ArchimMed

Saint-Jacques-de-la-Lande, France

ArchimMed

Saint-Jacques-de-la-Lande, France

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Verret V.,ArchimMed | Wassef M.,University Paris Diderot | Pelage J.-P.,Charles University | Ghegediban S.H.,ArchimMed | And 9 more authors.
Biomaterials | Year: 2011

Embolization with microspheres is widely applied to treat uterine fibroids. However, the foreign body reaction that could result from the degradation of the microspheres remains to be evaluated to adequately appreciate the tissular tolerance to such biomaterials. We compared herein the in situ degradation of PMMA microspheres coated with polyphosphazene (PMMA-PPms) and trisacryl gelatin microspheres (TGms) and we thoroughly investigated the induced local inflammatory responses, at 1 and 4 weeks after uterine artery embolization in sheep, by using immunohistochemistry and microarray analyses. PMMA-PPms underwent an acute and partial degradation that was associated with the early recruitment of phagocytic cells (CD172a+ and MHCII+), and with the up-regulated expression of genes involved in the movement of phagocytes (ALOX5AP, CXCL2, CXCL5, IL8, PTGS2, YARS). By contrast, TGms were not degraded and triggered a different inflammation profile including the recruitment of FBR Giant Cells and T-lymphocytes (CD4+) and the increased expression of genes involved in lymphocyte activation (CXCL10, IL2RG, IRAK4, MALT1). Our results indicate that, in contrast to a non-degradable microsphere such as TGms which is associated to a poorly inflammatory foreign body reaction that rapidly resolves, PMMA-PPms, which is partially degradable, rapidly recruits and activates inflammatory phagocytes, thus delaying the resolution of the foreign body reaction. © 2010 Elsevier Ltd.


Namur J.,Archimmed | Pascale F.,Archimmed | Maeda N.,Osaka University | Sterba M.,Archimmed | And 11 more authors.
Journal of Vascular and Interventional Radiology | Year: 2015

Purpose To compare irinotecan-eluting HepaSphere (BioSphere Medical, Roissy-en-France, France) and DC Bead (Biocompatibles UK Ltd, London, United Kingdom) embolization microspheres for distribution in tumors, release properties, tolerance, and antitumor effects in a model of liver metastases in the rabbit. Materials and Methods Multiple liver tumors were created by injection of a VX2 cell suspension in the portal vein of rabbits. After 2 weeks, embolization of the proper hepatic artery was performed with a fixed volume of bland HepaSphere (n = 5), irinotecan-loaded HepaSphere (n = 6), or irinotecan-loaded DC Bead (n = 5) microspheres. Untreated animals injected with VX2 cells served as control animals (n = 5). Plasma pharmacokinetics of irinotecan and its metabolite SN38 were assessed. Histopathology and gene expression analysis were performed 3 days after treatment. Results Among all treated groups, there was no significant difference in liver enzymes or liver damage on histology. Irinotecan-loaded HepaSphere microspheres showed a faster release of drug than DC Bead microspheres leading to a twofold higher concentration of drug in plasma for HepaSphere microspheres. HepaSphere microspheres were less frequently found inside tumor nodules on histology than DC Bead microspheres (11% vs 48%, P <.001) because of their larger size. Tumor necrosis was significantly greater for rabbits given irinotecan-loaded HepaSphere microspheres (69% of total tumor surface) and rabbits given DC Bead microspheres (50% of total tumor surface) compared with control animals (24% of total tumor surface, P =.006 and P =.047). Conclusions HepaSphere and DC Bead microspheres loaded with irinotecan caused significant necrosis of tumor nodules in a model of VX2 liver metastases. This outcome was mostly due to irinotecan delivery rather than vascular occlusion by the microspheres and was greater for HepaSphere microspheres compared with DC Bead microspheres. © 2015 SIR.


