The Self-Assembly Soluplus Nanomicelles of Nobiletin in Aqueous Medium Based on Solid Dispersion and Their Increased Hepatoprotective Effect on APAP-Induced Acute Liver Injury

Abstract

Purpose APAP-induced liver injury (AILI) is a common cause of acute liver failure (ALF). Nobiletin (NOB) is a potential hepatoprotective agent for the treatment of APAP-induced liver injury. However, the poor solubility and low bioavailability of NOB hinders its application. In this study, a novel self-assembly nano-drug delivery system of nobiletin (solid dispersion of NOB, termed as NOB/SD) was developed based on solid dispersion technology to improve the bioavailability and hepatoprotective ability of NOB for APAP-induced liver injury therapy. Methods The optimized NOB/SD system was constructed using the amphiphilic copolymers of Soluplus and PVP/VA 64 via hot melt extrusion technology (HME). NOB/SD was characterized by solubility, physical interaction, drug release behavior, and stability. The bioavailability and hepatoprotective effects of NOB/SD were evaluated in vitro and in vivo. Results NOB/SD maintained NOB in matrix carriers in a stable amorphous state, and self-assembled NOB-loaded nanomicelles in water. Nanostructures based on solid dispersion technology exhibited enhanced solubility, improved release behavior, and promoted cellular uptake and anti-apoptosis in vitro. NOB/SD displayed significantly improved bioavailability in healthy Sprague Dawley (SD) rats in vivo. Furthermore, NOB/SD alleviated the APAP-induced liver injury by improving anti-oxidative stress with reactive oxygen species (ROS) scavenging and nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Conclusion These results suggested that NOB/SD could be considered as a promising hepatoprotective nano-drug delivery system for attenuating APAP-induced acute liver injury with superior bioavailability and efficient hepatoprotection, which might provide an effective strategy for APAP-induced acute liver injury prevention and treatment.

Nobiletin from citrus peel: a promising therapeutic agent for liver disease-pharmacological characteristics, mechanisms, and potential applications

“…AILI accounts for 39% and 57% of acute liver failure cases in the USA and UK, respectively. Several studies have reported NOB’s protective effects and possible mechanisms in AILI ( Figure 2 ) ( Lin et al, 2019 ; Guvenc et al, 2020 ; Ning et al, 2023 ). In the AILI model in rats pretreated with NOB (10 mg/kg) for 10 days, NOB significantly enhanced anti-oxidative stress and anti-inflammatory protective effects by inducing HO-1 and Nrf-2 expression, attenuating liver injury ( Guvenc et al, 2020 ).…”

“…NOB/SD displayed significantly enhanced bioavailability in healthy Sprague Dawley rats in vivo . Furthermore, NOB/SD alleviated AILI by improving anti-oxidative stress with ROS scavenging and Nrf2 activation ( Ning et al, 2023 ).…”