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ABSTRACT: Novel surfactants made of diglutamic acid (DG) polar head linked to lithocholic, arachidonic, linoleic or stearic acids were designed for drug solubilization.
Surfactants 3-D conformer and packing parameter were determined by molecular modelling and self-assembling properties by pyrene fluorescence measurements. Cytotoxicity was assessed on Human Umbilical Vein Endothelial Cells (HUVEC) and haemolyitic activity on rat red blood cells. Drug solubilization was quantified and its interaction with hydrophobic moieties was characterized using differential scanning calorimetry and X-ray diffraction. Self organisation of stearoyl-DG was observed by cryogenic transmission electron microscopy. Toxicity after repeated injections of stearoyl-DG was investigated in Wistar rats.
DG-based surfactants self-assemble into water and their critical micellar concentrations are comprised between 200 and 920 μg/mL. Cytotoxicity and haemolysis were lower than for polysorbate 80. At best, stearoyl-DG solubilized the drug up to 22% (w/w). Solid-state characterization evidenced drug/lipid interactions leading to the formation of a new complex. Stearoyl-DG formed spherical micelles of 20 nm, as predicted by packing parameter calculation. However, it induced a possible liver toxicity after intravenous administration in rats.
Among the surfactants tested, stearoyl-DG is the more efficient for drug solubilization but its use is limited by its possible liver toxicity.
Pharmaceutical Research 03/2012; 29(7):1882-96. · 4.09 Impact Factor
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ABSTRACT: 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.
CardioVascular and Interventional Radiology 03/2012; · 2.09 Impact Factor
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ABSTRACT: To overcome poor water-solubility of new drug candidates, four innovative surfactants based on naturally-occuring hydrophilic and hydrophobic moities were designed and synthesized: cholesteryl-glutamic acid, cholesteryl-poly[N-2-hydroxyethyl-l-glutamine] (PHEG), ursodeoxycholanyl-PHEG (UDCA-PHEG) and ursodeoxycholanyl-poly-l-glutamic acid (UDCA-PGA). Their self-assembling capacity was evaluated using pyrene fluorescence measurements which allow to determine their critical aggregation concentration (CAC). Size measurements were carried out using dynamic light scattering (DLS). Surfactant cytotoxicity was investigated on human umbilical vein endothelial cells (HUVEC) by determining tetrazolium salt (MTT) activity and lactate dehydrogenase (LDH) release. In addition, surfactant haemolytic activity was assessed using rat red blood cells (RBCs). Finally, the ability of these surfactants to solubilize a model poorly soluble drug was quantified. Surfactant self-assembly, cytotoxicity and solubilization properties were compared to those obtained with polysorbate 80, a model solubilizer. Except for cholesteryl-glutamic acid, surfactants were water-soluble. UDCA-PGA was not able to self-assemble or to increase significantly drug solubility. Results showed that cholesteryl-PHEG and UDCA-PHEG were self-assembling with low CAC values (17 and 120μg/ml) into nano-structures with mean diameters of 13 and 250nm, respectively. Cholesteryl-PHEG was the most efficient surfactant in increasing drug solubility (2mg/ml) but exhibited a similar or higher toxicity than polysorbate 80. UDCA-PHEG did not present any cytotoxicity but was far less efficient to solubilize the drug (0.2mg/ml). These results evidence interesting properties of cholesteryl-PHEG and UDCA-PHEG as novel solubilizers.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 12/2011; 44(5):595-601. · 2.61 Impact Factor
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ABSTRACT: To improve solubilization of a water insoluble anticancer drug, novel surfactants were synthesized. All surfactants derived from lysine, with a so-called nitrilo triacetic acid (NTA) polar head, and differed from the length and saturation degree of their hydrophobic moieties: C19:0-NTA, C20:4-NTA, C25:0-NTA and C25:4-NTA. Self-assembling properties and critical micellar concentration (CMC) values were determined using pyrene fluorescence and cytotoxicity using MTT and LDH assays on endothelial cells. Surfactant haemolytic activity and drug solubilization capacity were also evaluated. All surfactants self-assemble with low CMC values from 0.012 to 0.430 mg/mL. Cytotoxicity assays showed that C20:4-NTA and C25:0-NTA were less cytotoxic than polysorbate 80. Unsaturations and alkane chain length have a marked influence on toxicity. Saturated surfactants had a similar haemolytic activity, explained by their low CMC values and the linear configuration of their hydrophobic tail. C20:4-NTA and C25:4-NTA were less haemolytic than polysorbate 80. Furthermore, C19:0-NTA, C25:0-NTA and C25:4-NTA increased drug solubility from <0.15 μg/mL up to 7 mg/mL, with 46% (w/w) drug loading, due to their linear and flexible hydrophobic chain configuration, as evidenced by molecular modelling. Although these solubilizers are promising, a compromise between drug solubilization and toxicity remains to be found.