Verret V.,ArchimMed | Namur J.,ArchimMed | Ghegediban S.H.,ArchimMed | Wassef M.,University Paris Diderot | And 5 more authors.
CardioVascular and Interventional Radiology | Year: 2013

Purpose: The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques. Methods: The left hepatic arteries of two pigs were embolized with 1 mL of doxorubicin-loaded (25 mg; (DoxMS)) or non-loaded (BlandMS) microspheres. The histopathological effects of the embolization were analyzed at 1 week. RNAs extracted from both the embolized and control liver areas were hybridized onto Agilent porcine microarrays. Genes showing significantly different expression (p < 0.01; fold-change > 2) between two groups were classified by biological process. Results: At 1 week after embolization, DoxMS caused arterial and parenchymal necrosis in 51 and 38 % of embolized vessels, respectively. By contrast, BlandMS did not cause any tissue damage. Up-regulated genes following embolization with DoxMS (vs. BlandMS, n = 353) were mainly involved in cell death, apoptosis, and metabolism of doxorubicin. Down-regulated genes (n = 120) were mainly related to hepatic functions, including enzymes of lipid and carbohydrate metabolisms. Up-regulated genes included genes related to cell proliferation (growth factors and transcription factors), tissue remodeling (MMPs and several collagen types), inflammatory reaction (interleukins and chemokines), and angiogenesis (angiogenic factors and HIF1a pathway), all of which play an important role in liver healing and regeneration. Conclusions: DoxMS caused lesions to the liver, provoked cell death, and disturbed liver metabolism. An inflammatory repair process with cell proliferation, tissue remodeling, and angiogenesis was rapidly initiated during the first week after chemoembolization. This pilot study provides a comprehensive method to compare different types of DoxMS in healthy animals or tumor models. © 2012 Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).


Verret V.,Archimmed | Ghegediban S.H.,Archimmed | Ghegediban S.H.,University Paris Diderot | Wassef M.,University Paris Diderot | And 5 more authors.
Journal of Vascular and Interventional Radiology | Year: 2011

Purpose To compare the in vivo distribution of the new embolic Embozene versus Embosphere as a control in the sheep renal and uterine vasculature. Materials and Methods Twelve sheep (three per group of product and size) were selectively embolized with Embozene 700 μm, Embozene 900 μm, Embosphere 500-700 μm, or Embosphere 700-900μm, in one renal artery (0.5 mL microspheres) and in the two uterine arteries (0.25 mL each) and sacrificed 72 hours later for pathologic examination of kidney and uterus. Partition of microspheres in the vasculature was determined according to a classification of the renal and the uterine vasculatures into several zones. Vascular diameters and microsphere deformation were measured. Results Embozene 700 μm and Embozene 900 μm occluded significantly more distally than Embosphere 500-700μm and Embosphere 700-900 μm in renal and uterine vasculature. For Embozene, the vessel diameter was not significantly different between the two sizes, for each organ, whereas it was significantly larger for Embosphere 700-900 μm than for Embosphere 500-700 μm in each organ. Embozene deformation was significantly higher than that of Embosphere in renal and uterine vasculature, increased from proximal to distal in location for both organs and correlated negatively with vessel diameter (Rho = 0.623; P < .0001). Embosphere deformation did not vary according to the zone. Conclusions Embozene microspheres have a higher in vivo deformation, which results in a more distal occlusion within the vascular network compared with reference Embosphere microspheres. The diameter of occluded vessels varied for the tested size range for Embosphere but was independent of the tested microsphere size range used for Embozene. The deformation of Embozene appears to determine the size of the vessels occluded as opposed to the granulometric particle size, which makes level of occlusion unpredictable. © 2011 SIR.


Pascale F.,ArchimMed | Pascale F.,Interventional Imaging | Bedouet L.,Occlugel | Baylatry M.,Saint Antoine Hospital | And 4 more authors.
Anticancer Research | Year: 2015

