Photodynamic Polymers as Comprehensive Anti-Infective Materials

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Cite This: ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

Photodynamic Polymers as Comprehensive Anti-Infective Materials: Staying Ahead of a Growing Global Threat Bharadwaja S.T. Peddinti,† Frank Scholle,‡ Reza A. Ghiladi,*,§ and Richard J. Spontak*,†,∥ †

Department of Chemical & Biomolecular Engineering, ‡Department of Biological Sciences, §Department of Chemistry, and Department of Materials Science & Engineering, North Carolina State University, Raleigh, North Carolina 27695, United States

∥

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S Supporting Information *

ABSTRACT: To combat the global threat posed by surface-adhering pathogens that are becoming increasingly drug-resistant, we explore the anti-infective efficacy of bulk thermoplastic elastomer films containing ∼1 wt % zinc-tetra(4-N-methylpyridyl)porphine (ZnTMPyP4+), a photoactive antimicrobial that utilizes visible light to generate singlet oxygen. This photodynamic polymer is capable of inactivating five bacterial strains and two viruses with at least 99.89% and 99.95% success, respectively, after exposure to noncoherent light for 60 min. Unlike other anti-infective methodologies commonly requiring oxidizing chemicals, carcinogenic radiation, or toxic nanoparticles, our approach is nonspecific and safe/nontoxic, and sustainably relies on the availability of just oxygen and visible light. KEYWORDS: antimicrobial photodynamic inactivation, antibacterial surface, anti-infective polymer, antibiotic-resistant bacteria, antiviral, block copolymer, olefin thermoplastic elastomer

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bacterial infections by 2050, leading to 10 million deaths annually and surpassing the death rate due to cancer. Previously, infections that were easily treatable can now become fatal. While infections caused by antibiotic-resistant pathogens can occur anywhere, they are most prolific in healthcare settings such as hospitals (resulting in hospitalacquired infections, HAIs) and nursing home or care facilities for the elderly.6 There, pathogens commonly adhere to surfaces such as linens, countertops, drapes/blinds, monitoring equipment, and sanitaryware, and remain infectious for long periods of time on the order of weeks.7 They later proliferate upon coming in patient contact, thus inducing infection. Moreover, patients in hospitals are at particular risk because of potentially overall poor health conditions and/or compromised immune systems. In response to this growing health problem, acute care hospitals expended about $9.8 billion in 2012 to treat such infections. Although several methods such as chemical disinfectants9 and UV exposure10 are used in conjunction with antibiotics, they are not effective for various reasons. Chemical disinfectants and ionizing radiation are not always safe, whereas radiation techniques are expensive and UV radiation is harmful to healthy cells. Although silver,11 copper,12 zinc oxide,13 or titanium dioxide14 have been used as surfaces or introduced as nanoparticles into a broad range of substrates to serve as antimicrobial agents and eradicate a wide range of pathogens, they all suffer from eventual reservoir

he adherence of pathogens such as bacteria and viruses on various surfaces routinely leads to subsequent transmission to new hosts, significantly promoting the proliferation of potentially harmful organisms. This sequence is particularly worrisome in the case of antibiotic-resistant pathogens, which are becoming a global threat to human health.1 According to the Centers for Disease Control and Prevention,2 1 out of every 20 hospital patients is affected by nosocomial infections, subsequently resulting in 100 000 deaths annually in the United States alone. Out of these, about 23 000 deaths are attributed to drug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (S. aureus) or vancomycin-resistant Enterococcus faecium (E. faecium). Strains popularly referred to as “nightmare bacteria” with highly elevated resistance to last-resort antibiotics annually account for about 700 000 deaths worldwide.3 To mitigate this rampant problem, we examine a photodynamic polymer composed of a polyethylene-based thermoplastic elastomer modified with zinc-tetra(4-N-methylpyridyl)porphine (ZnTMPyP4+), a photoactive antimicrobial, and demonstrate that this combination is remarkably effective at inactivating 5 bacterial strains, including S. aureus and Escherichia coli (E. coli) often associated with food poisoning, and 2 different viruses upon exposure to noncoherent light. The growing increase of bacterial strains exhibiting antibiotic resistance continues to impact the healthcare industry and distress the general public.4 With only a handful of new antibiotics discovered since the last two decades (often referred to as the discovery void), drug resistance in pathogens has increased at an alarming rate. Recent predictions suggest5 that current antibiotics will be largely ineffective against © XXXX American Chemical Society

Received: June 2, 2018 Accepted: July 18, 2018

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DOI: 10.1021/acsami.8b09139 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

