Hyaluronic acid-coated ZIF-8 for the treatment of pneumonia caused by methicillin-resistant Staphylococcus aureus

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Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common causes of hospital infection. Here, we showed that hyaluronic acid modified organic metal framework material ZIF-8 could be a Trojan horse of vancomycin (Van) for effective treatment of MRSA infections. The Van-loaded nanoparticles were readily up-taken by macrophages via a CD44-mediated process and collapsed in the acidic condition of endosome/lysosome, as a consequence, it could eradicate MRSA with high efficiency in macrophages. This drug delivery system with negligible toxicity could resolve MRSA infections in a well-established mouse pneumonia model.

Introduction

Nowadays, MRSA has emerged as one of the greatest public health threats in the history of antibiotic chemotherapy [1].Scientific reports have proven that MRSA is a major cause of hospital-acquired infections not only includes mild skin and soft tissue injury but also links to life-threatening endocarditis, chronic osteomyelitis and severe pneumonia [2,3].Even worse, these diseases are known to be associated with organ dysfunction, poor outcomes with excess morbidity and mortality, and high costs to the healthcare system, which are awaited to be treated urgently through a novel and efficient antimicrobial therapy. Van, a broad-spectrum glycopeptide antibiotic which is sensitive to Gram-positive bacteria, has been widely employed to prevent and treat staphylococcal isolates such as MRSA [4]. However, large doses of intravenous use of that may cause side effects such as ototoxicity and nephrotoxicity [5]. Nanotechnology has significantly impacted the outcome of cancer treatments and is showing impressive potential in the management of bacterial infection. However, most reported nanomaterials are enormously toxic and also need a multistep synthetic process. In the face of these challenges, there is a growing need for a simpler, more effective method of synthesis and safe antibacterial agents for combating MRSA.

Hyaluronic acid (HA) is a natural acidic mucopolysaccharide composed of D-glucuronic acid and N-acetyl-D-glucosamine. In view of its good biodegradability, low toxicity and high hydrophilicity, it has a wide range of applications in biomedical fields. HA is widely used as active targeting moiety because it is the ligand of CD44 receptors [6], which area type I transmembrane glycoprotein highly expressed in mesenchymal cells and endothelial cells, particularly in tumor and site of inflammation [7]. When the body is attacked by microbial pathogens, the inflammatory response occurs to deal with various inflammatory factors and local injuries. Thus, the carrier of HA for antibiotics is expected to achieve targeted administration, thereby increasing effective drug concentration at the lesion site and reducing the side effects caused by excessive use of antibiotics.

More and more people apply nano metal organic framework to nano drug delivery materials because it has good biocompatibility, high porosity and adjustable size [[8], [9], [10]]. A highly porous zeolite imidazolate framework (ZIF-8) offers great potential in the construction of drug delivery systems as it is stable in neutral and alkaline aqueous solutions but decomposes quickly in acidic solutions [11,12]. Similar to the tumor microenvironment, the accumulation of lactic acid and acetic acid in the inflammatory site was caused by anaerobic fermentation triggered by hypoxia, and the pH value was as low as 5.5.This would be beneficial for specific drug release in inflammatory site. However, the shortcomings of ZIF-8 nanoparticles, such as easy polymerization, poor water dispersibility, and lack of surface functional groups, make it difficult to functionalize ZIF-8, which limits its further application.

Here, we designed a targeted drug-loading system that complexed hyaluronic acid with ZIF-8 through a simple and fast process. We hypothesized that HA were deposited to a zeolite-type metal-organic framework (ZIF-8) through the coordination interaction of the carboxyl groups of HA and Zn2+ (ZVH). Herein the presence of HA restricts agglomeration of nano-ZIF-8 particles scattered and enhances the water dispersibility. HA was expected to specifically bind to CD44 receptors that highly expressed on macrophages, thus eradicating pathogenic bacteria effectively once stimulated by the acidic environment at inflammation sites.

Section snippets

Materials

Hyaluronic acid (10 kDa) was purchased Bloomage Freda Biopharm. Co., Ltd. (Jinan, China) Van, Zinc nitrate hexahydrate (Zn(NO3)2·6H2O), 2-methylimidazole (2-MIM), 4′,6-Diamidino-2-phenylindole(DAPI), MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazoliumbromide) and Rhodamine B were purchased from Aladdin Chemical Reagent Co., Ltd. (Shanghai, China). Other reagents and solvents were purchased locally and all of analytical grade.

RAW 264.7 cells and MRSA were generous gifts received from

Synthesis and characterization

As vividly illustrated in Fig. 1, Van was encapsulated in MOFs formed by the combination of metal ions and organic ligands by a simple one-pot aqueous phase method. HA acted as coating to modify the surface of MOFs/antibiotics particles based on coordination bond to improve targeting capability. The typical morphologies of the ZVH were manifested by scanning electron microscope (SEM), in which isolated particle's three-dimensional structure was rougher than pure ZIF-8 (Fig. 2A, B). As shown in

Conclusions

In summary, we encapsulated antibiotic in a controlled drug delivery system to improve drug targeting and restore antibacterial effectiveness. ZIF-8 nanoparticles have the advantages of low cytotoxicity, simple synthesis and pH-response, etc., thus playing a basic structural role in the nano systems. HA can specifically bind to receptors such as CD44, and plays a vital targeting role in nano systems, providing the possibility for more efficient removal of bacteria. The results of competitive

Conflicts of interest

We have no conflicts of interest to declare.

CRediT authorship contribution statement

Yinyin Liu: Formal analysis, Investigation, Writing - original draft, Conceptualization. Zehao Li: Formal analysis, Data curation. Shuiyang Zou: Investigation, Methodology. Chunbo Lu: Resources. Yao Xiao: Software. Hu Bai: Validation. Xiaoli Zhang: Supervision. Haibo Mu: Writing - review & editing. Xiuyun Zhang: Writing - review & editing. Jinyou Duan: Funding acquisition, Writing - review & editing.

Acknowledgements

The authors thank for the Life Science Research Core Services of Northwest Agriculture and Forestry University for support of TEM. Our work was supported by the Fundamental Research Funds for the Central Universities (2452017026) and the National Natural Science Foundation of China (NSFC) (31870799, 51703181 and 31700707).

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    These authors contributed equally to this work.

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