Xiao Ya, Xu Mengran, Lv Na, Cheng Chen, Huang Pei, Li Jiabin, Hu Yi, Sun Ming
Department of Stomatology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Acta Biomater. 2021 Mar 1;122:291-305. doi: 10.1016/j.actbio.2020.12.045. Epub 2020 Dec 25.
The serious threat of drug-resistant bacterial pathogens has arisen through overuse of antibiotics. Photothermal therapy (PTT) has come to prominence as viable alternative strategy for antibacterial therapy. In this work, we report a NIR/pH dual stimuli-responsive antibacterial formulation based on zeolitic imidazolate frameworks-8 (ZIF-8) with strong antibacterial activity that combines photothermal heating with enhanced antibiotic delivery. ZIF-8 with polydopamine (PDA) surface modification was used to encapsulate the antibiotic vancomycin to construct a dual stimuli-responsive antimicrobial formulation (Van@ZIF-8@PDA). This treatment was tested against Gram-positive Mu50 (a vancomycin-intermediate S. aureus reference strain). Results showed that the PDA coating improved ZIF-8 stability and dispersion, while also conferring a high photothermal conversion efficiency. Hyperthermia activated by near-infrared (NIR) light irradiation, in conjunction with pH-dependent nanoparticle degradation to release vancomycin, enabled tight control of drug delivery that functioned synergistically in the elimination of both planktonic bacteria prior to biofilm formation and established biofilms. We found that this combined formulation compromises cell structure while also degrading bacterial DNA. Moreover, further investigation showed that the Van@ZIF-8@PDA nanoparticles exhibit good biocompatibility, with low toxicity toward host organs and tissues, while also reducing the antibiotic concentration needed for effective bacterial control. Finally, we treated Mu50 in a mouse model of skin abscess and found that Van@ZIF-8@PDA was effective and safe in vivo. Cumulatively, this study shows that this NIR/pH dual stimuli-responsive nanoparticle-based formulation offers a promising potential strategy for clinical application against bacterial infection that circumvents antibiotic resistance.
抗生素的过度使用引发了耐药性细菌病原体的严重威胁。光热疗法（PTT）作为一种可行的抗菌治疗替代策略而备受关注。在这项工作中，我们报道了一种基于沸石咪唑酯骨架-8（ZIF-8）的近红外/ pH双刺激响应抗菌制剂，该制剂具有强大的抗菌活性，将光热加热与增强的抗生素递送相结合。对ZIF-8进行聚多巴胺（PDA）表面改性，用于包裹抗生素万古霉素，构建双刺激响应抗菌制剂（Van@ZIF-8@PDA）。针对革兰氏阳性菌Mu50（一种万古霉素中介金黄色葡萄球菌参考菌株）对该治疗方法进行了测试。结果表明，PDA涂层提高了ZIF-8的稳定性和分散性，同时还赋予了高光热转换效率。近红外（NIR）光照射激活的热疗，结合pH依赖性纳米颗粒降解以释放万古霉素，能够严格控制药物递送，在生物膜形成之前消除浮游细菌和已形成的生物膜方面协同发挥作用。我们发现这种联合制剂破坏了细胞结构，同时还降解了细菌DNA。此外，进一步研究表明，Van@ZIF-8@PDA纳米颗粒具有良好的生物相容性，对宿主器官和组织毒性低，同时还降低了有效控制细菌所需的抗生素浓度。最后，我们在皮肤脓肿小鼠模型中对Mu50进行了治疗，发现Van@ZIF-8@PDA在体内有效且安全。总的来说，这项研究表明，这种基于近红外/ pH双刺激响应纳米颗粒的制剂为临床应用对抗细菌感染提供了一种有前景的潜在策略，可规避抗生素耐药性。
