phenylene-ethynylene - American Chemical Society

Invited Feature Article Cite This: Langmuir XXXX, XXX, XXX−XXX

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A Retrospective: 10 Years of Oligo(phenylene-ethynylene) Electrolytes: Demystifying Nanomaterials David G. Whitten,* Yanli Tang, Zhijun Zhou, Jianzhong Yang, Ying Wang, Eric H. Hill, Harry C. Pappas, Patrick L. Donabedian, and Eva Y. Chi*

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Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, New Mexico 87131, United States

ABSTRACT: In this retrospective, we first reviewed the synthesis of the oligo(phenylene-ethynylene) electrolytes (OPEs) we created in the past 10 years. Since the general antimicrobial activity of these OPEs had been reported in our previous account in Langmuir, we are focusing only on the unusual spectroscopic and photophysical properties of these OPEs and their complexes with anionic scaffolds and detergents in this Feature Article. We applied classical all-atom MD simulations to study the hydrogen bonding environment in the water surrounding the OPEs with and without detergents present. Our finding is that OPEs could form a unit cluster or unit aggregate with a few oppositely charged detergent molecules, indicating that the photostability and photoreactivity of these OPEs might be considerably altered with important consequences to their activity as antimicrobials and fluorescence-based sensors. Thus, in the following sections, we showed that OPE complexes with detergents exhibit enhanced light-activated biocidal activity compared to either OPE or detergent individually. We also found that similar complexes between certain OPEs and biolipids could be used to construct sensors for the enzyme activity. Finally, the OPEs could covalently bind to microsphere surfaces to make a bactericidal surface, which is simpler and more ordered than the surface grafted from microspheres with polyelectrolytes. In the Conclusions and Prospects section, we briefly summarize the properties of OPEs developed so far and future areas for investigation.

1. INTRODUCTION p-Phenylene-ethynylene polyelectrolytes (PPEs) have been well-studied over the past two decades.1−10 They are versatile and useful materials due to their strong fluorescence and their physical properties as polyelectrolytes that include water solubility as well as the ability to coat a variety of surfaces ranging from glass to microspheres to nanoparticles. Initial studies by our group in collaboration with other researchers demonstrated that the PPEs could be very effective biosensors.3,11−21 Some of these studies incorporated the PPEs as an effectively irreversible coating on oppositely charged microspheres. Interestingly, the microsphere-coated PPE retains its strong fluorescence when adsorbed onto the oppositely charged microspheres. The fluorescence of the PPE, both in aqueous solution and on microsphere supports, is readily quenched by both energy-transfer and electron-transfer quenchers.13,16,21 In 2003, we initiated a study of the potential of PPEs to function as antimicrobial agents against planktonic bacteria and spores.22 We found that aqueous solutions of a cationic PPE © XXXX American Chemical Society

when mixed with suspensions of E. coli or Bacillus spores and irradiated with light absorbed by the PPE resulted in rapid and efficient killing of both bacteria. We resumed this work at the University of New Mexico in 2008 with a study involving a cationic PPE grafted from microspheres.23,24 Although the surfaces containing the grafted conjugated polymers were quite rough, the grafted polymers on the surface were strongly fluorescent. The fluorescence was quenched by various electrontransfer and energy-transfer quenchers with elevated Stern− Volmer quenching constants. In studies of the interaction of planktonic bacteria with the microsphere-bound polymer (grafted from), we observed that bacteria would attach to the surface of the microspheres, first reversibly and subsequently permanently. We also found that upon irradiation with light absorbed by the polymer, there was a clear indication through live/dead staining that bacteria trapped on the polymer-coated Received: May 30, 2018 Revised: July 25, 2018 Published: July 29, 2018 A

DOI: 10.1021/acs.langmuir.8b01810 Langmuir XXXX, XXX, XXX−XXX

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Invited Feature Article

Scheme 1. Synthesis Route of Intermediatesa

(i) I2, KIO3, AcOH, and concentrated H2SO4; (ii) BBr3 and CH2Cl2; (iii) K2CO3 and acetone at 70 °C; (iv) 2-methyl-3-butyn-2-ol; (ix) t-BuOK; (vii) Pd(PPh3)2Cl2, CuI, CHCl3, Et2NH, and trimethylsilylacetylene; and (viii) NaOH and CH2Cl2. Reproduced from ref 25. Copyright 2009 American Chemical Society.

