Photothermal-Responsive Conjugated Polymer Nanoparticles for the

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Photothermal-Responsive Conjugated Polymer Nanoparticles for Rapid and Effective Killing of Bacteria Yunxia Wang, Shengliang Li, Libing Liu, and Liheng Feng ACS Appl. Bio Mater., Just Accepted Manuscript • Publication Date (Web): 28 May 2018 Downloaded from http://pubs.acs.org on May 28, 2018

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ACS Applied Bio Materials

Photothermal-Responsive

Conjugated

Polymer

Nanoparticles for Rapid and Effective Killing of Bacteria Yunxia Wang,† Shengliang Li,‡ Libing Liu*‡ and Liheng Feng*† †School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan, 030006, P.R. China; ‡Beijing National Laboratory for Molecular Science, Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China.

ABSTRACT: The emergence of drug-resistant bacterial strains makes antimicrobial treatment a big challenge. Thus, more novel and effective antimicrobial agents and treatments are urgently desired. Herein, we developed a facile and rapid photothermal antimicrobial nanoplatform based on near-infrared (NIR)-active and photothermal-responsive conjugated polymer nanoparticles functionalized with cell-penetrating peptide (CPNs-Tat). With positive charged Tat peptide, CPNs-Tat could enhance the interaction with bacteria cells with the formation of CPNsTat/bacteria aggregation. Under NIR irradiation, CPNs-Tat could convert the light into heat efficiently and produce local hyperthermia to kill bacteria within a few minutes. This photothermal-responsive strategy offers a rapid and effective modality to combating bacterial infections.

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KEYWORDS: conjugated polymer nanoparticles, photothermal conversion, NIR, bacterial infections, antimicrobial therapy

Bacterial infections always threaten the health of human and bring about approximately one-third of global mortality,1 therefore effectively antimicrobial treatment is urgently necessary. Furtherly, the appearance of drug-resistant bacterial strains with intensive use of antibiotics make it a big crisis to global health.2 The development of alternative antimicrobial treatment is crucial to address the crisis. To deal with this problem, novel antimicrobial agents, such as bacteriophages,3

antimicrobial

peptides,4,5

cationic

compounds,6,7

and

antimicrobial

photodynamic materials8,9 and so on, are employed in recent years. Recently, photothermal therapy (PTT) agent which can transform the photo into heat has received increasing interest in fighting against antibiotic-resistant microbes without phenotype change.10-12 More and more materials have been developed and used as photothermal agents, including inorganic nanomaterials (based on Au13,14, Ag15, CuS16) and semiconductors (based on graphene,

17,18

carbon nanotubes19). Although some progress has been made, more superior photothermal agents remain to be developed in rapid and effective antimicrobial photothermal therapy. Recently, conjugated polymer nanoparticles (CPNs) have emerged as a kind of outstanding nanomaterials with excellent properties, including simple preparation, various surface modification, preferable water dispersibility and tunable spectral properties.20 Since near-infrared (NIR) light possesses deep penetration ability and low phototoxicity, CPNs owning NIR absorption and emission have received increasing attention and been increasingly applied in bioimaging,21 PTT of cancer cells22,23 and regulation of cellular behaviors.24


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Herein, we developed a facile and rapid photothermal antimicrobial nanoplatform based on a CPNs-Tat that are NIR-absorbing, photothermal-responsive and positively charged peptide (Tat) modified. As shown in Figure 1, after conjugated the positive charged Tat peptide, CPNs-Tat could enhance the interaction with negative charged membranes of bacteria cells and formed CPNs-Tat/bacteria aggregation. Upon NIR irradiation, CPNs-Tat that are on the surface of bacteria could convert the light into heat efficiently, which could trigger a local hyperthermia to kill bacteria in a rapid and effective manner. Moreover, this photothermal-responsive nanoplatform was also used for the killing of pathogenic fungi. Thus, a rapid and efficient killing of microbes through the control of NIR light irradiation was realized.

Figure 1. Illustration of the photothermal killing of microbes by using CPNs-Tat as photothermal agent upon NIR light. The chemical structures of PDPP-DBT and DSPE-PEG2000-MAL for CPNs construction were also shown.

The CPNs-Tat used in this system was prepared as the previous reported work.25 Conjugated polymer PDPP-DBT and matrix polymer DSPE-PEG2000-MAL were co-precipitated to form PDPP-DBT nanoparticles with maleimide groups. By chemical conjugation between the


