Combined Silver Sulfadiazine Nanosuspension with Thermosensitive Hydrogel: An Effective Antibacterial Treatment for Wound Healing in an Animal Model

Abstract

Xiaoya Liu,1,2 Haiyang Fan,3 Zhiyun Meng,2 Zhuona Wu,2 Ruolan Gu,2 Xiaoxia Zhu,2 Hui Gan,2 Guifang Dou2 1Department of Pharmacy, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, 518026, People’s Republic of China; 2Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing, 100850, People’s Republic of China; 3Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong Province, 518102, People’s Republic of ChinaCorrespondence: Guifang Dou; Hui Gan, Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing, 100850, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]; [email protected]: Silver sulfadiazine (AgSD) is widely used in burn wound treatment due to its broad-spectrum antibacterial activity. However, its application in wound healing is greatly hindered by the low solubility of AgSD particles and their cellular cytotoxicity. Herein, we studied the safety and in vivo efficacy of nano-sized silver sulfadiazine loaded in poloxamer thermosensitive hydrogel (NS/Gel).Methods: In NS/Gel, silver sulfadiazine was prepared into silver sulfadiazine nanosuspension (NS) to improve the solubility and enhance its antibacterial activity, whereas the poloxamer thermosensitive hydrogel was selected as a drug carrier of NS to achieve slow drug release and reduced cytotoxicity. The acute toxicity of silver sulfadiazine nanosuspension was first evaluated in healthy mice, and its median lethal dose (LD50) was calculated by the modified Karber method. Furthermore, in vivo antibacterial effect and wound healing property of NS/Gel were evaluated on the infected deep second-degree burn wound mice model.Results: The mortality ratio of mice was concentration-dependent, and the LD50 for silver sulfadiazine nanosuspension was estimated to be 252.1 mg/kg (230.8 to 275.4 mg/kg, 95% confidence limit). The in vivo dosages used for burn wound treatment (40– 50 mg/kg) were far below LD50 (252.1 mg/kg). NS/Gel significantly accelerated wound healing in the deep second wound infection mice model, achieving > 85% wound contraction on day 14. Staphylococcus aureus in the wound region was eradicated after 7 days in NS/Gel group, while the bacterial colony count was still measurable in the control group. Histological analysis and cytokines measurement confirmed that the mice treated with NS/Gel exhibited well-organized epithelium and multiple keratinized cell layers compared to control groups with the modulated expression of IL-6, VEGF, and TGF-β.Conclusion: The combination of silver sulfadiazine nanosuspension and thermo-responsive hydrogel has great potential in clinical burn wound treatment.Keywords: silver sulfadiazine, antibacterial agent, thermosensitive hydrogel, acute toxicity, burn wound model, median lethal dose

Keywords

• antibacterial agent
• nanosuspension
• thermosensitive hydrogel
• silver sulfadiazine
• acute toxicity
• burn wound model.