neutrophils are recruited into the lung and release protease enzymes, which trigger lung injury. Corresponding to these studies, depletion of alveolar macrophages by liposomal clodronate treatment completely suppressed the downstream signaling after LPS stimulation (Koay et al., 2002). These results indicate that alveolar macrophages play a key role in the inflammation to release proinflammatory cytokines and chemokines after LPS stimulation.Glucocorticoids (GCs) are the drugs of choice for treatment of lung inflammation via systemic or local administration. Although inhalation of free GC is a promising therapy with less systemic toxicity, the therapeutic efficacy has been ques-
Purpose: To evaluate acute corneal epithelial toxicity induced by benzalkonium chloride (BAC) homologs with different alkyl chain lengths using an in vivo electrophysiological method.Methods: BAC homologs with C12, C14, and C16 alkyl chain lengths were used at concentrations of 0.0025%, 0.005%, and 0.01%, respectively. Cytotoxicity of BAC homologs on the normal rabbit corneal epithelial cells was examined by using a WST-1 assay. Corneal transepithelial electrical resistance (TER) was measured in living Japanese white rabbits by 2 Ag/AgCl electrodes placed in the anterior aqueous chamber and on the cornea. TER changes were then evaluated after a 60-second exposure to these BAC homologs. Morphological changes in corneal epithelium after exposure to the BAC homologs were examined using scanning electron microscopy. The antimicrobial activity of BAC homologs against Escherichia coli was also assessed.Results: All BAC homologs caused cytotoxicity and corneal barrier dysfunction in a concentration-dependent manner. However, the degree of corneal toxicity differed among the BAC homologs. Based on cytotoxicity and TER measurement, C14-BAC caused the greatest corneal impairment followed in order of severity by mixed BAC/C16-BAC and C12-BAC. Scanning electron microscopy images indicated an intact corneal epithelium after exposure to 0.005% C12-BAC, whereas 0.005% C14-BAC damaged the epithelium. There were no remarkable differences noted in the antimicrobial activity among the BAC homologs.Conclusions: Acute corneal epithelial toxicity induced by BAC homologs depends on the alkyl chain length. Thus, the use of C12-BAC instead of commercially available BAC is potentially safer for patients undergoing ophthalmological pharmacotherapy.
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