Letter

ACS Applied Materials & Interfaces depletion and tend to be pathogen- or condition-specific. Moreover, if not covalently bound or tightly embedded, nanoparticles can leach into the environment and introduce additional health concerns,15 and some pathogens have become immune to metal toxicity through reduced uptake, efflux, or intra/extracellular sequestration.16 While these and several other antimicrobial agents have been considered, they all suffer from one or more shortcomings, including (i) gradual loss of antimicrobial activity, (ii) consumption of germicidal components, (iii) biocidal leaching into the environment, (iv) direct pathogenic contact, or (v) inefficacy against diverse pathogens.8 Alternative strategies for surface disinfection must therefore be sought as nonspecific, robust preventive measures, rather than as specific cures with compromised performance. One such alternative that is gaining attention derives from photodynamic therapy (PDT).17 Commercial photosensitizers (PSs) are used in PDT to treat the initial stages of pathogeninduced acne, as well as nonpathogenic conditions such as skin cancer and psoriasis. After the PS is applied to an affected area, the target is illuminated by red light to activate the PS and kill pathogens or unhealthy cells for in vivo (patient) applications. In this work, we apply the same principle, designated antimicrobial photodynamic inactivation (aPDI), to inactivate pathogens for sterilization purposes. An activated PS exchanges energy with molecular oxygen to generate primarily highenergy singlet oxygen (1O2) or other reactive radical species and induce cytotoxicity by nonspecifically reacting with various constituents in a pathogen. In the specific case of photodynamic polymers, pathogens are highly unlikely to develop resistance to 1O2 for two reasons: nonspecific damage to the pathogen and nontriggering of the oxidative stress response.18 Prior studies of PSs derived from methylene blue 19 [methylthioninium chloride], rose bengal 20 [disodium 2,3,4,5-tetrachloro-6-(2,4,5,7-tetraiodo-6-oxido-3-oxo-3Hxanthen-9-yl)-benzoate] and borondipyrromethene21 have been conducted in solution, as well as in several polymer matrices (high-density polyethylene,19 polyacrylonitrile,22 and polyurethane23) and on cellulose nanocrystal surfaces and scaffolds.24,25 The polymer employed here is an olefinic thermoplastic elastomer, a multiblock copolymer composed of high-density polyethylene hard blocks and poly(ethylene-co-α-octene) soft blocks,26 and synthesized by a catalyst-shuttling reaction.27 This semicrystalline elastomer, designated as OBC26 to reflect its hard-block weight percent and provided by the Dow Chemical Co. (Midland, MI), has been selected in light of its facile processability, as well as its ability to exhibit extraordinary (electro)mechanical properties.28 To generate the photodynamic polymer, we incorporated ZnTMPyP4+ (depicted in Scheme 1) into the OBC26 matrix at ∼1 wt % by a combination of solution-casting from toluene/2-propanol and repeated melt-pressing conducted at 140 °C (additional experimental details are provided in the Supporting Information). Although most of the PS appears to be dispersed within the polymer matrix, discrete aggregates measuring ∼1 μm across are apparent in scanning electron microscopy (SEM) images of PS-embedded OBC26 surfaces (cf. Figure 1a). Elemental energy-dispersive X-ray spectroscopy (EDS) maps corresponding to the area displayed in Figure 1b are included in Figures 1c (for zinc) and 1d (for iodine) and confirm that these aggregates correspond to the PS. The existence of such aggregates implies either insufficient dispersion during

Scheme 1. Chemical Structure of the Photosensitizer Zinc Tetra(4-N-methylpyridyl)porphine (ZnTMPyP4+)

Figure 1. (a) Field-emission SEM image acquired from the surface of OBC26 modified with 1 wt % ZnTMPyP4+. Several aggregates are clearly visible, and the surface texture is due to the semicrystalline morphology of the copolymer. An enlargement of a ZnTMPyP4+ aggregate is included in the inset. (b) Additional SEM image, along with its corresponding EDS maps identifying the spatial distribution of (c) Zn and (d) I (due to the 4 iodine counterions on ZnTMPyP4+).

fabrication or thermodynamic incompatibility with the nonpolar matrix or, most likely, a combination of both considerations. Here, we examine three function/process-related matters regarding this photodynamic polymer. The first reflects the fact that microbial inactivation is restricted to the surface of OBC26. Since the effective distance over which 1O2 is reactive prior to reverting back to ground-state O2 is only ∼150 nm in aqueous solution but up to ∼2 μm in air,29 the concentration of ZnTMPyP4+ at the surface of the film must be sufficient to generate the level of 1O2 required to inactivate pathogens. Composition profiles acquired by time-of-flight secondary ion mass spectrometry (ToF-SIMS) for C6−, C5− and CN− ions in Figure 2a reveal that the polymer surface is enriched by ZnTMPyP4+, identified by its unique CN− signature. Such enrichment extends about 100 nm subsurface and is ∼7× higher at the surface than in the bulk. Moreover, the observation that ZnTMPyP4+ is detected and constant at depths below 1 μm from the surface is not only consistent with uniform ZnTMPyP4+ dispersion but also indicative that the PS B