International journal of pharmaceutics 11/2011; 423(2):312-20. · 2.96 Impact Factor
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ABSTRACT: The present study investigates the mechanical properties of three embolization microspheres (E-ms): tris-acryl gelatin microspheres (TG-ms), acrylamido polyvinyl alcohol microspheres (APVA-ms), and polyphosphazene-coated polymethylmethacrylate microspheres (PP-PMMA-ms). Compression and relaxation tests were performed on monolayers of particles and their Young's moduli and relaxation half times (RHTs) were determined. The elasticity of E-ms was evaluated by applying Hertz theory with the assumptions of incompressibility and a Poisson's ratio of 0.5. The Young's moduli of TG-ms, APVA-ms, and PP-PMMA-ms were 39.6±5.05 kPa, 18.8±4.00 kPa, and 13.6±1.98 kPa, respectively. The RHTs of TG-ms, APVA-ms, and PP-PMMA-ms were 52.3±5.56 s, 59.1±8.16 s, and 31.0±7.01 s, respectively. TG-ms have a high rigidity and deform slightly under a sustained compression since they have a high elasticity. PP-PMMA-ms are soft and deform a lot under sustained compression. They are more viscous than the other two microspheres. APVA-ms have intermediate material properties, having the same low rigidity as PP-PMMA-ms and being more elastic than TG-ms.
Journal of the mechanical behavior of biomedical materials. 11/2011; 4(8):2161-7.
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ABSTRACT: 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.
Biomaterials 10/2010; 32(2):339-51. · 7.40 Impact Factor
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ABSTRACT: The suppression of oestrogen receptor alpha (ERalpha) functions by silencing RNAs in association with or not with anti-oestrogens (AEs) both in vitro and in breast cancer cell xenografts was assessed. In vitro, a prolonged decrease in ERalpha protein expression and an enhanced AE-induced inhibition of ERalpha-mediated transcription, together with antiproliferative activity, were observed. Incorporation of ERalpha-siRNAs in pegylated nanocapsules (NC) was achieved; and their intravenous injections in MCF-7 xenografts, in contrast to scramble siRNA containing NCs, lead to decrease in ERalpha protein content and Ki67 labelling in tumour cells. The pure AE RU58668 (RU) both free and entrapped in stealth nanospheres (NS) at very low concentration (8 microg/kg/week) had no effect on tumour growth evolution. However, coinjection of the two nanocarriers potentiated the decrease in ERalpha protein, concomitantly with decreasing tumour vasculature and glucose transporter-1. These data support that the targeted delivery of ERalpha-siRNA in breast tumours potentiates the inhibition of E(2)-induced proliferative activity by encapsulated AE through enhanced anti-vascular activity. In the hormone-independent MDA-MB-231 xenograft model, RU-NS at 4 mg/kg/week induce also a strong tumour vascular normalisation. Together, these findings suggest that the anti-oestrogen activity of RU as well as that of targeted ERalpha-siRNA leads to anti-angiogenic activity. Their delivery in stealth nanocarriers may constitute a new anti-cancer therapeutic strategy in solid tumours.
