ReviewConstruction of nanomaterials with targeting phototherapy properties to inhibit resistant bacteria and biofilm infections
Introduction
Infectious diseases are health-related issues that have the potential for global catastrophic consequences. In the past few decades, the emergence of antibiotics has had a huge impact on the treatment of infectious diseases [1], [2], [3], [4], [5], [6]. In spite of the efficiency of antibiotics, the emergence of bacteria resistant to multiple antibiotics has become a common cause of refractory infectious diseases as the over-subscribing of antibiotics [7], [8]. For extracellular infections, antibacterial drugs are often quickly identified and cleared by phagocytes, resulting in the concentration of the drug at the infected site being too low to treat the infection [9], [10]. In addition, drugs can be partially degraded before reaching the infected site, which reduces the efficiency of drug. Thus, a repeated or higher dose of the drug is required for effective treatment of bacterial infections [11], [12], [13]. What’s more, drugs will be toxic to normal cells when they are not targeted to infective site and not responsive to specific stimuli, which not only reduce the therapeutic effect, but also increase the risks associated with treatment. In intracellular infections, most of the drugs cannot penetrate the cell membrane effectively, which reduce the concentration of the drug in the cells. Moreover, there is no guarantee that high concentrations of the drug in the cells will result in high antibacterial activity. The antimicrobial activity of intracellular drugs is not only related to the concentration and exposure time of the drug, but also to the physical and chemical environment in the cells. All of these factors severely reduce the therapeutic effect of antibacterial drugs and promote the overuse of the drugs, which lead to the emergence of drug-resistant bacteria [14], [15].
Pathogens obtain antibiotic resistance by a variety of mechanisms, including gene mutations, cell membrane permeability changing, long retention times in the cells, development of multidrug efflux pumps and the emergence of enzymes with the capacity to degrade the drug [16], [17]. Consequentially, a normal dose of antibiotics may be not effective and a higher dose or repeated administration of the drug is needed, which eventually lead to a range of side effects such as toxicity [18], [19]. To increase the local concentration and to prolong the cycle time of drugs, it is necessary to introduce carrier-assisted drug delivery with targeted and responsive properties [20], [21]. In recent years, more and more attentions have gradually been paid to the development of nanomaterials due to the high drug-loading capacity for the high local drug concentration [13], [22], [23]. Because of their small size, nanomaterials are not easily recognized and removed by macrophages in vivo. Modified nanomaterials can promote drug targeting to bacterial infective sites to reduce the invalid release of drugs [24], [25], [26], [27], [28].
It is noteworthy that the generation of antibiotic resistance is related not only to the transformation of the structure and gene mutations of planktonic bacteria [16], [29], but also to the formation of bacterial biofilms [30], [31]. More than 80% of human infectious diseases are related to biofilms [32], [33]. Biofilm is a hybrid of bacterial community wrapped in a bacterial aggregate membrane. The bacteria irreversibly attach on the surface of inert or active entities, reproduce, differentiate, and secrete extracellular polymeric substances (EPS) composed of polysaccharides, proteins, nucleic acids, and lipids [5], [32], [34], [35], [36], [37]. On one hand, EPS can protect bacteria against the infiltration of antibiotics and from the attacking by the host innate immune systems. On the other hand, the bacteria encapsulated in EPS undergo anaerobic glycolysis in biofilm in the hypoxic environment, which results in ion-channel turbulence and the production of acid [38], [39]. As a result, it is critical to find new strategies to combat drug-resistant bacteria and biofilms related infections.
As antibiotics cannot penetrate into biofilms very well, it is usually not effective to destroy biofilms through routine way of antibiotics delivery [34]. Biofilms protect bacteria from antibiotics which can also contribute to the formation of bacterial drug resistance [34], [40]. However, antibacterial systems based on nanomaterials have showed very effective in dealing with biofilms related infections. Many antibacterial agents have been developed to treat such infectious diseases, including antimicrobial peptides, inorganic nanoparticles, cationic polymers and photothermal therapy/photodynamic therapy (PTT/PDT) agents [41], [42]. Especially, phototherapy including PTT and PDT has received considerable attentions due to the high bactericidal efficiency. Moreover, it will not generate drug-resistant bacteria as not using antibiotics. As a therapeutic method, PTT has been used to treat many kinds of diseases such as cancer and biofilms related infections making using of light-absorbing materials with high light-thermal conversion efficiency. PDT has been used to diagnose and to treat disease through photosensitizer to produce reactive oxygen species (ROS) in particular singlet oxygen under appropriate irradiation. These methods can be used to treat infectious diseases caused by multidrug-resistant bacteria and to delay the development of other drug-resistant bacteria [43], [44].
The mechanism and wide applications have been reviewed in the reported reviews [45], [46], [47]. Herein, more attentions will be paid to the recent progress of PTT and PDT based on nanomaterials for the treatment of bacterial infectious diseases in this review. Nanomaterials with targeting property and responsive to bacterial infections microenvironment or external stimulus also will be discussed.
Section snippets
Photothermal therapy
PTT possess high light-thermal conversion efficiency under the irradiation of an external light source (usually near-infrared light). PTT showed efficient in treating diseases such as cancer and biofilms related infections. This method can inhibit the development of resistant bacteria and also prevent biofilms formation by destroying the structure. PTT nanoparticles such as gold nanoparticles [48], carbon nanotubes [49], [50], and grapheme [51] are all strong light-absorbing materials.
Photodynamic therapy (PDT)
PDT is a new technique that uses a photodynamic response to diagnose and to treat disease (Fig. 15). The three main features of PDT are light source, photosensitizer (PS) and oxygen. Absorbing photons of light, the PS molecule becomes activated from the ground state to a short-lived excited singlet state (1PS*). The excited PS can emit fluorescence and decay back to the ground state, which can be used for clinical imaging. PS can also be converted into a triplet excited state by intersystem
Conclusion
PTT and PDT are promising strategies for the treatment of bacterial infectious diseases, especially the inhibition of drug-resistant bacteria development and biofilms formation. NPs used for PTT and PDT possess many advantages such as high PS loading capacity and controlled release to increase the antibacterial properties. Through surface modification with targeting molecules, NPs will be targeted onto biofilms or infected sites to improve the utilization of PS and to reduce the toxicity to
Acknowledgment
This work was financially supported by the National Natural Science Foundation of China (31771026, 81771984, 41506091, 21601139), National Key R&D Program (2016YFC1101201), the Zhejiang National Nature Science Foundation (LQ16B010002), Medical and health science and technology project of Zhejiang Province (2016YKA139), Zhejiang provincial Public welfare project (2017C33035) and Science & Technology Program of Wenzhou (Y20160068, Y20160061) are greatly acknowledged.
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These authors contributed equally to this work and should be considered co-first authors.