Enzymosomes with surface-exposed superoxide dismutase: in vivo behaviour and therapeutic activity in a model of adjuvant arthritis.

Contains fulltext : 51828.pdf (publisher's version ) (Closed access)Acylated Superoxide Dismutase (Ac-SOD) enzymosomes, liposomal enzymatic systems expressing catalytic activity in the intact form, were previously characterized. The main scope of the present work was to investigate the biological behaviour of Ac-SOD inserted in the lipid bilayer of liposomes, in comparison with SOD located in the aqueous compartment of liposomes. Two types of liposomes were used: conventional liposomes presenting an unmodified external surface and long circulating liposomes coated with poly (ethylene glycol) (PEG). Liposomal formulations of Ac-SOD and SOD were prepared and labelled with indium-111 and their in vivo fate compared. Data obtained led us to the conclusion that, for liposomes coated with PEG the in vivo fate was not influenced by the insertion of Ac-SOD in the lipid bilayers. The potential therapeutic effect of Ac-SOD enzymosomes was compared with SOD liposomes in a rat model of adjuvant arthritis. A faster anti-inflammatory effect was observed for Ac-SOD enzymosomes by monitoring the volume of the inflamed paws. The present results allowed us to conclude that Ac-SOD enzymosomes are nano-carriers combining the advantages of expressing enzymatic activity in intact form and thus being able to exert therapeutic effect even before liposomes disruption, as well as acting as a sustained release of the enzyme

Subcutaneous administration of superoxide dismutase entrapped in long circulating liposomes. In vivo fate and therapeutic activity in an inflammation model.

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Intravenous administration of superoxide dismutase entrapped in long circulating liposomes. II. In vivo fate in a rat model of adjuvant arthritis

AbstractRheumatoid arthritis (RA) is a prevalent and debilitating autoimmune disease that affects the joints. RA is characterized by an infiltration of the affected joint by blood-derived cells. In response to activation, these cells generate reactive oxygen species, resulting in an oxidative stress situation. One approach to counteract this oxidative stress situation is the use of antioxidants as therapeutic agents. The free radical scavenger enzyme superoxide dismutase (SOD) may be used as a therapeutic agent in rheumatoid arthritis, but its rapid elimination from the circulation is a major limitation. Targeted delivery of SOD may overcome this limitation. In this study, the utility of PEGylated liposomes (PEG-liposomes) for targeting SOD to arthritic sites was explored. The targeting of SOD to arthritic sites following intravenous administration of both PEG-liposomes and positively charged liposomes lacking PEG but containing stearylamine (SA-liposomes) in rats with adjuvant arthritis was studied. At 24 h post injection, the blood levels of long circulating liposomes with a mean size of 0.11 μm and 0.20 μm were 8- and 3-fold higher, respectively, as compared to the SA-liposomes. The majority of SOD administered in liposomal form remains within the liposomes when they circulate in the bloodstream. The highest target uptake was observed with PEG-liposomes with a mean size of 0.11 μm and the lowest uptake with the SA-liposomes. These results demonstrate that SOD can be targeted to inflamed sites most efficiently via small-sized PEG-liposomes. Small-sized PEG-coated liposomes are to be preferred if prolonged circulation and enhanced localization of SOD at arthritic sites are desired

Superoxide dismutase enzymosomes: carrier capacity optimization, in vivo behaviour and therapeutic activity