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maleimide groups and thiol groups, the resulting PDPP-DBT nanoparticles were further modified with the positively charged Tat peptide (RKKRRQRRRC). As shown in Figure 2a, CPNs displayed a maximum absorption at 750 nm, and the broad absorption spectra ranged from 600 to 900 nm. However, the fluorescence emission (quantum yield ＜0.1%) of CPNs was scarcely observed. It was because of the diketopyrrolopyrrole units in polymer backbones had strong electron-withdrawing ability. Dynamic light scattering (DLS) showed the CPNs with an average diameter of about 100 nm, and transmission electron microscopy (TEM) image further revealed the spherical morphology of CPNs (Figure 2b). Since CPNs-Tat had strong absorption in NIR region and superior photothermal conversion efficiencies (34%), the photothermal performance was further investigated upon an 808 nm laser irradiation. Elevated temperature was observed with the prolonged time of NIR irradiation or the increased concentration of CPNs-Tat (Figure 2c). More significantly, after 2 min of NIR irradiation, the temperature of CPNs-Tat aqueous solution rapidly increase up to 55.3 ºC with a concentration of 8 µg/mL, which would result in the death of microbes through denaturation of proteins18. Besides, the CPNs-Tat could not sensitize oxygen molecules to produce any reactive oxygen species (ROS) under NIR light irradiation

compared

with

{[(9,9-bis(6′-N,N,Ntrimethylammonium)hexyl)

fluorenylene

phenylene] dibromide} (PFP), a traditional ROS producer (Figure 2d). All these results indicated that CPNs-Tat was an excellent photothermal agent with rapid and admirable photothermal conversion capacity.


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Figure 2. (a) Vis-NIR absorption spectrum of CPNs-Tat. (b) Representative DLS profiles of CPNs-Tat. The corresponding TEM image was inset. (c) Temperature elevation of CPNs-Tat aqueous solutions with different concentrations as a function of NIR irradiation time (808 nm laser, 2 W/cm2). (d) ROS generation by CPNsTat (6 µg/mL) under irradiation of an 808 nm laser compared with PFP under white light irradiation.

Bacteria and fungi are responsible for major pathogen infections, and their cell walls are both negatively charged. To interact with cell walls of microbes, the surface of CPNs-Tat was designed to bear positive charges. Since Escherichia coli (E. coli) was responsible for half of infections, we took ampicillin-resistant E. coli as an example to investigate the interaction with CPNs-Tat. As a control, we synthesized no positively charged nanoparticles (CPNs-PEG) by using DSPE-PEG2000 as the matrix polymer (Figure S1).

As shown in Table 1, the zeta

potentials of E. coli treated with CPNs-Tat changed from -42.6 mV to +11.1 mV, while that of E.


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coli treated with CPNs-PEG were almost the same as E. coli alone. It indicated that CPNs-Tat successfully bonded to the outer membranes of E. coli. through electrostatic interactions. To further testify the electrostatic interaction, confocal laser scanning microscope (CLSM) was employed to observe E. coli treated with different CPNs. SYTO9, a fluorescent dye which could penetrate both live and dead bacteria was used to indicate E. coli. cells with bright green fluorescence. As shown in Figure 3a, E. coli cells treated with CPNs-PEG remained well dispersed and no change compared with E. coli cells alone was observed. CPNs-Tat treated E. coli, by contrast, gathered into agglomerates, which demonstrated that CPNs-Tat could interact with E. coli cells inducing the aggregation of them. Moreover, the bacteria treated with CPNsTat exhibited an obviously elevated temperature compared to those of treated with CPNs-PEG, where CPNs were removed by centrifugation (Figure 3b). All these results indicated that Tat conjugated CPNs could enhance the interaction between CPNs-Tat and bacteria, and then facilitate the fast killing of microbes13. To investigate the photothermal antibacterial efficiency of CPNs-Tat, E. coli were treated with CPNs-Tat (6 µg/mL) and irradiated with an 808 nm laser. As shown in Figure 3c, after treatment of CPNs-Tat, the bacterial aqueous solution revealed elevated temperature with the prolonged time of light irradiation at a laser density of 2 W/cm2, then reached about 58 ºC after 5 min. The temperature of bacterial aqueous solution without CPNs-Tat treatment remained no change under the same condition, which indicated that the CPNs-Tat could convert the light into heat and produce the hyperthermia rapidly. Under treatment, E. coli could be killed 99.8% only after 5 min of 808 nm laser irradiation, whereas the majority of bacteria without irradiation survived and the killing efficiency was only 30.2% (Figure 3d). As the concentration of CPNs-Tat was reduced to be 5 µg/mL, the killing efficiency


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declined to be 68 %. It illustrated that the CPNs-Tat killed bacteria in a concentration-dependent behavior. Table 1. Zeta potentials of E. coli before and after treatment of CPNs-PEG and CPNs-Tat, respectively.

Figure 3. (a) CLSM images of E. coli stained by SYTO9 under different treatments. (b) Temperature changes of E. coli with treatment of CPNs-PEG and CPNs-Tat at the concentration of 6 µg/mL under irradiation of an 808 nm laser. (c) Temperature changes of E. coli with treatment of CPNs-Tat (6 µg/mL) and E. coli alone under an 808 nm laser irradiation. (d) Antibacterial activity of CPNs-Tat toward E. coli with and without an 808 nm laser irradiation at different concentrations. The laser density of the NIR irradiation is 2 W/cm2.