Aim: To compare the cytotoxic effects of 11 anticancer agents against VX2 and HepG2 cells in order to establish candidate drugs that can be tested preclinically on VX2 tumor model for transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). Materials and Methods: VX2 and HepG2 cells were incubated with different drug concentrations. The half-maximal inhibitory concentration (IC50) values were determined by total cell protein assay for anthracyclines, platins, irinotecan, mytomicin-C (MMC), 5-fluorouracil (5-FU) and antiangiogenics. Results: IC50 values for VX2 and HepG2 were found close for doxorubicin (0.8 μM vs. 1.1 μM), MMC (13.9 μM vs. 8.7 μM), sunitinib (32.7 vs. 33.7 μM), sorafenib (10.3 vs. 8.9 μM), lapatinib (30 vs. 18.3 μM) and different for platins and irinotecan. Oxaliplatin was less active against VX2 than HepG2 (IC50=41 μM vs. 2.7 μM), cisplatin was more active against VX2 than HepG2 (IC50=8.0 μM vs. 15.9 μM), whereas carboplatin had a low toxicity against both cell lines (70.4 μM vs. 538.3 μM). The toxicity of 5-FU against VX2 and HepG2 was low (IC50=560.6 μM vs. 323.2 μM). Irinotecan was less active against VX2 vs. HepG2 (IC50=44.5 μM vs. 15.3 μM). Bevacizumab had no effect on either of the cell lines up to 6.7 μM. Conclusion: Drugs recommended for pre-clinical trials of TACE in the VX2 model are doxorubicin, sunitinib, sorafenib, MMC, lapatinib and 5-FU.


PubMed | Interventional Imaging, Saint Antoine Hospital, Occlugel, ArchimMed and University Paris Diderot
Type: Journal Article | Journal: Anticancer research | Year: 2015

To compare the cytotoxic effects of 11 anticancer agents against VX2 and HepG2 cells in order to establish candidate drugs that can be tested preclinically on VX2 tumor model for transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC).VX2 and HepG2 cells were incubated with different drug concentrations. The half-maximal inhibitory concentration (IC50) values were determined by total cell protein assay for anthracyclines, platins, irinotecan, mytomicin-C (MMC), 5-fluorouracil (5-FU) and antiangiogenics.IC50 values for VX2 and HepG2 were found close for doxorubicin (0.8 M vs. 1.1 M), MMC (13.9 M vs. 8.7 M), sunitinib (32.7 vs. 33.7 M), sorafenib (10.3 vs. 8.9 M), lapatinib (30 vs. 18.3 M) and different for platins and irinotecan. Oxaliplatin was less active against VX2 than HepG2 (IC50=41 M vs. 2.7 M), cisplatin was more active against VX2 than HepG2 (IC50=8.0 M vs. 15.9 M), whereas carboplatin had a low toxicity against both cell lines (70.4 M vs. 538.3 M). The toxicity of 5-FU against VX2 and HepG2 was low (IC50=560.6 M vs. 323.2 M). Irinotecan was less active against VX2 vs. HepG2 (IC50=44.5 M vs. 15.3 M). Bevacizumab had no effect on either of the cell lines up to 6.7 M.Drugs recommended for pre-clinical trials of TACE in the VX2 model are doxorubicin, sunitinib, sorafenib, MMC, lapatinib and 5-FU.


Bize P.,University of Lausanne | Duran R.,University of Lausanne | Fuchs K.,University of Geneva | Dormond O.,University of Lausanne | And 5 more authors.
Radiology | Year: 2016

Purpose: To measure plasmatic sunitinib concentration (PSC) and intratumoral sunitinib concentration (ITSC) after transcatheter arterial chemoembolization (TACE) with two different sizes of sunitinib-eluting beads (SEBs) in rabbits with VX2 hepatic allografts and to investigate treatment effects on vascular endothelial growth factor receptor type 2 (VEGFR2) phosphorylation, tumor volume, and histopathologic changes. Materials and Methods: The protocol was approved by the French Ethics Committee for Animal Experiments (Comité d'Ethique en Expérimentation Animale du Centre INRA de Jouy-en-Josas et AgroParisTech, or COMETHEA, approval no. 11/028). Two experiments were performed. In the first, seven animals received 0.05 mL of 100-300-mm SEBs (1.5 mg of sunitinib) in the hepatic artery, and six animals received saline injections. In the second, eight animals received 0.05 mL of 70-150-mm SEBs (1.5 mg of sunitinib), seven received 0.05 mL of 70-150-mm unloaded beads, and seven received oral sunitinib (6 mg every day). Tumor size was monitored with ultrasonography. PSC, ITSC, and phosphorylation of VEGFR2 were assessed on days 1 and 14. After the animals were sacrificed, histopathologic analysis was performed. The Kruskal-Wallis test, Mann-Whitney U test, and Fisher exact test were used to look for statistically significant differences between groups. Results: Maximum PSC after TACE with 100-300-mm SEBs was 0.002 mg/mL on day 1. ITSC was 17.8 mg/g on day 1 and 0.16 mg/g on day 14. After TACE with 70-150-mm SEBs, ITSC was 40.4 mg/g on day 1 and 27.4 mg/g on day 14. Phosphorylation of VEGFR2 was inhibited until day 14 after TACE with both sizes of SEBs. The size of VX2 tumors treated with 70-150-mm SEB TACE increased less (22%) than that of tumors treated with unloaded beads (+42%) and oral sunitinib (6 mg every day; +1853%; P =.044). Conclusion: SEB TACE resulted in minimal PSC, high ITSC, and sustained VEGFR2 phosphorylation inhibition until day 14. © 2016 RSNA.


