RESUMEN
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: SOD-enzymosomes were shown to be a new and successful therapeutic approach to oxidative stress-associated inflammatory situations/diseases.
Asunto(s)
Portadores de Fármacos/química , Polietilenglicoles/química , Superóxido Dismutasa/administración & dosificación , Superóxido Dismutasa/uso terapéutico , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Composición de Medicamentos , Liberación de Fármacos , Liposomas , Hígado/irrigación sanguínea , Masculino , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Ratas Wistar , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Superóxido Dismutasa/farmacocinética , Propiedades de Superficie , Distribución Tisular , Resultado del TratamientoRESUMEN
New long circulating magnetoliposomes coated with polyethylene glycol (PEG), and loaded with PEG-coated 10nm superparamagnetic iron oxide nanoparticles (SPION), were developed. The magnetoliposomes relaxivities r1, r2 measured in a magnetic field of 7 T showed a minor effect on T1, but a major effect on T2. These nanosystems were used as a negative contrast agent for MRI in a nonclinical study to visualize, in a rat model of liver ischemia, ischemia-reperfusion injuries. Magnetic resonance micro-images (MRM) at 7 T were obtained for rat liver with and without magnetoliposomes administration and analyzed in comparison with liver biomarkers and histological results. These new long circulating magnetoliposomes enhanced the detection of lesions indicating their potential use as efficient MRI negative contrast agent for the detection of liver ischemia-reperfusion injuries. FROM THE CLINICAL EDITOR: This paper describes the generation of PEGylated magnetoliposomes and demonstrates their feasibility as negative contrast agents in a liver ischemia-reperfusion rat model.