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To further verify the photothermal killing efficiency of CPNs-Tat, a BacLight Live/Dead viability kit was utilized. The fluorescent dye of SYTO9 labeled live bacterial cells with green fluorescence and propidium iodide (PI) labeled dead bacterial cells with red fluorescence. As the CLSM images shown in Figure 4a, E. coli cells treated with CPNs-Tat displayed agglomerates and red fluorescence after irradiation for 5 min, while that of without light irradiation displayed agglomerates with green fluorescence. It indicated that CPNs-Tat could induce bacteria aggregation with little toxicity until carrying out a NIR laser irradiation. And the percentage of colony forming units (CFU) also proved that E. coli cells treated with CPNs-Tat were completely killed after irradiation.


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Figure 4. (a) CLSM images of E. coli stained by SYTO9 & PI after treatment with CPNs-Tat with and without an 808 nm laser irradiation. (b) CFU of E. coli and after treatment with CPNs-Tat with and without an 808 nm laser irradiation. (c) SEM images of E. coli under different treatments. The scale bar is 1 µm.

In contrast, E. coli cells treated with CPNs-Tat could mostly survive and form colonies without irradiation (Figure 4b). The scanning electron microscopy (SEM) was performed to directly observe the morphologies of bacteria under different treatments. As shown in Figure 4c, the morphology of E. coli cells was rod shaped and the surface of cell walls was clear and integral. After treated with CPNs-Tat, bacteria obviously aggregated and the surface of cell walls remained clear and integral. However, under laser irradiation, E. coli cells treated with CPNs-Tat not only aggregated but also became smaller, and the surface of the cell walls was not clear and intact with holes. All these results indicated that the photothermal treatment could effectively kill Gram negative E. coli. Next, we also assessed the photothermal antibacterial activities of CPNs-Tat against Staphylococcus aureus (S. aureus) (Gram positive bacteria) and Candida albicans (C. albicans) (pathogenic fungi). After photothermal treatment, the growth of S. aureus and C. albicans could be inhibited around 90 % and 100 %, respectively (Figure S2). And the treatment of NIR irradiation and CPNs-Tat both had little effect on the growth of them (Figure S3, S4). The difference of killing efficiency toward E. coli and S. aureus could be ascribed to the difference in heat sensitivity between them. Usually, the heat resistance of Gram-positive bacteria is better than that of Gram-negative. In conclusion, we developed a novel system to kill microbes by using NIR-absorbing and photothermal-responsive CPNs that were modified with positively charged Tat peptide. This new photothermal antimicrobial agent could interact with bacteria intensely with the formation of


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CPNs-Tat/bacteria aggregation. Under NIR irradiation, local hyperthermia produced by CPNsTat could kill bacteria effectively within a few minutes, including Gram-negative E. coli, Grampositive S. aureus and pathogenic fungi C. albicans. Such easily prepared, rapid and effective antibacterial agent based on photothermal-responsive CPNs makes it potential in biomedical applications for further combating antibiotic-resistant bacterial infections. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami. Detailed experimental procedures, chemical structure, antibactrial activity, and plate counting (PDF) AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] (Feng L.H.) * E-mail: [email protected] (Liu L.B.) ORCID Liheng Feng: 0000-0003-3829-2136 Libing Liu: 0000-0003-4827-6009 Notes The authors declare no competing financial interest.


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ACKNOWLEDGMENTS The work described herein was supported by the National Nature Science Foundation (No. 21571116), the Program for the Outstanding Innovative Teams of Higher Learning Institutions of Shanxi (No. 2017-07), and SanJin Scholars Support Plan under Special Funding (No. 201706). We are also grateful to the Scientific Instrument Cente of Shanxi University for the assistance of the characterizations of compounds. REFERENCES (1) Jones, K. E.; Patel, N. G.; Levy, M. A.; Storeygard, A.; Balk, D.; Gittleman, J. L.; Daszak, P. Global Trends in Emerging Infectious Diseases. Nature 2008, 451, 990-993. (2) Bai, H. T.; Yuan, H. X.; Nie, C. Y.; Wang, B.; Lv, F. T.; Liu, L. B.; Wang, S. A Supramolecular Antibiotic Switch for Antibacterial Regulation. Angew. Chem. Int. Ed. 2015, 54, 13208-13213. (3) Lu, T. K.; Collins, J. J. Engineered Bacteriophage Targeting Gene Networks as Adjuvants for Antibiotic Therapy. Proc. Natl. Acad. Sci. 2009, 106, 4629-4634. (4) Tew, G. N.; Scott, R. W.; Klein, M. L.; DeGrado, W. F. De Novo Design of Antimicrobial Polymers, Foldamers, and Small Molecules: From Discovery to Practical Applications. Acc. Chem. Res. 2010, 43, 30-39. (5) Liu, L. H.; Xu, K. J.; Wang, H. Y.; Tan, P. K. J.; Fan, W. M.; Venkatraman, S. S.; Li, L. J.; Yang, Y.-Y. Self-Assembled Cationic Peptide Nanoparticles as an Efficient Antimicrobial Agent. Nat. Nanotechnol. 2009, 4, 457-463.


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Photothermal-Responsive Conjugated Polymer Nanoparticles for the

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