Hyaluronic Acid-Modified Micelles of Azithromycin and Quercetin Against Infections Caused by Methicillin-Resistant Staphylococcus Aureus

Zixu Zhang,1,2 Muhan Chen,1,2 Jiahua Wang,1,2 Mo Liu,1,2 Ruibo Guo,1,2 Lu Zhang,1,2 Liang Kong,1,2 Yang Liu,1,2 Yang Yu,1– 3 Xuetao Li1,2 1School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, People’s Republic of China; 2Shenyang Key Laboratory of Chinese Medicine targeted Delivery Key laboratory, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China; 3Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, People’s Republic of ChinaCorrespondence: Xuetao Li; Yang Yu, School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, People’s Republic of China, Tel +86411 8589 0170, Fax +86411 8589 0128, Email [email protected]; [email protected]: Resistance of intracellular pathogens is a challenge in microbial therapy. Methicillin-resistant Staphylococcus aureus (MRSA), which is able to persist inside the cells of infected tissues, is protected from attack by the immune system and many antimicrobial agents. To overcome these limitations, nano-delivery systems can be used for targeted therapy of intracellular MRSA.Methods: Hyaluronic acid-modified azithromycin/quercetin micelles (HA-AZI/Qe-M) were synthesized by thin film hydration. The micelles were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR), and the drug loading (DL) and encapsulation efficiency (EE) were detected by high performance liquid chromatography (HPLC). The uptake ability of RAW264.7 cells was investigated, and its distribution in mice was evaluated by in vivo imaging. The inhibitory effect of the micelles against MRSA in vitro and its ability to eliminate intracellular bacteria were evaluated. Bacterial muscle-infected mice were constructed to evaluate the therapeutic effect of the micelles on bacterial infections in vivo and the biocompatibility of the micelles was investigated.Results: HA-AZI/Qe-M had suitable physical and chemical properties and characterization. In vitro antibacterial experiments showed that HA-AZI/Qe-M could effectively inhibit the growth of MRSA, inhibit and eliminate the biofilm formed by MRSA, and have an excellent therapeutic effect on intracellular bacterial infection. The results of RAW264.7 cells uptake and in vivo imaging showed that HA-AZI/Qe-M could increase the cellular uptake, target the infection site, and prolong the treatment time. The results of in vivo antibacterial infection experiments showed that HA-AZI/Qe-M was able to ameliorate the extent of thigh muscle infections in mice and reduce the expression of inflammatory factors.Conclusion: HA-AZI/Qe-M is a novel and effective nano-drug delivery system that can target intracellular bacterial infection, and it is expected to be safely used for the treatment of MRSA infection.Keywords: MRSA, hyaluronic acid, antibiotics, micelles, azithromycin, quercetin