a

microspheres were largely dead whereas bacteria that were not trapped by the microspheres remained alive.24 As we continued our studies of conjugated polyelectrolytes as biocidal agents, we recognized that the bead-bound PPE was a very disordered and heterogeneous medium, and we were interested to determine the mechanistic basis for the antimicrobial activity. We decided that it would be useful to have a molecular phenylene ethynylene electrolyte with a defined molecular weight that we could bind to a similar microsphere support by a covalent link that would provide a more homogeneous surface. Thus, Drs. Yanli Tang and Zhijun Zhou undertook the synthesis of the unsymmetrical and symmetrical cationic oligo(phenylene-ethynylene) (OPE-n) having n = 1, 2, and 3 repeat units.25

from structurally similar byproducts. The conjugated backbone of OPE-n was built up by series of Sonogashira cross-coupling reactions in which the precursors were synthesized by attaching a protected alkyne group to a benzene ring, followed by the deprotection of the alkyne group to lead to the intermediates with end alkyne groups. The alkylamino groups were attached to a benzene ring in an early synthesis step and were converted into the quaternary ammonium derivatives in the last step to obtain the final OPE-n products.25 The above synthesis is tedious and features low yields in several steps, where the desired product must be separated from a byproduct with similar properties. We also synthesized symmetrical OPE-n compounds in good yields that took many fewer steps (Schemes 3 and 4). The symmetrical S-OPEs have photophysical properties that are very similar to those of the OPE-n and were made with a series of different end groups. Scheme 3 shows the synthesis of cationic S-OPE terminated with hydrogen (S-OPE-n (H)), while Scheme 4 shows the synthesis of S-OPE terminated with COOEt (S-OPE-n (COOEt)).25

2. STRUCTURES AND SYNTHESIS OF OPEs The synthesis route of OPE-n is depicted in Schemes 1 and 2. It started from commercially available 1,4-dimethoxybenzene, which was converted to 4-(4-iodophenyl)-2-methyl-3-butyn-2ol in a low yield since the desired products must be separated B


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Scheme 2. Synthesis Route of Unsymmetrical OPE-na

a

Reproduced from ref 25. Copyright 2009 American Chemical Society.

Scheme 3. Synthesis Route of Symmetrical S-OPE-n (H)a

a


by this route are shown in Figure 1, and their synthesis routes are

We also found that it was possible to synthesize a somewhat similar S-OPE-1 derivative with ionic end groups (EO-OPE) by an even simpler synthesis path.26 The compounds synthesized

outlined in Scheme 5. C


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Scheme 4. Synthesis Route of Symmetrical S-OPE-n (COOEt)a

a


3. INITIAL STUDIES OF SPECTROSCOPIC AND PHOTOPHYSICAL PROPERTIES OF OPE-n AND S-OPE-n AND THEIR COMPLEXES WITH ANIONIC SCAFFOLDS AND DETERGENTS Since we published an account of the general antimicrobial activity of the OPE and PPE in Langmuir, we are focusing on the unusual spectroscopic and photophysical properties of the OPE in this Feature Article.27 Figure 2 compares absorption and fluorescence spectra of the S-OPE-n (COOEt) in water (A and B) and in methanol (C and D). For both series, there is a red shift in the absorption with an increase in n. The increase between S-OPE-1 (COOEt) and S-OPE-2 (COOEt) is 16 nm in water and 14 nm in methanol.28 In contrast, the shift between the corresponding S-OPE-2 (COOEt) and S-OPE-3 (COOEt) is 6 nm in water and 8 nm in methanol. For both solvents, the shifts in fluorescence are much smaller. It is noteworthy that the observation of a moderate red shift in going from an OPE-1 to an OPE-2 and a smaller red shift between OPE-2 and OPE-3 is quite general and suggests that there may be a suppression of extended conjugation as the phenylene ethynylenes increase in the number of repeat units. Remarkably, when one compares the OPE-3s with phenylene

Figure 1. Structures of symmetrical end-only group OPE-1 (EO-OPE1) compounds.