Purpose\ud A strategy not usually used to improve carrier-mediated delivery of therapeutic enzymes is the attachment of the enzymes to the outer surface of liposomes. The aim of our work was to design a new type of enzymosomes with a sufficient surface-exposed enzyme load while preserving the structural integrity of the liposomal particles and activity of the enzyme.\ud \ud Methods\ud The therapeutic antioxidant enzyme superoxide dismutase (SOD) was covalently attached to the distal terminus of polyethylene glycol (PEG) polymer chains, located at the surface of lipid vesicles, to obtain SOD-enzymosomes.\ud \ud Results\ud The in vivo fate of the optimized SOD-enzymosomes showed that SOD attachment at the end of the activated PEG slightly reduced the residence time of the liposome particles in the bloodstream after IV administration. The biodistribution studies showed that SOD-enzymosomes had a similar organ distribution profile to liposomes with SOD encapsulated in their aqueous interior (SOD-liposomes). SOD-enzymosomes showed earlier therapeutic activity than both SOD-liposomes and free SOD in rat adjuvant arthritis. SOD-enzymosomes, unlike SOD-liposomes, have a therapeutic effect, decreasing liver damage in a rat liver ischemia/reperfusion model.\ud \ud Conclusions\ud SOD-enzymosomes were shown to be a new and successful therapeutic approach to oxidative stress-associated inflammatory situations/diseases

Incorporation of 2-styrylchromones in liposomes: preliminaries studies

Several compounds with a 2-styrylchromone chemical structure have been shown to hold a high antioxidant activity in vitro, at low concentrations, which indicates a potential therapeutic value that needs to be confirmed in vivo [1-2] . The evaluation of the antioxidant potential of 2- styrylcromones, in vivo, is expected to beneficiate from a formulation that delivers the compound to specific target sites. Due to the structural analogies of 2-styrylcromones with flavonoids, a controlled delivery system - liposomes - was chosen to take advantage of the well known pharmacokinetic behaviour of liposome-incorporated flavonoids. Liposomes are lamellar lipidic structures which form almost spontaneously when certain lipids are hydrated in aqueous media [3 ,4]. This work presents, for the first rime, the results of the incorporation of 2-styrylcromones in liposomes. The characterization of the obtained formulations was based in the study of the encapsulation efficiency of the compound in liposomes, the knowledgment of the primary concentration of compound in the incorporation process and the effect of the addition of freeze-drying protector, threalose to the formulation. The obtained results showed that 2-syrylcromones could be encapsulated in lipossomes with high incorporation efficiency. The highest encapsulation efficiency was achieved with a concentration of drug of 1 μmol of total lipid. The results concerning the addition of threalose to the formulation indicated that the use of the freeze-drying protector reduces the effects caused by freeze-drying, such as the growth of the vesicles. This liposomal formulations is expected to allow the diffusion of these compounds to the target site in therapeutic concentrations

Measurement of psi (2S) production cross-sections in proton-proton collisions at v s=7 and 13 TeV

The cross-sections of \u3c8(2 S) meson production in proton-proton collisions at s=13TeV are measured with a data sample collected by the LHCb detector corresponding to an integrated luminosity of 275pb-1. The production cross-sections for prompt \u3c8(2 S) mesons and those for \u3c8(2 S) mesons from b-hadron decays (\u3c8(2S)-from-b) are determined as functions of the transverse momentum, pT, and the rapidity, y, of the \u3c8(2 S) meson in the kinematic range 2<20GeV/c and 2.0 < y< 4.5. The production cross-sections integrated over this kinematic region are \u3c3(prompt\u3c8(2S),13TeV)=1.430\ub10.005(stat)\ub10.099(syst)\u3bcb,\u3c3(\u3c8(2S)-from-b,13TeV)=0.426\ub10.002(stat)\ub10.030(syst)\u3bcb.A new measurement of \u3c8(2 S) production cross-sections in pp collisions at s=7TeV is also performed using data collected in 2011, corresponding to an integrated luminosity of 614pb-1. The integrated production cross-sections in the kinematic range 3.5<14GeV/c and 2.0 < y< 4.5 are \u3c3(prompt\u3c8(2S),7TeV)=0.471\ub10.001(stat)\ub10.025(syst)\u3bcb,\u3c3(\u3c8(2S)-from-b,7TeV)=0.126\ub10.001(stat)\ub10.008(syst)\u3bcb.All results show reasonable agreement with theoretical calculations