title: IL6 and TNF expression in vessels and surrounding tissues after embolization with ibuprofen-loaded beads confirms diffusion of ibuprofen.
abstract: OBJECTIVE
  In the treatment of uterine fibroid embolization related pain, the use of embolics loaded with non-steroidal anti-inflammatory drugs (NSAID) relies on an efficient delivery and impregnation of the embolized tissue. Immuno-labelling and spectroscopic techniques have demonstrated the release of ibuprofen from drug eluting beads (Wassef et al., 2008; Namur et al., 2009) but failed to demonstrate diffusion of the drug beyond the vascular wall (VW). We investigated whether ibuprofen diffused beyond the VW in surrounding tissues (ST), by tracking its biological effects through the modulation of expression of two main inflammatory cytokines.
  
  
  METHODS
  Uterine arteries of 6 sheep were embolized with ibuprofen loaded beads (IBU-BB) or non-loaded beads (BB) and sacrificed at one week. On frozen tissue slices, VWs of occluded arteries were isolated from ST using laser capture microdissection. RNA was extracted from VW and ST samples. Gene expression of IL6 and TNFα genes was measured by quantitative real-time PCR (qPCR).
  
  
  RESULTS
  IL6 expression was significantly increased in IBU-BB compared to BB group both in VW (VW: fold-change (FC)=4.9, p=0.0009) and ST (ST: FC=8.7, p=0.0003). In IBU-BB, IL6 was significantly more expressed in VW than in ST (FC=4.4; p=0.0009). TNFα expression was not significantly different between IBU-BB and BB groups.
  
  
  CONCLUSIONS
  Using qPCR+microdissection was useful to evaluate the spread of the biological effects of drug-loaded systems which attest of the tissular release. This approach can be considered when other drug detection techniques are unsuccessful or difficult to achieve. IL6 can be used as a marker of ibuprofen released by drug eluting beads in uterus. Gradient of expression of IL6 suggests diffusion of ibuprofen across the VW into the ST.
authors.affiliation: ArchimMed, ParisBiotech, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France.
authors.forename: Valentin
authors.initials: V
authors.lastname: Verret
authors.forename: Claudia
authors.initials: C
authors.lastname: Bevilacqua
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schwartz-Cornil
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pelage
authors.forename: Michel
authors.initials: M
authors.lastname: Wassef
authors.forename: Julien
authors.initials: J
authors.lastname: Namur
authors.forename: Laurent
authors.initials: L
authors.lastname: Bédouet
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Lewis
authors.forename: Patrice
authors.initials: P
authors.lastname: Martin
authors.forename: Alexandre
authors.initials: A
authors.lastname: Laurent
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007052:Ibuprofen / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007834:Lasers; D007889:Leiomyoma / Q000098:blood supply / Q000601:surgery; D042282:Microdissection; D008863:Microspheres; D010149:Postoperative Pain / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D055988:Uterine Artery / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D055357:Uterine Artery Embolization / Q000379:methods*; D014594:Uterine Neoplasms / Q000098:blood supply / Q000601:surgery; D014599:Uterus / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003692:Delayed-Action Preparations; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007052:Ibuprofen