Breast Cancer Research and Treatment 09/2009; 122(1):145-58. · 4.43 Impact Factor
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ABSTRACT: We report the preparation of an embolic agent based on specific association of an acrylic copolymer with dedicated particles formulated in ethanol. The copolymers were synthesized by radical polymerization of tertiobutylacrylamide (tBA) and 2-hydroxypropyl methacrylate (HPMA). Influences of the monomers composition, molecular weight and copolymer concentration have been evaluated on an in vitro model. Introduction of tBA units improves significantly the occlusion properties but these properties are similar whatever the molecular weight of the copolymer. As observed by viscosity studies, it seems necessary to work with a relatively high polymer concentration (C > Ce) to form a cohesive embolus. Addition of solid particles composed by a crosslinked polymer of 2-hydroxyethyl methacrylate (HEMA) and N-trishydroxymethyl methacrylamide (TRIS) in the acrylic copolymer solution has allowed to obtain an embole having an enhanced cohesion and giving a more compact structure. An in vivo evaluation has been performed by injection of this embolic agent in intercostal arteries and renal artery of sheep. There was no fragmentation of the plug during and after injection and a complete arterial occlusion by a cohesive embole. The pathological examination confirmed that there was a complete arterial occlusion by the plug and that the dedicated particles were as expected embedded in the precipitate acrylic copolymer.
Biomaterials 04/2009; 30(20):3436-43. · 7.40 Impact Factor
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ABSTRACT: Specific siRNAs that target estrogen receptor alpha (ERalpha) were encapsulated in nanocapsules (NCs). We produced small (approximately 100-200 nm) ERalpha-siRNA NCs with a water core by incorporating two mixed duplexes of specific ERalpha-siRNAs (ERalpha-mix-siRNA) into NCs. The encapsulation yield that was obtained with poly(iso-butylcyanoacrylate) (PIBCA) NCs was low, whereas no release of trapped siRNA was observed for poly(ethylene)glycol-poly(D,L-lactide-co-glycolide) (PEG-PLGA) NCs. High levels of ERalpha-siRNA incorporation into PEG-epsilon-caprolactone-malic acid (PEG-PCL/MA) NCs (3.3 microM in a polymer solution at 16 mg/mL) were observed (72% yield). No difference in size or zeta potential was observed between siRNA NCs that were based on PEG-PCL/MA and empty NCs. Fluorescence quenching assays confirmed the incorporation of siRNA into the NC core. A persistent loss of ERalpha (90% over 5 days) was observed in MCF-7 human breast cancer cells that were exposed to PEG-PCL/MA NCs that were loaded with ERalpha-siRNA. The intravenous injection of these NCs into estradiol-stimulated MCF-7 cell xenografts led to a significant decrease in tumor growth and a decrease in ERalpha expression in tumor cells. These data indicate that a novel strategy, based on ERalpha-siRNA delivery, could be developed for the treatment of hormone-dependent breast cancers.
Biomacromolecules 10/2008; 9(10):2881-90. · 5.48 Impact Factor
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ABSTRACT: The aim of this work was to investigate the impact of electron beam irradiation at different dose rates on the molecular structure of linear methacrylate–acrylamide copolymer. In the first part, the radiation chemical yields of scission (Gs) and crosslinking (Gx) have been determined after irradiation for various initial molecular weights CL1 (40 000 g/mol), CL2 (90 000 g/mol) and CL3 (425 000 g/mol). Based on this calculation, solvent (ethanol) was found to increase the impact of irradiation especially at low concentration of copolymer. In the second part, the presence of branching in samples before and after e-beam irradiation was explored, and branching calculation was performed.
Polymer Degradation and Stability 94(4):584-590. · 2.77 Impact Factor