D


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Scheme 5. Synthesis Route of Symmetrical End-Only OPE-1 (EO-OPE-1) Compounds26 a

a

(a) Trimethylsilyl acetylene, Pd(PPh3)2Cl2, CuI, diisopropylamine, and CHCl3, (b) K2CO3, CH3OH, and CH2Cl2, (c) KOH, DMSO, and 3chloro-N,N-dimethyl-propan-1-amine, (d) 2-chloro-N,N-dimethyl-ethanamine, (e) NaOH, dioxane, H2O, and oxathiolane, (f) Pd(PPh3)2Cl2, CuI, diisopropylamine, and CHCl3, (g) Pd(PPh3)2Cl2, CuI, H2O, and diisopropylamine, and (h) CH3I and CH2Cl2. Reproduced from ref 26. Copyright 2010 American Chemical Society.

ethynylene polymers from n ≈ 5−50, there is only a small incremental change between the OPE-3 and n ∼ 50.29 This gave us the first indication that there is a segment chromophore that is somewhere between OPE-2 and OPE-3 or between five and seven phenyl units in length. This seems quite reasonable in terms of previous work by others and ourselves in both theoretical and experimental studies.28,30−33 Our computational study indicated that OPE-1 and S-OPE-1 (COOEt) derivatives are planar and there is only a small barrier to the rotation of a phenyl ring out of a planar structure. Moreover, OPE-2 and OPE-3 are found to be nonplanar, thus we conclude that it is reasonable that the larger phenylene ethynylene polyelectrolytes exist as a series of segment chromophores and that electronic communication between segment chromophores occurs by hopping rather than through conjugation.28 Thus, fluorescence quenching by oppositely charged electron acceptors or energy transfer has somewhat lower Stern−Volmer quenching constants than other compounds such as phenylene vinylene polyelectrolytes. Another noteworthy discovery from our initial studies of the OPE-n and S-OPE-n (COOEt) photophysical properties was the remarkable weakness of the fluorescence of the derivatives with terminal COOEt substituents in water.25 For the cationic SOPE-1 (COOEt) 1, S-OPE-2 (COOEt) 2, and S-OPE-3 (COOEt) 3, the fluorescence efficiencies in water are 0.023, 0.039, and 0.069 respectively.34 In contrast, the same compounds show high fluorescence efficiencies (∼0.6) in methanol and in aqueous anionic detergent solutions. We examined several other side-chain OPE derivatives with different

end groups such as H, CHO, and COOH and observed that they all had similar high fluorescence efficiencies in methanol and water. We suspected that interfacial hydrogen bonds between water and the carboxyester groups were the cause of the reduced fluorescence. Eric Hill initiated a combined computational and experimental study to determine the source of this effect.34 We hypothesized that the excited singlet state of the OPE extended to the carboxyester groups and was deactivated by a partial proton transfer from water to the OPE terminal oxygen causing rapid deactivation of the singlet state. This hypothesis was tested by both computations and by comparing the fluorescence of the OPE (20 μM, repeat unit concentration) in water and in D2O (Figure 3). Table 1 shows the quantum yields of fluorescence in H2O and D2O and is consistent with an isotope effect that can be attributed to partial transfer of a hydrogen to the excited singlet. The fluorescence quantum yields increase in D2O by factors of 2.2, 2.3, and 1.6 for OPEs 1−3, respectively. The significant increase in fluorescence in D2O compared to that in H2O shown in Figure 3 and Table 1 is consistent with nonradiative deactivation of the excited singlet state by nonradiative decay involving specific interactions between interfacial water and the fluorophore.35 By the time these experiments were carried out, we had recognized that the quenching of the fluorescence of OPEs 1−3 in water was useful for fluorescence-based sensing activities. We found that the addition of a small amount of oppositely charged detergent (sodium dodecyl sulfate) (SDS) was able to dramatically increase the OPE fluorescence. As shown in Figure 4, the absorption spectrum changed a little but the fluorescence E


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Figure 2. Absorbance and fluorescence spectra of S-OPE-n (COOEt) in H2O (A and B) and methanol (C and D). Excitation wavelengths for S-OPE-1 (COOEt), S-OPE-2 (COOEt), and S-OPE-3 (COOEt) are 362, 378, and 384 nm in H2O and 366, 380, and 388 nm in methanol, respectively. Reproduced from ref 28. Copyright 2011 American Chemical Society.

