DEFAR - Artigos publicados em periódicos
URI permanente para esta coleçãohttp://www.hml.repositorio.ufop.br/handle/123456789/531
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Item Interactions between a macrophage cell line (J774A1) and surface-modified poly(D, L-lactide) nanocapsules bearing poly(ethylene glycol).(1999) Mosqueira, Vanessa Carla Furtado; Legrand, Philippe; Gref, Ruxandra; Heurtault, Béatrice; Appel, M.; Barratt, GillianThe interactions of naked and surface-modified poly(D,L-lactic acid) (PLA) nanocapsules (NC), where polyethyleneglycol (PEG) was adsorbed or covalently attached, have been studied with a macrophage-like cell line. The fluorescent oil marker, DiD, was successfully encapsulated in NCs in order to follow their interactions with cells. The cell-associated fluorescence obtained with PEG-PLA NC was about 3- to 13-fold lower than that obtained with naked-PLA NC. The effects of PEG chain length, its content as a percentage of total polymer and NC concentration in the culture medium were evaluated. PEG-PLA NC showed dramatically reduced fluorescence association with cells during an 18 h incubation compared with naked-PLA NC, showing that covalent attachment of PEG is important for the persistence of low uptake. The best results in reducing cell-associated fluorescence were obtained with a surface-modified PEG-PLA NC bearing a chain with 20000 MW. Increasing the percentage of PEG produced a reduction in marker association for a given PEG chain length. Moreover, when the PEG-containing poloxamer was simply adsorbed, marker association was dependent on the extent of dilution and the type of serum in the culture medium. Serum proteins, especially immunoglobulins, increased cell-associated fluorescence for PEG-adsorbed NC, but had very little effect on PEG-PLA NC. Marker association was only partially inhibited in the presence of cytochalasin B. The mechanisms of cell-NC interaction depended on the characteristics of the NC surface in each formulation. When the NC was physically separated from cells no diffusion of fluorescent marker in aqueous medium occurred. Nevertheless, collision-mediated transfer of DiD from NC to J774 cells was a non-negligible route of marker transfer, mainly for naked NC. However, this collision-mediated transfer was reduced for the PEG-PLA NC probably due to the restricted contact between NC and cells afforded by PEG steric hindrance at the surface.Item Poly (D,L-lactide) nanocapsules prepared by solvent displacement process : influence of composition on physico-chemical and structural properties.(2000) Mosqueira, Vanessa Carla Furtado; Legrand, Philippe; Alphandary, Huguette Pinto; Puisieux, Francis; Barratt, GillianNanocapsules (NC) were prepared by interfacial deposition of preformed biodegradable polymer (PLA50) after a solvent displacement process. The influence of the composition used for the preparation of NC was evaluated in terms of particle size, polydispersity, zeta potential, homogeneity, and structural characteristics of the systems. The nature of the oil phase, polymer molecular weight, type and concentration of different surfactants were investigated to optimize the formulation to obtain NC suitable for intravenous administration. The influence of the physicochemical properties of the different oils used in NC preparation on the NC size was evaluated. The interfacial tension between the oil and water phases seems to have a greater effect on NC size than the oil viscosity. Miglyol 810 and ethyl oleate lead to the formation of smaller NC, probably because of the reduced interfacial tension. The polymer molecular weight plays only a small role in NC surface charge in the presence of lecithin, whereas NC surface charge, size, polydispersity, and short-term stability were highly influenced by lecithin purity. It appears that the absence of poloxamer 188 leads to smaller polydispersity, less contamination with nanospheres, and reduced formation of structures other than NC. Furthermore, electron microscopy and density gradient density techniques were used to examine the structure of the particles formed and their homogeneity. NC formation was evidenced by the bands with intermediate density between nanoemulsion and nanospheres; however, other bands of low intensity were observed. The presence of liposomes and multilayers in NC preparation was confirmed by electron microscopy. The percentage of carboxyfluorescein entrapped in different NC formulations allowed us to estimate the contamination by liposomes. It has been show that, under our experimental conditions, an excess of lecithin is an essential prerequisite for a stable preparation of PLA NC.Item Efficacy and pharmacokinetics of intravenous nanocapsule formulation of halofantrine in Plasmodium berghei-infected mice.(2004) Mosqueira, Vanessa Carla Furtado; Loiseau, Philippe Marie Rene; Bories, Christian; Legrand, Philippe; Devissaguet, Jean-Philippe; Barratt, GillianThe efficacy and pharmacokinetics of a new parenteral formulation of halofantrine were studied in mice infected with Plasmodium berghei. The formulation consisted of nanocapsules with an oily core, prepared from either poly(D,L-lactide) (PLA) homopolymer or PLA that was surface modified with grafted polyethylene glycol chains. They were compared with a previously described intravenous halofantrine preparation. No toxic effects were observed with halofantrine in form of nanocapsules after intravenous administration for doses of up to 100 mg/kg, whereas the solubilized form in polyethylene glycol-dimethylacetamide was toxic at this dose. The halofantrine-loaded nanocapsules showed activity that was similar to or better than that of the solution in the 4-day test and as a single dose in severely infected mice, with only minimal differences between the two nanocapsule formulations. Halofantrine pharmacokinetics were determined in parallel with parasite development in severely infected mice. Nanocapsules increased the area under the curve for halofantrine in plasma more than sixfold compared with the solution throughout the experimental period of 70 h. Furthermore, nanocapsules induced a significantly faster control of parasite development than the solution in the first 48 h posttreatment. While the parasitemia fell more rapidly with PLA nanocapsules, the effect was more sustained with the surface-modified ones. This is consistent with surface-modified nanocapsules remaining longer in the circulation. These results suggest that nanocapsule formulations could provide a more favorable halofantrine profile in the plasma and reduce the intravenous dose necessary and therefore the toxicity, thus suggesting the use of halofantrine by a parenteral route in severe malaria.Item Biodistribution of long-circulating PEG-Grafted nanocapsules in mice : effects of PEG chain length and density.