Photothermal responsive nanocarrier for efficient treatment of multidrug-resistant bacterial infection by synergetic chemo-photothermal therapy

Combating multidrug-resistant bacteria through the NIR-activated Thermo-Responsive-Inspired Drug-dElivery Nano-Transporter (TRIDENT)

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Sep 26, 2019
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Bacterial infectious diseases and consequent antimicrobial resistance have become leading threats to human health all over the world in recent decades1. Once handled improperly, they will cause a variety of human diseases, ranging from skin and soft tissue infections to life-threatening infections, such as bacteremia, pneumonia, meningitis, and sepsis2. Great success in fighting against pathogen infections has been achieved in clinical practice owing to the discovery of novel antibiotics. However, improper use or abuse of these antibiotics significantly promotes the occurrence of antibiotic-resistant bacteria3. According to WHO, failure to address infection caused by antibiotic-resistant bacteria is predicted to kill more than 10 million people annually and cost up to 100 trillion dollars by 20504. Therefore, it is essential for us to develop novel antimicrobial approaches with minimal resistance-producing potentials. 

Recently, nanotechnology-based antibacterial strategies have been proposed due to their enhanced efficacy and therapeutic index5. Systems based on smart nanoparticles, which can respond to a variety of exogenous or endogenous stimuli to deliver sustained drug release, are particularly desirable. Compared with other stimulus-responsive nanostructures, thermo-responsive nanostructure (TRN) with a large latent heat of fusion and reversible solid-liquid transition over a narrow temperature range is more suitable for precise control of drug release6. Inspired by the success of the TRN in cancer therapy, which can be attributed to their convenient assembly, chemical stability, and high biocompatibility, we envisioned that it could be exploited as a novel nanocarrier for effective antimicrobial treatment.

Figure. 1 Near infrared (NIR)-activated TRIDENT for antibiotic-resistant bacteria killing. The prepared thermo-responsive-inspired drug-delivery nanotransporter (TRIDENT, also named IMP/IR780@TRN) is “melted” when the temperature rises to above 43 °C under the NIR irradiation, leading to the release of imipenem to the infected site. Consequently, the multidrug-resistant bacteria can be efficiently damaged through a synergistic antibiotic-photothermal strategy with a relatively low dosage of antibiotic, eventually accelerating the recovery of the infected skin

Under the guidance of this thought, professor Yang Luo from Chongqing University worked with professor Xing-Jie Liang from CAS key laboratory for biomedical effects of nanomaterials and nanosafety, and professor Weisheng Guo from Guangzhou medical university, and try to integrate the multi-disciplinary advantages of chemical, material, and medical science to find a new way. Finally, we developed a smart triple-functional nanostructure, namely TRIDENT (Thermo-Responsive-Inspired Drug-dElivery Nano-Transporter), for reliable bacterial eradication7. The robust antibacterial effectiveness is attributed to integrated fluorescence monitoring and synergistic chemo-photothermal killing. We noticed that temperature risen generated by near-infrared irradiation not only melt the nanotransporter via phase change mechanism, but also irreversibly damaged bacterial membrane to facilitate imipenem (a broad-spectrum antibiotic but not for MRSA) permeation to interfere cell wall biosynthesis, eventually leading to rapid bacterial death. Both in vitro and in vivo evidence demonstrated that even low dose of imipenem-encapsulated TRIDENT could eradicate some kinds of drug-resistant bacteria isolated from clinic. An interesting phenomenon was observed that the imipenem played a positive role in fighting against methicillin-resistant Staphylococcus aureus with the help of photothermal therapy, which is general resistant to the classical β-lactam antibiotic (including imipenem)8. This phenomenon enlightens us that physical damage of resistant bacteria may assist antibiotic to fight against them better. Additionally, good biosafety observed during the treating process also revealed that our TRIDENT is suitable for various applications in vitro and in vivo.

In summary, we have proven the feasibility of the proposed TRIDENT system in fighting against pathogenic bacteria, especially some antibiotic resistant bacteria. And we believe that after continuous optimizing the drug loading capacity, loading contents as well as the structure of the nanotransporter, the proposed TRIDENT system can be further developed into a universal antimicrobial platform for other multidrug-resistant (MDR) or extremely drug-resistant (XDR) pathogenic bacteria.

By Guangchao Qing, Weisheng Guo, Yang Luo and Xing-Jie Liang.

Link to the paperhttps://www.nature.com/articles/s41467-019-12313-3

Reference

1. Brown, E.D. & Wright, G.D. Antibacterial drug discovery in the resistance era. Nature 529, 336-343 (2016).

2. Tong, S.Y., Davis, J.S., Eichenberger, E., Holland, T.L. & Fowler, V.G. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin. Microbiol. Rev. 28, 603-661 (2015).

3. Marston, H.D., Dixon, D.M., Knisely, J.M., Palmore, T.N. & Fauci, A.S. Antimicrobial Resistance. JAMA 316, 1193-1204 (2016).

4. Organization, W.H. Antimicrobial resistance: global report on surveillance. (World Health Organization, 2014).

5. Gupta, A., Mumtaz, S., Li, C.H., Hussain, I. & Rotello, V.M. Combatting antibiotic-resistant bacteria using nanomaterials. Chem. Soc. Rev. 48, 415-427 (2019).

6. Zhu, C. et al. A Eutectic Mixture of Natural Fatty Acids Can Serve as the Gating Material for Near-Infrared-Triggered Drug Release. Adv. Mater. 29 (2017).

7. Qing, G. et al. Thermo-responsive triple-function nanotransporter for efficient chemo-photothermal therapy of multidrug-resistant bacterial infection. Nat. Commun. 10, 4336 (2019).

8. Lee, A.S. et al. Methicillin-resistant Staphylococcus aureus. Nat. Rev. Dis. Primers 4, 18033 (2018).

Go to the profile of Guangchao Qing

Guangchao Qing

PhD student, Chongqing University

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