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Dual Drug Loaded pH-sensitive Micelles for Efficient Bacterial Infection Treatment

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Abstract

Purpose

Methicillin-resistant Staphylococcus aureus (MRSA) infection at impaired wound is associated with high risks of developing to persistent bacterial infections since bacterial biofilm is easy to form in MRSA infected wounds. An advanced therapeutic approach to effectively penetrate and eliminate bacterial biofilm and to accelerate cell proliferation and migration at the wound is crucial.

Methods

The poly(ε-caprolactone)-monomethoxyl poly (ethylene glycol) (PCL-mPEG) micelles loaded with Quercetin and Rifampicin (QRMs) were prepared. Bacterial biofilm proliferation and elimination effect of QRMs were evaluated with confocal laser scanning microscopy. Antibacterial assay was further performed to detect antibacterial activity and mechanism. The cell scratch assay and cellular uptake were performed in HaCaT skin epithelial cells.

Results

Our results showed that the small sized QRMs could penetrate the interior of MRSA biofilm to disperse and eradicate biofilm. Then, antibiotics are released and accumulated in the acidic biofilm environment. QRMs could kill bacteria through increasing bacterial membrane permeability and altering membrane potential and membrane fluidity. Moreover, QRMs improved intracellular and cytoplasmic delivery efficiency of drugs to epithelial cells, and in the scratch test, presented a stronger ability to promote migration and proliferation of HaCaT cells compared with free drugs. Hemolysis test further proved good biocompatibility of QRMs.

Conclusions

QRMs could potentially be used as a novel dual-functional nanotherapeutic for anti-bacterial infection by eradicating biofilm and accelerating cells proliferation at MRSA infected wound.

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Abbreviations

C6:

Coumarin 6

CMs:

Coumarin 6 loaded micelles

CV:

Crystal violet

DLS:

Dynamic light scattering spectroscopy

EM:

Empty micelles

EPS:

Extracellular polymeric substances

GP:

Generalized polarization

HaCaT:

Human epidermal keratinocyte line

MRSA:

Methicillin-resistant Staphylococcus aureus

MβCD:

Methyl-β-cyclodextrine

PCL-mPEG:

Poly(ε-caprolactone)-monomethoxyl poly (ethylene glycol)

QR:

Combination of quercetin and rifampicin

QRMs:

Quercetin and rifampicin loaded micelles

Que:

Quercetin

Rif:

Rifampicin

ROS:

Reactive oxygen species

TEM:

Transmission electron microscope

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Acknowledgements

The authors have no conflicts of interest to declare that are relevant to the content of this article. The laboratory animals (mice) used in our experiments were in accordance with the relevant Chinese laws and according to the China Agriculture University regulations concerning protection of animals used for scientific purposes (2010-SYXK-0037). The mice used in this study were approved by the Ethics Committee on Experimental Animals and Animal Tests of China Agricultural University. The review number is AW22011202-2-1.

Funding

This research was supported by the National Key Research and Development Program of China (No: 2021YFD1801000). Chinese National Natural Science Foundation project (No: 31971312 and No: 32171389), China Agriculture Research System of MOF and MARA (CARS-36), and the 2115 Talent Development Program of China Agricultural University.

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Author notes

  1. Yingxian Chen and Qian Zhao contributed equally.

Authors and Affiliations

  1. Beijing Key Laboratory of Detection Technology for Animal–Derived Food Safety, National Center for Veterinary Drug Safety Evaluation, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China

    Yingxian Chen, Qian Zhao, Junhua Han & Xiaowei Ma

  2. CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences and National Center for Nanoscience and Technology of China, Beijing, 100190, China

    Xing-Jie Liang

  3. School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100013, China

    Xinmiao Lan

  4. School of Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, China

    Jing Che

  5. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China

    Meiwan Chen

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  1. Yingxian Chen
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Chen, Y., Zhao, Q., Han, J. et al. Dual Drug Loaded pH-sensitive Micelles for Efficient Bacterial Infection Treatment. Pharm Res 39, 1165–1180 (2022). https://doi.org/10.1007/s11095-022-03182-5

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