title: Oral Delivery of Particulate Transforming Growth Factor Beta 1 and All-Trans Retinoic Acid Reduces Gut Inflammation in Murine Models of Inflammatory Bowel Disease.
abstract: OBJECTIVE
  We investigated oral delivery of transforming growth factor beta 1 [TGFβ]- and all-trans retinoic acid [ATRA]-loaded microspheres as therapy for gut inflammation in murine models of inflammatory bowel disease [IBD].
  
  
  METHODS
  ATRA and TGFβ were separately encapsulated in poly [lactic-co-glycolic] acid or polylactic acid microspheres [respectively]. TGFβ was encapsulated using proprietary phase-inversion nanoencapsulation [PIN] technology.
  
  
  RESULTS
  PIN particles provided sustained release of bioactive protein for at least 4 days and were stable for up to 52 weeks when stored at either 4(0)C or -20(0)C. In the SCID mouse CD4 + CD25- T cell transfer model of IBD, oral treatment starting at disease onset prevented weight loss, significantly reduced average disease score [~ 50%], serum amyloid A levels [~ 5-fold], colon weight-to-length ratio [~ 50%], and histological score [~ 5-fold].
  
  
  CONCLUSIONS
  Both agents given together outperformed either separately. Highest TGFβ doses and most frequent dose schedule were most effective. Activity was associated with a significant increase [45%] in Foxp3 expression by colonic lamina propria CD4+ CD25+ T-cells. Activity was also demonstrated in dextran sulphate sodium-induced colitis. The data support development of the combination product as a novel, targeted immune based therapy for treatment for IBD.
authors.affiliation: TherapyX , Buffalo, NY, USA State University of New York, at Buffalo, NY, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Conway
authors.affiliation: TherapyX , Buffalo, NY, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Hammer
authors.affiliation: TherapyX , Buffalo, NY, USA Brown University, Department Biomedical and Molecular Pharmacology, Providence, RI, USA.
authors.forename: Stacia
authors.initials: S
authors.lastname: Furtado
authors.affiliation: Brown University, Department Biomedical and Molecular Pharmacology, Providence, RI, USA.
authors.forename: Edith
authors.initials: E
authors.lastname: Mathiowitz
authors.affiliation: University of Catania, Department of Biomedical and Biotechnological Sciences, Catania, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: University of Catania, Department of Biomedical and Biotechnological Sciences, Catania, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Mangano
authors.affiliation: TherapyX , Buffalo, NY, USA State University of New York, at Buffalo, NY, USA nejat.egilmez@louisville.edu.
authors.forename: Nejat K
authors.initials: NK
authors.lastname: Egilmez
authors.affiliation: TherapyX , Buffalo, NY, USA.
authors.forename: Dominick L
authors.initials: DL
authors.lastname: Auci
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008863:Microspheres; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000627:therapeutic use; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D016212:Transforming Growth Factor beta; D014212:Tretinoin
keywords: ATRA; IBD; TGFβ