title: Biodegradable microspheres targeting mucosal immune-regulating cells: new approach for treatment of inflammatory bowel disease.
abstract: Several studies have indicated that active monocytes, such as macrophages and T cells, play an important role in the pathogenesis of chronic human inflammatory bowel disease (IBD), although the etiology remains unclear. Manipulation of these cells appears essential for the treatment of patients with IBD. Recently, considerable attention has been paid to the use of polymer microspheres for the sustained release of various drugs and the targeting of therapeutic agents to their site of action. It was reported that biodegradable poly-D,L-lactic acid (PDLLA) microspheres can be efficiently taken up by macrophages and M cells. We evaluated the effect of a new drug delivery system targeting microfold cells and macrophages with PDLLA microspheres and gelatin microspheres (GM) on colitis models. In the first experiment, colitis was induced in Balb/c mice by 5% dextran sodium sulfate, and microspheres containing dexamethsone (Decadrone, Dx; Dx microspheres) were orally administered to these mice. Serum levels of Dx did not reach a detectable level after administration of Dx microspheres. The tissue distribution of microspheres containing 125I-Dx in inflamed colon was significantly higher than that in other organs. The histological score, myeloperoxidase activity, and nitric oxide production of mice treated with Dx microspheres were significantly lower than in those treated with Dx alone. Gene expression of proinflammatory cytokines was remarkably downregulated in mice treated with Dx microspheres compared to Dx alone. Next, we investigated the effect of elimination of resident macrophages using microspheres containing dichloromethylene diphosphonate (DMDP) on IL-10 knockout mice. We administered DMDP microspheres to IL-10 KO mice rectally and assessed whether this reagent could reduce the number of local Mac-1-positive cells in the intestine and suppress the development of colitis in IL-10 KO mice. DMDP microspheres reduced the numbers of resident macrophages in the colon of IL-10 KO mice but did not reduce the percentage of Mac-1-positive cells in the spleen, peritoneal cavity, or mesenteric lymph nodes. Depletion of intestinal macrophages significantly suppressed development of chronic colitis in IL-10 KO mice, however. Third, we developed gelatin microspheres containing IL-10, which can be released sustainedly to a local site without losing bioactivity. We administered these microspheres to IL-10 KO mice rectally to investigate whether this treatment can ameliorate colitis. Colonic inflammation in mice treated with GM-IL-10 is remarkably reduced compared to those treated with IL-10 alone. Moreover, expression of CD 40 on Mac-1-positive cells treated with GM-IL-10 is decreased more notably than in mice treated with IL-10 alone. These data suggest that a drug delivery system using these microspheres containing immunomodulatory agents may be a therapeutic approach to human IBD.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Graduate School of Kyoto University, 54 Shogoinkawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakase
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D020341:Absorbable Implants; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D004002:Clodronic Acid / Q000008:administration & dosage* / Q000627:therapeutic use*; D003907:Dexamethasone / Q000008:administration & dosage* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000295:instrumentation*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology*; D016753:Interleukin-10 / Q000008:administration & dosage* / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008863:Microspheres; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D018712:Analgesics, Non-Narcotic; D000893:Anti-Inflammatory Agents; D004002:Clodronic Acid; D016753:Interleukin-10; D003907:Dexamethasone