International Journal of Nanomedicine (Sep 2023)

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

  • Ning J,
  • Zheng G,
  • Cai Y,
  • Hu Y,
  • Liu Y,
  • Lai E,
  • Chen B,
  • Liu Y,
  • Liang Z,
  • Fu J,
  • Wei M

Journal volume & issue
Vol. Volume 18
pp. 5119 – 5140

Abstract

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Jinrong Ning,1,* Guodong Zheng,1,* Yi Cai,1,* Yunguang Hu,2,* Yiqi Liu,1 Enping Lai,1 Baizhong Chen,3 Yujie Liu,1 Ziqi Liang,1 Jijun Fu,1 Minyan Wei1 1Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, People’s Republic of China; 2Medical Department, Guangdong Yifang Pharmaceutical Co., Ltd, Foshan, Guangdong, 528200, People’s Republic of China; 3Guangdong Xinbaotang Biological Technology Co., Ltd, Jiangmen, Guangdong, 529000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Minyan Wei; Jijun Fu, Guangzhou Medical University, Guangzhou, 511436, People’s Republic of China, Tel +86-20-37103268, Email [email protected]; [email protected]: 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.Graphical Abstract: Keywords: nobiletin, self-assembly micelles, solid dispersion technology, hot melt extrusion, acetaminophen-induced liver injury

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