Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa; Department of Pharmaceutics, Faculty of Pharmacy, University of Gezira, Wad Medani, Sudan.
Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa; United States International University-Africa, School of Pharmacy and Health Sciences, Department of Pharmaceutics, P. O. Box 14634-00800, Nairobi, Kenya.
Int J Pharm. 2024 Sep 5;662:124493. doi: 10.1016/j.ijpharm.2024.124493. Epub 2024 Jul 22.
Sepsis is a life-threatening syndrome resulting from an imbalanced immune response to severe infections. Despite advances in nanomedicines, effective treatments for sepsis are still lacking. Herein, vancomycin free base (VCM)-loaded dual functionalized biomimetic liposomes based on a novel TLR4-targeting peptide (P3) and hyaluronic acid (HA) (HA-P3-Lipo) were developed to enhance sepsis therapy. The nanocarrier revealed appropriate physicochemical parameters, good stability, and biocompatibility. The release of VCM from HA-P3-Lipo was found to be sustained with 76 % VCM released in 48 h. The biomimicry was elucidated by in silico tools and MST and results confirmed strong binding between the system and TLR4. Furthermore, HA-P3-Lipo revealed 2-fold enhanced antibacterial activity against S. aureus, sustained antibacterial activity against MRSA over 72 h and 5-fold better MRSA biofilm inhibition compared to bare VCM. Bacterial-killing kinetics and flow cytometry confirmed the superiority of HA-P3-Lipo in eliminating MRSA faster than VCM. The in vivo potential of the nanocarrier was elucidated in an MRSA-induced sepsis mice model, and the results confirmed the superiority of HA-P3-Lipo compared to free VCM in eliminating bacteria and down-regulating the proinflammatory markers. Therefore, HA-P3-Lipo exhibits potential as a promising novel multi-functional nanosystem against sepsis and could significantly contribute to the transformation of sepsis therapy.
脓毒症是一种危及生命的综合征，是由严重感染引起的免疫反应失衡引起的。尽管纳米医学取得了进展，但脓毒症的有效治疗方法仍然缺乏。在此，开发了一种基于新型 TLR4 靶向肽（P3）和透明质酸（HA）的万古霉素游离碱（VCM）负载的双功能仿生脂质体（HA-P3-Lipo），以增强脓毒症治疗效果。该纳米载体具有合适的物理化学参数、良好的稳定性和生物相容性。研究发现，HA-P3-Lipo 中 VCM 的释放是持续的，48 小时内释放了 76%的 VCM。通过计算机模拟工具和 MST 阐明了仿生学原理，结果证实了该系统与 TLR4 之间具有很强的结合能力。此外，HA-P3-Lipo 对金黄色葡萄球菌的抗菌活性提高了 2 倍，对耐甲氧西林金黄色葡萄球菌（MRSA）的抗菌活性可持续 72 小时以上，对 MRSA 生物膜的抑制作用比游离 VCM 强 5 倍。细菌杀伤动力学和流式细胞术证实，HA-P3-Lipo 在消除 MRSA 方面优于 VCM。该纳米载体在 MRSA 诱导的脓毒症小鼠模型中的体内潜力得到了阐明，结果证实，HA-P3-Lipo 比游离 VCM 更能有效地消除细菌并下调促炎标志物。因此，HA-P3-Lipo 作为一种有前途的新型多功能纳米系统，具有治疗脓毒症的潜力，有望为脓毒症治疗带来重大变革。
