Noverl Carvedilol Pro-Phytomicelles And Its Protective And Treatment Efficacy On Liver Injury In Mice

Drug-induced liver injuries caused by acetaminophen overdose is a common clinical emergency.The only clinically available antidote for severe liver damage currently is N-acetylcysteine(NAC).However,the clinical applicability of NAC is limited by its low bioavailability and short therapeutic window,which is only effective at the startup stage of liver injury.Thus,developing alternative strategies to manage acetaminophen-induced liver injuries is crucial.Carvedilol(CAR)is one of the most promising conventional drugs for pretreating or treating acetaminophen-induced liver injuries.However,as a biopharmaceutical classification system class II drug,CAR demonstrates extremely low solubility in intestinal fluids,resulting in poor oral bioavailability and a compromised treatment effect.This article was to develop a novel nanomedicine,named CAR pro-phytomicelles,was prepared via a simple ethanol evaporation process with rebaudioside A(RA)and dipotassium glycyrrhizinate(DG),as mixed nanomaterials,and to explore the improved efficacy and mechanism of this novel CAR pro-phytomicelle formulation against acetaminophen-induced liver injury in mice.The CAR pro-phytomicelle formulation was optimized using Design-Expert software and a central composite design.The optimizing formulation of CAR prophytomicelles showed that a CAR to DG&RA weight ratio of 1:16 and a DG to RA ratio of 8.13:1 would result in optimal entrapment efficiency(99.67± 0.02%)for CAR prophytomicelles.The physical mixture of DG and RA could self-assemble into micelles immediately after dissolved into water.Spectrophotometer and high performance liquid chromatography(HPLC)were successfully established for the qualitative and quantitative analysis of CAR.The obtained CAR pro-phytomicelles was a uniform white powder and at ×50000magnification the pro-phytomicelles were found to be as aggregated but uniform nanospheres.The formulation leading to a 502-fold increase in apparent solubility of CAR in water and CAR was a noncrystalline state in CAR pro-phytomicelles as a result of encapsulation within mixed phytomicelles based on DG and RA.CAR prophytomicelles samples could be instantly dissolved into aqueous media to formulate clear nanomicelle solutions with small micelle size of 15.62±0.27 nm and a narrow polydispersity index of 0.126±0.01,negative zeta potential distribution of-11.77±0.93 m V.CAR pro-phytomicelles exhibited good storage stability at 25°C,rapid in vitro release in simulated intestinal fluid with no p H-dependent,and improved in vitro antioxidant activity.CAR pro-phytomicelles had good biocompatibility which could be used in oral drug delivery systems.Protective and treatment efficacy evaluation revealed that acetaminophen overdose could induce high mortality and severe liver injury in mice.While CAR pro-phytomicelle exhibited significant protective and treatment effect against acetaminophen overdose,which can effectively improve the liver tissue status and reduce serum AST and ALT levels.This protective or treatment efficacy was due to a mechanism that involved the of oxidative stress and the regulation of high-mobility group box 1(HMGB1)and its signaling-related proinflammatory cytokines.CAR pro-phytomicelles could be fabricated with simple process and the formulation ingredients were FDA-approved drugs or exicipents,might lead to the formulation having a smooth path to clinical use.CAR pro-phytomicelles demonstrated excellent characteristics and strong protective and treatment efficacies against liver injury,which regulated HMGB1 signaling in liver.CAR pro-phytomicelles could provide a new concept and promising therapeutics as nanomedicines for improving the activities of CAR against acetaminophen-induced liver injury.