Figure 3. Absorbance and fluorescence spectra of OPEs 1−3 in H2O (red trace) and D2O (black trace). Reproduced with permission from ref 35. Copyright 2014 John Wiley and Sons.

increased by an order of magnitude for S-OPE-1(COOEt). The quantum yields of fluorescence in the presence of SDS are shown in Table 2. The complex of the n = 1 OPE (1) with SDS in water has a quantum yield of nearly unity (0.92), and in D2O, it drops to 0.78. The complex formed with compound 2 also shows a strong

enhancement to 0.46 in H2O and to 0.33 in D2O. The larger oligomer with n = 3 (3) has an increase in quantum yield from 0.07 to 0.28 in water, but no significant change in quantum yield is observed between the compound alone in D2O and the complex formed in D2O.35 F


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Table 1. Fluorescence Quantum Yields (Φf) of OPEs 1−3 in H2O and D2O35 OPEs

solvent

Φf

1

H2O D2O H2O D2O H2O D2O

0.023 0.050 0.039 0.090 0.069 0.113

2 3

Table 2. Fluorescence Quantum Yields (Φf) of Fluorescence for OPEs 1−3 in H2O and in D2O in the Presence of 75 μM SDS35 sample

solvent

Φf

1-SDS

H2O D2O H2O D2O H2O D2O

0.92 0.78 0.46 0.33 0.28 0.12

2-SDS 3-SDS

4. EVIDENCE OF STRUCTURED INTERFACIAL WATER FROM CLASSICAL ALL-ATOM MD SIMULATIONS Using classical all-atom molecular dynamics (MD) simulations (Amber12 software package), Eric Hill and Deborah Evans studied the hydrogen bonding between interfacial water and its involvement in aggregation with surfactant.35 Figure 5 shows representative snapshots that display the hydrogen-bonding environment in the water surrounding the OPE with and without SDS present. From Figure 5, it can be seen that there is hydrogen bonding primarily off the carboxyester oxygens but also on the ether oxygens on the side chains. As these carboxyester groups become a less dominant feature of the molecule with an increase in backbone length, these results suggest that the amount of hydrogen bonding with solvent would not change. However, a much larger portion of the chromophore would no longer be under the influence of the carboxyester end-groups as the size increases, especially if a loss of coplanarity of the backbone occurs. The loss of coplanarity would prevent the quenching effect of the interfacial water from traveling along the backbone, while isolated segment chromophores which are excited in the vicinity of the COOEts would likely still be quenched.35

red shifts observed could be attributed to either aggregate formation on the scaffold or to planarization of the oligomer from a twisted conformation. Our finding that both OPE-n/SOPE-n (COOEt) and the end-only OPE could form clusters with oppositely charged detergents in which a few detergent molecules and one or more OPEs can form a unit cluster or unit aggregate well below the detergent critical micelle concentration (CMC) suggested that the photostability and photoreactivity might be considerably altered, with important consequences as to their activity as antimicrobials and fluorescence-based sensors. In this study,34 we examined the reactivity of four OPE derivatives shown in Figure 6. The two end-only OPEs have terminally charged groups, while each S-OPE has charged groups pendant to the middle aromatic ring. Figure 7 indicates that the absorption of EO1 blue shifts with the addition of SDS (well below the CMC) and that the fluorescence is largely quenched. A similar spectral change is observed for the addition of cationic surfactant tetradecyl trimethylammonium bromide (TTAB) to EO2 below the CMC. In both cases, a reasonable interpretation is that repulsion between the like-charged end groups is reduced sufficiently to allow an edge-to-face or face-to-face “H” dimer to form. However, when the concentration of TTAB reaches the CMC (3.79 mM), the spectral shift reverses (Figure 8), and in the micelle, the spectrum is predominantly the same as for monomer EO2 in water.

