title: Nanoparticle-based clodronate delivery mitigates murine experimental colitis.
abstract: In inflammatory bowel disease (IBD) the disruption of the intestinal barrier function and the strong presence of immune-related cells like macrophages in inflamed tissue allow the selective accumulation of particulate carrier systems at the site of action. We developed clodronate loaded nanoparticles (ClNP) based on a cationic polymethacrylate (Eudragit RL) using a modified solvent displacement method. Particle diameter of ClNP was around 120nm and dissolution experiments showed that ionic interactions with either the dissolution medium or mucin have to take place to enable complete drug release. In murine experimental colitis in-vivo, myeloperoxidase activity decreased significantly in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-colitis and oxazolone (OXA)-colitis models after treatment with ClNP while free clodronate did not show a mitigating effect. Similarly, alkaline phosphatase could be lowered significantly from 12.5±1.9 to 6.8±2.2ng/mg tissue in TNBS-colitis and from 16.6±6.2 to 11.8±2.7ng/mg tissue in OXA-colitis. In cultured RAW 264.7 cells, only ClNP but not clodronate alone led to a decrease in tumor necrosis factor-alpha and interleukin-6 secretion of the activated macrophages. The therapeutic benefit of ClNP was confirmed in-vivo although it is limited compared to data with other drugs. Cell culture experiments indicated that intracellular delivery of clodronate was necessary to obtain an anti-inflammatory effect.
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmaceutics, University of Bonn, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Niebel
authors.forename: Katharina
authors.initials: K
authors.lastname: Walkenbach
authors.forename: Arnaud
authors.initials: A
authors.lastname: Béduneau
authors.forename: Yann
authors.initials: Y
authors.lastname: Pellequer
authors.forename: Alf
authors.initials: A
authors.lastname: Lamprecht
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D018938:Caco-2 Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004002:Clodronic Acid / Q000008:administration & dosage*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010081:Oxazolone; D011108:Polymers / Q000737:chemistry; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D000893:Anti-Inflammatory Agents; D011108:Polymers; D004002:Clodronic Acid; D010081:Oxazolone; C058665:Eudragit RL; D014302:Trinitrobenzenesulfonic Acid