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An inflammation-targeted nanoparticle with bacteria forced release of polymyxin B for pneumonia therapy
Peisen Zhang1, Qiuhong Ouyang1, Tianshu Zhai2
1Beijing Advanced Innovation Centre for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, PR China. yuqs@mail.buct.edu.cn.
Abstract:
The epidemic of multidrug-resistant Gram-negative bacteria is an ever-growing global concern. Polymyxin B (PMB), a kind of "old fashioned" antibiotic, has been revived in clinical practice and mainly used as last-line antibiotics for otherwise untreatable serious infections because the incidence of the resistance to PMB is currently relatively low in comparison with other antibiotics in vivo owing to the unique bactericidal mechanism of PMB. However, serious adverse side effects, including nephrotoxicity and neurotoxicity, hamper its clinical application. Herein, we describe the development of a nanoparticle that can target sites of inflammation and forcedly release PMB specifically in the area of Gram-negative bacteria. This particle was constructed through the electrostatic self-assembly of hyaluronic acid (HA) and PMB molecules in order to realize the safe and effective treatment of pneumonia. After systemic administration, PMB-HA nanoparticles were found to actively accumulate in the lungs, precisely target the CD44 receptors over-expressed on the membrane of activated endothelial cells in inflammatory sites, and then come into contact with the bacteria resident in the damaged alveolar-capillary membrane. Due to the electrostatic and hydrophobic interactions between PMB and the lipopolysaccharide (LPS) in the outer membranes of bacteria, the PMB molecules in the PMB-HA nanoparticles are expected to escape from the nanoparticles to insert into the bacteria via competitive binding with LPS. Through shielding the cationic nature of PMB, PMB-HA nanoparticles also possess outstanding biosafety performance in comparison to free PMB. It is thus believed that this smart delivery system may pave a new way for the resurrection of PMB in the future clinical treatment of bacterial inflammatory diseases.
Insights
Researchers developed a novel nanoparticle delivery system for Polymyxin B (PMB) to combat multidrug-resistant Gram-negative bacteria. This targeted approach enhances PMB efficacy and reduces toxicity, offering a promising strategy for treating bacterial infections.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Infectious Diseases
Background:
- Multidrug-resistant Gram-negative bacteria pose a significant global health threat.
- Polymyxin B (PMB) is a last-resort antibiotic with a low resistance rate but significant toxicity (nephrotoxicity, neurotoxicity).
- Existing treatments are limited by bacterial resistance and drug side effects.
Purpose of the Study:
- To develop a targeted nanoparticle system for safe and effective delivery of Polymyxin B.
- To improve the therapeutic index of PMB by concentrating it at infection sites and reducing systemic exposure.
- To address the challenge of multidrug-resistant bacterial infections, particularly pneumonia.
Main Methods:
- Electrostatic self-assembly of hyaluronic acid (HA) and Polymyxin B (PMB) to create PMB-HA nanoparticles.
- Systemic administration of nanoparticles and assessment of their accumulation in lung inflammation sites.
- Evaluation of nanoparticle targeting of CD44 receptors on activated endothelial cells.
- Investigation of PMB release mechanism via interaction with bacterial lipopolysaccharide (LPS).
Main Results:
- PMB-HA nanoparticles actively accumulated in the lungs after systemic administration.
- Nanoparticles demonstrated targeted delivery to inflammatory sites via CD44 receptor interaction.
- PMB was released from nanoparticles upon contact with Gram-negative bacteria, binding to LPS.
- PMB-HA nanoparticles exhibited improved biosafety compared to free PMB by shielding its cationic properties.
Conclusions:
- The developed PMB-HA nanoparticle system enables targeted delivery of PMB to Gram-negative bacterial infection sites.
- This nanotechnology approach significantly enhances PMB's safety profile by reducing systemic toxicity.
- This smart drug delivery system represents a potential new strategy for utilizing PMB in treating bacterial inflammatory diseases.