Letter

ACS Applied Materials & Interfaces

discerned from thermal calorimetry,28 the melting temperature of OBC26 is 123 °C, which means that melt processing is possible below 200 °C. According to the thermal gravimetric analysis (TGA) measurements presented in Figure 2c, ZnTMPyP4+ gradually loses ∼3 wt % at 200 °C and then undergoes catastrophic degradation at about 260 °C. In contrast, OBC26 is stable up to 200 °C and begins to decompose near 360 °C. Addition of ∼1 wt % ZnTMPyP4+ to OBC26 has little effect on low-temperature stability but improves high-temperature stability by shifting the decomposition temperature closer to 400 °C. In vitro aPDI inactivation studies of ZnTMPyP4+/OBC26 at ∼1 wt % PS have been performed under fixed illumination conditions (60 min, 400−700 nm) to enable comparison with previous studies. Bacteria cultured to a concentration of ∼1 × 108 colony-forming units (CFUs) per mL and resuspended in PBS buffer have been added directly to the material and subsequently illuminated using noncoherent light intensities of either 65 ± 5 or 80 ± 5 mW/cm2 for Gram-positive or Gramnegative bacteria, respectively. The bacteria examined here include S. aureus, vancomycin-resistant E. faecium, E. coli, Acinetobacter baumannii (A. baumannii), and Klebsiella pneumoniae (K. pneumonia). Some of these bacteria, such as E. faecium and K. pneumonia, are selected because their resistance to a broad palette of traditional, as well as contemporary, pharmaceuticals is of growing public health concern in terms of both patient mortality and infrastructure expense. 8 Experimental details of the aPDI assays are provided in the Supporting Information, and resultant survival levels are displayed for two Gram-positive bacteria in Figure 3a, which includes data collected from a ZnTMPyP4+-free OBC26 control, a ZnTMPyP4+-modified OBC26 control maintained under dark conditions, and a ZnTMPyP4+-modified OBC26 sample after exposure to noncoherent light (with a wavelength between 400 and 700 nm). In both cases, the controls register 100% pathogen survival, whereas the photodynamic polymers reach the MDL at 10−4 (a 6 logarithmic unit reduction, with a statistical significance ascertained by a two-tailed, unpaired Student’s t-test of P < 0.001). These results are very promising in terms of the reduction levels achieved, especially when one considers that the photodynamic methodology induces nonspecific cytotoxicity. In other words, since a particular component of a pathogen is not purposefully targeted for chemical attack (as in the case of conventional pharmaceuticals), antibiotic-resistant pathogens such as the ones included in Figure 3a, b are unlikely to become immune against cytotoxic 1O2 induced during aPDI.21 Survival levels for three Gram-negative bacteria, A. baumannii, K. pneumoniae and E. coli, are presented in Figure 3b. These and other examples of Gram-negative bacteria are responsible for outbreaks of, for example, Legionnaire’s disease and food poisoning. The controls in Figure 3b are comparable to those shown in Figure 3a, but the survival levels achieved by photodynamic treatment of these bacteria at 80 mW/cm2 for 60 min, while still excellent, are reduced relative to the Grampositive bacteria in Figure 3a. This difference is attributed to the additional outer lipopolysaccharide cell membrane present in Gram-negative bacteria. With this morphological obstacle notwithstanding, measured survival reduction levels are nonetheless promising: 99.89% (P < 0.033) for A. baumannii, 99.96% (P < 0.0001) for K. pneumonia, and 99.95% (P < 0.0011) for E. coli.

Figure 2. (a) Three ToF-SIMS depth profiles collected from OBC26 modified with 1 wt % ZnTMPyP4+. The data corresponding to CN− represent the PS and reveal the existence of surface enrichment. (b) Time-dependent survival of S. aureus at different light intensities (labeled, in mW/cm2). The minimum detection limit (MDL) is identified, and estimates of the time to reach the MDL are displayed as a function of light intensity in the inset. The solid lines serve to connect the data. (c) TGA results for ZnTMPyP4+, OBC26, and OBC26 modified with 1 wt % ZnTMPyP4+ (labeled).