PubMed | ArchimMed
Type: Journal Article | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2011

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.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 TNF genes was measured by quantitative real-time PCR (qPCR).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). TNF expression was not significantly different between IBU-BB and BB groups.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.


PubMed | ArchimMed
Type: Comparative Study | Journal: Cardiovascular and interventional radiology | Year: 2013

The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques.The left hepatic arteries of two pigs were embolized with 1mL of doxorubicin-loaded (25mg; (DoxMS)) or non-loaded (BlandMS) microspheres. The histopathological effects of the embolization were analyzed at 1week. RNAs extracted from both the embolized and control liver areas were hybridized onto Agilent porcine microarrays. Genes showing significantly different expression (p<0.01; fold-change>2) between two groups were classified by biological process.At 1week after embolization, DoxMS caused arterial and parenchymal necrosis in 51 and 38% of embolized vessels, respectively. By contrast, BlandMS did not cause any tissue damage. Up-regulated genes following embolization with DoxMS (vs. BlandMS, n=353) were mainly involved in cell death, apoptosis, and metabolism of doxorubicin. Down-regulated genes (n=120) were mainly related to hepatic functions, including enzymes of lipid and carbohydrate metabolisms. Up-regulated genes included genes related to cell proliferation (growth factors and transcription factors), tissue remodeling (MMPs and several collagen types), inflammatory reaction (interleukins and chemokines), and angiogenesis (angiogenic factors and HIF1a pathway), all of which play an important role in liver healing and regeneration.DoxMS caused lesions to the liver, provoked cell death, and disturbed liver metabolism. An inflammatory repair process with cell proliferation, tissue remodeling, and angiogenesis was rapidly initiated during the first week after chemoembolization. This pilot study provides a comprehensive method to compare different types of DoxMS in healthy animals or tumor models.


PubMed | Archimmed
Type: Comparative Study | Journal: Journal of vascular and interventional radiology : JVIR | Year: 2011

To compare the in vivo distribution of the new embolic Embozene versus Embosphere as a control in the sheep renal and uterine vasculature.Twelve sheep (three per group of product and size) were selectively embolized with Embozene 700 m, Embozene 900 m, Embosphere 500-700 m, or Embosphere 700-900 m, in one renal artery (0.5 mL microspheres) and in the two uterine arteries (0.25 mL each) and sacrificed 72 hours later for pathologic examination of kidney and uterus. Partition of microspheres in the vasculature was determined according to a classification of the renal and the uterine vasculatures into several zones. Vascular diameters and microsphere deformation were measured.Embozene 700 m and Embozene 900 m occluded significantly more distally than Embosphere 500-700 m and Embosphere 700-900 m in renal and uterine vasculature. For Embozene, the vessel diameter was not significantly different between the two sizes, for each organ, whereas it was significantly larger for Embosphere 700-900 m than for Embosphere 500-700 m in each organ. Embozene deformation was significantly higher than that of Embosphere in renal and uterine vasculature, increased from proximal to distal in location for both organs and correlated negatively with vessel diameter (Rho = -0.623; P < .0001). Embosphere deformation did not vary according to the zone.Embozene microspheres have a higher in vivo deformation, which results in a more distal occlusion within the vascular network compared with reference Embosphere microspheres. The diameter of occluded vessels varied for the tested size range for Embosphere but was independent of the tested microsphere size range used for Embozene. The deformation of Embozene appears to determine the size of the vessels occluded as opposed to the granulometric particle size, which makes level of occlusion unpredictable.

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