IL6 and TNF expression in vessels and surrounding tissues after embolization with ibuprofen-loaded beads confirms diffusion of ibuprofen

PurposeIn 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 and 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.Materials and methodsUterine 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).ResultsIL6 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.ConclusionUsing 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.

Graphical abstractIbuprofen from loaded embolization beads released in tissues and induced over-expression of IL6 beyond the vascular wall, in the surrounding tissues, which confirmed diffusion of the drug in a gradient of concentration.Figure optionsDownload full-size imageDownload as PowerPoint slide