Liquiritigenin-Loaded Submicron Emulsion Protects Against Doxorubicin-Induced Cardiotoxicity via Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Activity

Abstract

Changcan Shi,1,* Hongjuan Wu,2,* Ke Xu,3 Ting Cai,3 Kunming Qin,4 Li Wu,1 Baochang Cai1,4 1School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, People’s Republic of China; 2Nanjing Jiangning District Hospital of Traditional Chinese Medicine, Nanjing 211100, People’s Republic of China; 3School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People’s Republic of China; 4Nanjing Haichang Chinese Medicine Group Corporation, Nanjing 210061, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li WuSchool of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, People’s Republic of ChinaEmail [email protected] CaiSchool of Pharmacy Nanjing University of Chinese Medicine, Nanjing 210046, People’s Republic of ChinaEmail [email protected]: The clinical use of doxorubicin (DOX) is severely limited due to its cardiotoxicity. Thus, there is a need for prophylactic and treatment strategies against DOX-induced cardiotoxicity.Purpose: The purpose of this study was to develop a liquiritigenin-loaded submicron emulsion (Lq-SE) with enhanced oral bioavailability and to explore its efficacy against DOX-induced cardiotoxicity.Methods: Lq-SE was prepared using high-pressure homogenization and characterized using several analytical techniques. The formulation was optimized by central composite design response surface methodology (CCD-RSM). In vivo pharmacokinetic studies, biochemical analyses, reactive oxygen species (ROS) assays, histopathologic assays, and Western blot analyses were performed.Results: Each Lq-SE droplet had a mean particle size of 221.7 ± 5.80 nm, a polydispersity index (PDI) of 0.106 ± 0.068 and a zeta potential of − 28.23 ± 0.42 mV. The area under the curve (AUC) of Lq-SE was 595% higher than that of liquiritigenin (Lq). Lq-SE decreased the release of serum cardiac enzymes and ameliorated histopathological changes in the hearts of DOX-challenged mice. Lq-SE significantly reduced oxidative stress by adjusting the levels of ROS, increasing the activity of antioxidative enzymes and inhibiting the protein expression of NOX4 and NOX2. Furthermore, Lq-SE significantly improved the inflammatory response through the mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) signalling pathway and induced cardiomyocyte apoptosis.Conclusion: Lq-SE could be used as an effective cardioprotective agent against DOX in chemotherapy to enable better treatment outcomes.Keywords: liquiritigenin, submicron emulsion, bioavailability, cardiotoxicity, protective efficacy

Keywords

• liquiritigenin
• submicron emulsion
• bioavailability
• cardiotoxicity
• protective efficacy