5. SURFACTANT COMPLEXES OF OPE AND AGGREGATION In our initial studies of OPE-n and S-OPE-n (COOEt) and their interactions with anionic scaffolds, we proposed that the spectral

Figure 4. Absorbance and fluorescence of 20 μM OPEs 1−3 after complexation with 75 μM SDS. Samples in D2O are in black, and samples in H2O are in red. Reproduced with permission from ref 35. Copyright 2014 John Wiley and Sons. G


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Figure 5. Snapshots from simulation trajectories with and without SDS. The OPE is shown in orange, and the SDS has gray hydrocarbon and a yellow sulfur in the center of the headgroup. Hydrogen bonds are depicted as dark lines. The green circle encompasses two water molecules which are each Hbonded to both SDS and the OPE-1. Reproduced with permission from ref 35. Copyright 2014 John Wiley and Sons.

6. OPE COMPLEXES WITH SURFACTANTS AND THEIR LIGHT-ACTIVATED BIOCIDAL ACTIVITY In our earlier studies, we noted that EO-OPEs were very easily photobleached and that under conditions where they photobleached extensively they still exhibited some attenuated lightactivated biocidal activity. The photobleaching of both S-OPE and EO-OPE could be attributed to the photochemical addition of water or O2 across one of the acetylene units.36 Since surfactant complex formation was found to release a significant portion of the interfacial water, we suspected that it might also extend the antimicrobial activity for a longer term.36,37 One of the EO-OPEs that is most photolabile is EO1 (Figure 6).36 To test this hypothesis we separately exposed samples of EO1 and EO1 plus SDS (premicellar complex) to light and evaluated their light-induced biocidal killing of E. coli and S. aureus. The samples were preirradiated (pretreatment) for 30, 60, and 120 min and then tested with bacteria. For E. coli samples containing EO1 irradiated with light and no pretreatment, there was almost 100% killing by flow cytometry after 30 min. However, after an EO1 sample preirradiated for 30 min was again irradiated with E. coli, the killing was reduced by about 20%. The samples of EO1 preirradiated for 60 and 120 min and then irradiated with E. coli showed about 60 and 35% killing, respectively. For S. aureus samples treated similarly with preirradiated EO1, there was somewhat less initial attenuation of killing, but for the EO1 that had been preirradiated for 2 h, there was no killing. The samples of EO1 with SDS (with SDS/EO1 = 4:1 or 0.24% of the CMC) showed extended biocidal activity: for both E. coli and S. aureus, killing was nearly 95% for all samples. The occurrence of some bacterial survival for all of the EO1/SDS samples was somewhat unanticipated and is not yet fully understood.38

Figure 6. Structures of OPE compounds used in the surfactant complex study. Reproduced from ref 34. Copyright 2013 American Chemical Society.

MD simulations suggest that an H-dimer structure is likely for EO2.34 For the OPE with side arms (S-OPE-1 (H) and −1SOPE-1 (H)) shown in Figure 6, we suspected that H-aggregate formation would not be likely even in the presence of oppositely charged detergent. When TTAB is added to a solution of −1SOPE-1 (H) in water, there is a red shift in both absorption and fluorescence and a moderate decrease in the fluorescence efficiency. The absorption and fluorescence blue shift when the CMC of TTAB is reached and the fluorescence efficiency increases. When SDS is added to a solution of S-OPE-1 (H), there is only a very weak aggregate formed. Scheme 6 provides a summary of these results.

Figure 7. Absorption (A) and fluorescence (B) spectra of EO1 (15 μM) upon sequential addition of 1 μL aliquots of SDS (15 mM). The spectrum of OPE in pure water is plotted with black triangles, and OPE to SDS ratios increased as follows 3:1, 3:2, 1:1, 3:4, 3:5, and 1:2. Reproduced from ref 34. Copyright 2013 American Chemical Society. H


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Figure 8. Absorption (A) and fluorescence (B) of aqueous solutions of EO2 upon addition of TTAB below and above the CMC. Reproduced from ref 34. Copyright 2013 American Chemical Society.

