Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa; Faculty of Pharmacy, University of Khartoum, El Qasr Street P.O. Box 1996, Khartoum, Sudan.
Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa.
Int J Pharm. 2023 Jun 10;640:122967. doi: 10.1016/j.ijpharm.2023.122967. Epub 2023 Apr 20.
In this work, a potent hyaluronidase inhibitor (ascorbyl stearate (AS)) was successfully employed to design vancomycin-loaded solid lipid nanoparticles (VCM-AS-SLNs) with biomimetic and enzyme-responsive features, to enhance the antibacterial efficacy of vancomycin against bacterial-induced sepsis. The VCM-AS-SLNs prepared were biocompatible and had appropriate physicochemical parameters. The VCM-AS-SLNs showed an excellent binding affinity to the bacterial lipase. The in vitro drug release study showed that the release of the loaded vancomycin was significantly accelerated by the bacterial lipase. The in silico simulations and MST studies confirmed the strong binding affinity of AS and VCM-AS-SLNs to bacterial hyaluronidase compared to its natural substrate. This binding superiority indicates that AS and VCM-AS-SLNs could competitively inhibit the effect of hyaluronidase enzyme, and thus block its virulence action. This hypothesis was further confirmed using the hyaluronidase inhibition assay. The in vitro antibacterial studies against sensitive and resistant Staphylococcus aureus revealed that the VCM-AS-SLNs had a 2-fold lower minimum inhibitory concentration, and a 5-fold MRSA biofilm elimination compared to the free vancomycin. Furthermore, the bactericidal-kinetic showed a 100% bacterial clearance rate within 12 h of treatment with VCM-AS-SLNs, and <50 % eradication after 24 h for the bare VCM. Therefore, the VCM-AS-SLN shows potential as an innovative multi-functional nanosystem for effective and targeted delivery of antibiotics.
在这项工作中，成功地使用了一种有效的透明质酸酶抑制剂（抗坏血酸硬脂酯（AS））来设计具有仿生和酶响应特性的万古霉素负载固体脂质纳米粒（VCM-AS-SLNs），以增强万古霉素对细菌诱导性败血症的抗菌功效。制备的 VCM-AS-SLNs 具有生物相容性和适当的物理化学参数。VCM-AS-SLNs 与细菌脂肪酶表现出优异的结合亲和力。体外药物释放研究表明，负载的万古霉素的释放被细菌脂肪酶显著加速。计算机模拟和 MST 研究证实，与天然底物相比，AS 和 VCM-AS-SLNs 与细菌透明质酸酶具有很强的结合亲和力。这种结合优势表明，AS 和 VCM-AS-SLNs 可以竞争性抑制透明质酸酶的作用，从而阻断其毒力作用。这一假设通过透明质酸酶抑制测定得到了进一步证实。对敏感和耐药金黄色葡萄球菌的体外抗菌研究表明，与游离万古霉素相比，VCM-AS-SLNs 的最低抑菌浓度低 2 倍，对耐甲氧西林金黄色葡萄球菌生物膜的消除率高 5 倍。此外，杀菌动力学显示，用 VCM-AS-SLNs 治疗 12 小时内细菌清除率达到 100%，而 bare VCM 治疗 24 小时后清除率<50%。因此，VCM-AS-SLN 有望成为一种用于有效和靶向递送抗生素的创新多功能纳米系统。
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