RESUMEN
Oxidative side reaction is one of the major factors hindering the development of hemoglobin-based oxygen carriers (HBOCs). To avoid the oxidative toxicity, we designed and synthesized polydopamine-coated hemoglobin (Hb-PDA) nanoparticles via simple one-step assemblage without any toxic reagent. Hb-PDA nanoparticles showed oxidative protection of Hb by inhibiting the generation of methemoglobin (MetHb) and ferryl (Fe IV) Hb, as well as excellent antioxidant properties by scavenging free radicals and reactive oxygen species (ROS). Interestingly, the scavenging rate of Hb-PDA nanoparticles for ABTS+ radical is at most 89%, while for DPPH radical it reaches 49%. In addition, Hb-PDA efficiently reduced the intracellular H2O2-induced ROS generation. Moreover, Hb-PDA nanoparticles exhibited high oxygen affinity, low effect on blood constituents, and low cytotoxicity. The results indicate that polydopamine-coated hemoglobin might be a promising approach for constructing novel oxygen carriers with the capacity to reduce oxidative side reaction.
Asunto(s)
Antioxidantes/farmacología , Materiales Biocompatibles/farmacología , Sustitutos Sanguíneos , Hemoglobinas/farmacología , Indoles/farmacología , Oxígeno/química , Polímeros/farmacología , Animales , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Antioxidantes/química , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/efectos adversos , Materiales Biocompatibles/química , Compuestos de Bifenilo/química , Bovinos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Reactivos de Enlaces Cruzados/química , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Hemoglobinas/administración & dosificación , Hemoglobinas/efectos adversos , Hemoglobinas/química , Hemólisis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Indoles/administración & dosificación , Indoles/efectos adversos , Indoles/química , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Nanopartículas/química , Picratos/química , Agregación Plaquetaria/efectos de los fármacos , Polímeros/administración & dosificación , Polímeros/efectos adversos , Polímeros/química , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Sepsis-associated acute liver injury contributes to the pathogenesis of multiple organ dysfunction syndrome and is associated with increased mortality. Currently, no specific therapeutics for sepsis-associated liver injury are available. With excess levels of reactive oxygen species (ROS) being implicated as key players in sepsis-induced liver injury, we hypothesize that ROS-responsive nanoparticles (NPs) formed via the self-assembly of diblock copolymers of poly(ethylene glycol) (PEG) and poly(propylene sulfide) (PPS) may function as an effective drug delivery system for alleviating sepsis-induced liver injury by preferentially releasing drug molecules at the disease site. However, there are no reports available on the biocompatibility and effect of PEG-b-PPS-NPs in vivo. Herein, this platform was tested for delivering the promising antioxidant therapeutic molecule melatonin (Mel), which currently has limited therapeutic efficacy because of its poor pharmacokinetic properties. The mPEG-b-PPS-NPs efficiently encapsulated Mel using the oil-in-water emulsion technique and provided sustained, on-demand release that was modulated in vitro by the hydrogen peroxide concentration. Animal studies using a mouse model of sepsis-induced acute liver injury revealed that Mel-loaded mPEG-b-PPS-NPs are biocompatible and much more efficacious than an equivalent amount of free drug in attenuating oxidative stress, the inflammatory response, and subsequent liver injury. Accordingly, this work indicates that mPEG-b-PPS-NPs show potential as an ROS-mediated on-demand drug delivery system for improving Mel bioavailability and treating oxidative stress-associated diseases such as sepsis-induced acute liver injury.