Multifunctional hyaluronic acid-based biomimetic/pH-responsive hybrid nanostructured lipid carriers for treating bacterial sepsis.

IF 9 2区 医学 Q1 CELL BIOLOGY
Eman Elhassan, Calvin A Omolo, Mohammed A Gafar, Eman A Ismail, Usri H Ibrahim, Rene Khan, Mathieu Lesouhaitier, Paul Kubes, Thirumala Govender
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引用次数: 0

Abstract

Introduction: The application of biomimetic and stimuli-responsive nanocarriers displays considerable promise in improving the management of bacterial sepsis and overcoming antimicrobial resistance. Therefore, the study aimed to synthesize a novel hyaluronic acid-lysine conjugate (HA-Lys) and to utilize the attributes of the synthesized HA-Lys with Tocopherol succinate (TS) and Oleylamine (OLA) in the formulation of multifunctional biomimetic pH-responsive HNLCs loaded with vancomycin (VCM-HNLCs), to combat bacterial sepsis.

Methods: A novel hyaluronic acid-lysine conjugate (HA-Lys) was synthesized and characterized using FTIR and 1H NMR spectroscopy. Vancomycin-loaded hybrid nanosystems (VCM-HNLCs) were prepared through hot homogenization ultrasonication and evaluated for particle size, polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE%). In vitro biocompatibility was assessed via MTT assay and red blood cell hemolysis test. The binding affinity to TLR2 and TLR4 was measured using microscale thermophoresis (MST). Drug release was evaluated using the dialysis bag method. Antimicrobial activity against MRSA and efflux pump inhibition were also determined. Efficacy was demonstrated in an MRSA-induced sepsis mice model.

Results: The VCM-HNLCs, produced via hot homogenization ultrasonication, exhibited particle size (PS), polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE%) of 110.77 ± 1.692 nm, 0.113 ± 0.022, - 2.92 ± 0.210 mV, and 76.27 ± 1.200%, respectively. In vitro, biocompatibility was proven by hemolysis and cytotoxicity studies. The VCM-HNLCs demonstrated targetability to human Toll-like receptors (TLR 2 and 4) as validated by microscale thermophoresis (MST). VCM-HNLCs showed a twofold reduction in MIC values at physiological pH compared to the bare VCM against S. aureus and MRSA for 48 h. While at pH 6.0, MIC values were reduced by fourfold in the first 24 h and by eightfold in the subsequent 48 and 72 h against tested strains. Furthermore, VCM-HNLCs showed inhibitory effects against MRSA efflux pumps, reactive oxygen species (ROS), and lipopolysaccharide (LPS)-induced hyperinflammation. In an MRSA-induced sepsis mice model, VCM-HNLCs demonstrated superior efficacy compared to free VCM, significantly eliminated bacteria and improved survival rates.

Conclusions: Overall, these results highlight the potential of VCM-HNLCs as novel multifunctional nanocarriers to combat antimicrobial resistance (AMR) and enhance sepsis outcomes.

多功能透明质酸仿生/ ph响应混合纳米结构脂质载体治疗细菌性败血症。
仿生和刺激反应纳米载体的应用在改善细菌性败血症的管理和克服抗菌素耐药性方面显示出相当大的希望。因此,本研究旨在合成一种新型透明质酸-赖氨酸缀合物(HA-Lys),并利用所合成的HA-Lys与琥珀酸生育酚(TS)和油胺(OLA)的特性,制备负载万古霉素的多功能仿生ph响应型hnlc (vcm - hnlc),以对抗细菌性脓毒症。方法:合成了一种新型透明质酸-赖氨酸缀合物(HA-Lys),并用FTIR和1H NMR对其进行了表征。采用热均质超声法制备了万古霉素负载的杂化纳米体系(vcm - hnlc),并对其粒径、多分散性指数(PDI)、ζ电位(ZP)和包封效率(EE%)进行了评价。采用MTT法和红细胞溶血试验评价其体外生物相容性。采用微尺度热泳法(MST)测定其与TLR2和TLR4的结合亲和力。采用透析袋法评价药物释放度。测定了对MRSA的抑菌活性和外排泵抑制作用。在mrsa诱导的脓毒症小鼠模型中证实了疗效。结果:热均质超声法制备的vcm - hnlc粒径(PS)为110.77±1.692 nm,多分散性指数(PDI)为0.113±0.022,ζ电位(ZP)为- 2.92±0.210 mV,包封率(EE%)为76.27±1.200%。体外溶血和细胞毒性研究证实了其生物相容性。通过微尺度热泳(MST)验证了vcm - hnlc对人类toll样受体(tlr2和4)的靶向性。与裸VCM相比,VCM- hnlc在生理pH下对金黄色葡萄球菌和MRSA的MIC值降低了2倍,而在pH 6.0时,对测试菌株的MIC值在前24小时降低了4倍,在随后的48和72小时降低了8倍。此外,vcm - hnlc对MRSA外排泵、活性氧(ROS)和脂多糖(LPS)诱导的高炎症有抑制作用。在mrsa诱导的脓毒症小鼠模型中,与游离VCM相比,VCM- hnlc表现出更好的疗效,显著消除细菌并提高生存率。结论:总的来说,这些结果突出了vcm - hnlc作为新型多功能纳米载体的潜力,可以对抗抗菌素耐药性(AMR)并改善败血症的预后。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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