(2001) Mosqueira, Vanessa Carla Furtado; Legrand, Philippe; Morgat, Jean-Louis; Vert, Michel; Mysiakine, Evgueni; Gref, Ruxandra; Devissaguet, Jean-Philippe; Barratt, GillianPurpose: To study the pharmacokinetics and biodistribution of novel polyethyleneglycol (PEG) surface-modified poly(rac-lactide) (PLA) nanocapsules (NCs) and to investigate the influence of PEG chain length and content. Methods: The biodistribution and plasma clearance in mice of different NC formulations were studied with [3H]-PLA. PLA-PEG copolymers were used in NC preparations at different chain lengths (5 kDa and 20 kDa) and PEG contents (10% and 30% w/w of total polymer). In vitro and in vivo stability were also checked. Results: Limited [3H]-PLA degradation was observed after incubation in mouse plasma for 1 h, probably because of to the large surface area and thin polymer wall. After injection into mice, NCs prepared with PLA-PEG copolymers showed an altered distribution compared to poloxamer-coated PLA NCs. An increased concentration in plasma was also observed for PLA-PEG NCs, even after 24 h. A dramatic difference in the pharmacokinetic parameters of PLA-PEG 45–20 30% NCs compared to poloxamer-coated NCs indicates that covalent attachment, longer PEG chain lengths, and higher densities are necessary to produce an increased half-life of NCs in vivo. Conclusions: Covalently attached PEG on the surface of NCs substantially can reduce their clearance from the blood compartment and alter their biodistribution.Item The antileishmanial properties of surface-modified, primaquine-loaded nanocapsules tested against intramacrophagic Leishmania donovani amastigotes in vitro.(2001) Heurtault, Béatrice; Legrand, Philippe; Mosqueira, Vanessa Carla Furtado; Devissaguet, Jean-Philippe; Barratt, Gillian; Bories, ChristianItem Relationship between complement activation, cellular uptake and surface physicochemical aspects of novel PEG-modifed nanocapsules.(2001) Mosqueira, Vanessa Carla Furtado; Legrand, Philippe; Gulik, Annette; Bourdon, Olivier; Gref, Ruxandra; Labarre, Denis; Barratt, GillianThe aim of our work was to examine the relationship between modi"cations of the surface of nanocapsules (NC) by adsorption or covalent grafting of poly(ethylene oxide) (PEG), and changes in their phospholipid (PL) content on complement activation (C3 cleavage) and on uptake by macrophages. The physicochemical characterization of the NC included an investigation of their properties, such as surface charge, size, hydrophilicity, morphology and homogeneity. This is the "rst time that such properties have been correlated with biological interactions for NC, a novel carrier system with a structure more complex than nanospheres. C3 crossed immunoelectrophoresis revealed the reduced activation for NC with longer PEG chain and higher density, although all formulations induced C3 cleavage to a lesser or greater extent. NC bearing PEG covalently bound to the surface were weaker activators of complement than plain PLA [poly(D,L-lactide)] NC or nanospheres (NS). Furthermore, the #uorescent/confocal microscopy of J774A1 cells in contact with NC reveal a dramatically reduced interaction with PEG-bearing NC. However, the way in which PEG was attached (covalent or adsorbed) seemed to a!ect the mechanism of uptake. Taken together, these results suggest that the low level of protein binding to NC covered with a high density of 20 kDa PEG chains is likely to be due to the steric barriers surrounding these particles, which prevents protein adsorption and reduces their interaction with macrophages. 2001 Elsevier Science Ltd. All rights reserved.Item Cardiotoxicity reduction induced by halofantrine entrapped in nanocapsule devices.(2007) Leite, Elaine Amaral; Guimarães, Andrea Grabe; Guimarães, Homero Nogueira; Coelho, George Luiz Lins Machado; Barratt, Gillian; Mosqueira, Vanessa Carla FurtadoThe main objective of the present study was to evaluate the reduction in halofantrine (Hf) toxicity, an antimalarial drug frequently associated with QT interval prolongation in electrocardiogram, by its entrapment in poly-ε-caprolactone nanocapsules (NC). The acute lethal dose (LD100) of Hf.HCl experimentally observed was 200 mg/kg whereas the calculated LD50 was 154 mg/kg. In contrast, the LD100 for Hf-NC was 300 mg/ kg with a longer mean time to death than Hf.HCl. The calculated LD50 was 249 mg/kg for Hf-NC. The Hf entrapped in PCL NC presented a greater efficacy than PLA-PEG NC and than Hf solution in P. berghei-infected mice at 1 mg/kg. The cardiovascular parameters, ECG and arterial blood pressure, were evaluated in anaesthetized Wistar rats after the IV administration of a single, especially high dose (100 and 150 mg/kg) of halofantrine base loaded-nanocapsules (Hf-NC) or halofantrine chlorhydrate (Hf.HCl) solution. It was observed that Hf solution caused prolongation of the QT and PR intervals of the ECG; however, this effect was significantly (Pb0.001) reduced when Hf was administered entrapped in nanocapsules. The treatment with Hf.HCl induced a pronounced bradycardia and severe hypotension leading to death. The effect of Hf-NC upon heart rate was reduced from 58 to 75% for 100 and 150 mg/kg, respectively, when compared with Hf.HCl solution. These findings show that the encapsulation of halofantrine reduces the QT interval prolongation of ECG in rats and suggest that a modification of drug distribution was possible by using nanocapsules. Hf encapsulation was the main factor responsible for the significant reduction in cardiac toxicity observed.