is available if the material becomes abraded. Although the SEM images in Figure 1 confirm the existence of ZnTMPyP4+ aggregates at the surface of OBC26, the ToF-SIMS results included in Figure 2a provide unequivocal evidence that ZnTMPyP4+ is distributed throughout the polymer film. The second consideration is the time dependence of pathogen survival at different light intensity levels. These measurements for S. aureus are displayed in Figure 2b and confirm that intensities of 60−80 mW/cm2 are adequate to reduce survival to the minimum detection limit (MDL) of 10−4% after exposure for 45 min, with longer times being required to reach the MDL at lower light intensities (linear extrapolation of the data provided in Figure 2b yields the estimated MDL times included in the inset). Relative to other photodynamic materials,21,24 the light intensities determined here for achieving the MDL against S. aureus with ZnTMPyP4+/OBC26 suggest that a fluence rate of 60−80 mW/cm2 will be broadly applicable for the photodynamic inactivation of both Gram-positive and Gram-negative bacteria, as well as viruses. The final issue to be considered concerns the thermal stability of ZnTMPyP4+ as OBC26 is melt-pressed. As C


Letter


In conclusion, as pathogens such as bacteria and viruses become increasingly resistant to target-specific pharmaceuticals, alternative strategies must be developed to protect the public health and avoid rising medical costs. In this work, we have demonstrated that a photodynamic polymer containing only ∼1 wt % of the ZnTMPyP4+ PS is comprehensively effective against several Gram-positive and Gram-negative bacteria comprising most of the ESKAPE family (where ESKAPE is an acronym for the most common nosocomial infectious agents:30 E. faecium, S. aureus, K. pneumoniae, A. baumannii, Pseudomonas aeruginosa and Enterobacter species), as well as enveloped and nonenveloped viruses. Because photodynamic inactivation is nonspecific and does not target a particular constituent species, it is unlikely that pathogens can become resistant to the 1O2 generated by exposure of a PS to light in the visible and infrared wavelength range and possessing a lifetime of a few microseconds in solution. Our findings reported here are very promising and warrant further investigation and optimization for commercialization. The performance of ZnTMPyP4+-modified OBC26 can most likely be improved through the use of twin-screw melt extrusion to improve PS dispersion in the polymer matrix and melt spinning to generate high-surface-area (micro)fibers. Use of readily synthesized PSs in conjunction with commercially relevant polymers will greatly benefit process scale-up so that these materials can provide a near-term and viable solution to HAI prevention and, in so doing, save valuable lives and tremendous cost involved in the treatment of potentially dangerous infections worldwide.

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ASSOCIATED CONTENT

S Supporting Information *

Figure 3. Experimental results obtained from photodynamic inactivation of (a) two Gram-positive bacteria, (b) three Gramnegative bacteria, and (c) two viral strains (all pathogens are defined in the text and labeled). PS-free (blue) and dark (black) controls and the ZnTMPyP4+/OBC26 light study (red), as well as the MDL, are displayed in (a) and (b). In addition to the same controls, a PS-free dark control (green) is included in (c) to discern if the solvent used to prepare the OBC26 has a deleterious effect. The virus density is expressed in plaque-forming units (PFU) per mL, and the error bars correspond to the standard error.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.8b09139. Detailed account of experimental procedures including polymer film preparation/characterization, bacterial cell culturing, and antibacterial/antiviral photodynamic

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Antiviral aPDI testing has likewise been performed against two virus strains here: vesicular stomatitis virus (VSV), which belongs to the same viral family responsible for rabies, and human adenovirus-5 (HAd-5), a respiratory pathogen. An important difference between the two is that VSV is enveloped with an outer lipid shell, whereas HAd-5 is nonenveloped. Nonenveloped viruses are protected by their protein shell and are notoriously more difficult to inactivate than enveloped viruses. Results acquired from virus inactivation assays are displayed as a function of the number of plaque-forming units (PFUs) in Figure 3c and include two additional controls, viz., neat OBC26 maintained in the dark and exposed to light. As anticipated, the controls indicate relatively little (statistically insignificant) inactivation, whereas the ZnTMPyP4+-modified OBC26 exposed to light achieves 99.96% (P < 0.0127) inactivation of HAd-5 and, more impressively, 99.9998% (P < 0.003) inactivation of VSV. Taken together, the experimental results provided in Figure 3 establish that the photodynamic polymer utilized here can be used against Gram-positive/ negative bacteria and viruses with >99.9+% efficacy.

inactivation (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Richard J. Spontak: 0000-0001-8458-0038 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

We are grateful to the NC State Nonwovens Institute for support. This work was performed in the Analytical Instrumentation Facility (AIF) at North Carolina State University, which is supported by the State of North Carolina and the National Science Foundation (Award ECCS1542015). The AIF is a member of the North Carolina Research Triangle Nanotechnology Network (RTNN), a site in the National Nanotechnology Coordinated Infrastructure (NNCI). D


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Photodynamic Polymers as Comprehensive Anti-Infective Materials

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