Scheme 6. Addition of Surfactants to Different OPE below the CMCa

a


The anionic EO-OPE, EO2 shown in Figure 6, was anticipated to show very little, if any, light-activated antibacterial activity against Gram-negative E. coli since it is expected that the anionic oligomers will be repelled by the negative charge on the Gram-negative cell envelope. Reduced light-activated antibacterial activity was anticipated for Gram-positive S. aureus for EO2 compared to EO1. The observed killing under irradiation for EO2 was in fact found to be 74 and 68% for E. coli and S. aureus, respectively, after 1 h of irradiation.38 We hypothesized that using a TTAB/EO2 complex might increase the antimicrobial activity against both bacteria.38 A 1:4 OPE/TTAB molar ratio was employed to give a complex that has a net positive charge and would be attracted to the envelopes of both bacteria.38 As shown in Figure 9 for E. coli and Figure 10 for S. aureus, there is enhanced bacterial killing for the OPE/TTAB complex in each case over either OPE or TTAB individually.39 The logarithmic viability plots emphasize that the EO2-TTAB complex is a powerful antibacterial for either bacterium and is

Figure 10. Viability of S. aureus on a logarithmic scale after 1 h of exposure to OPE, TTAB, or the EO2-TTAB complex. Viability is calculated relative to that of a negative control exposed to UVA light for 1 h. Reproduced from ref 39. Copyright 2014 American Chemical Society.

much more powerful than either reagent by itself. A proposed mechanism for the enhanced killing is shown in Scheme 7.39

7. BIOSENSING WITH COMPLEXES OF OPE AND BIOLIPIDS Having found that OPE complexes with detergents are useful antimicrobials, we hypothesized that similar complexes between certain OPEs and biolipids, reactive with certain enzymes, could be used to construct sensors for the activity of these enzymes. Specifically, we initiated an investigation into the use of the OPE shown in Figure 11 with the biolipids lauroyl choline chloride (LaCh) and l,2-dilauryl-sn-glycero-3-phospho-(1′-rac-glycerol) (DLPG) as sensors for phospholipase and acetylcholinesterase (AChE) enzymes.40 As shown in Figure 12, S-OPE-2 (COOEt) forms a complex with DLPG with strong changes in absorption (panel A) and a large increase in fluorescence (panel B). Similarly, we see a strong red shift in absorption (panel C) and a

Figure 9. Viability of E. coli on a logarithmic scale after 1 h of exposure to EO2, TTAB, or the EO2-TTAB complex. Viability is calculated relative to that of a negative control exposed to UVA light for 1 h. Reproduced from ref 39. Copyright 2014 American Chemical Society. I


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Scheme 7. Proposed Mechanism behind the Enhancement of Light-Activated Biocidal Activitya

a

(1) The OPE-TTAB complex is formed and added to the bilayer (lipids shown with yellow headgroups). (2) The OPE-TTAB complex, with net positive charge, intercalates with the anionic lipid bilayer. (3) The TTAB from the complex dissociates into the bilayer and associates with anionic lipids; this results in a repulsive electrostatic force between the OPE and the bilayer, ejecting it from the membrane into either the periplasmic space (for Gram-negative bacterial outer membranes) or the cytoplasm. Reproduced from ref 39. Copyright 2014 American Chemical Society.

Figure 11. Carboxyester-terminated p-phenylene ethynylenes used in an OPE-biolipid study, including cationic OPEs with n = 1−3 and a single anionic OPE with n = 1 (−1S-OPE-1 (COOEt)). Reproduced from ref 40. Copyright 2015 American Chemical Society.

Figure 12. Absorbance (A) and fluorescence (ex, 375 nm) (B) spectra of 1.4 μM S-OPE-2 (COOEt) with DLPG. Absorbance (C) and fluorescence (ex, 370 nm) (D) spectra of 5 μM −1S-OPE-1 (COOEt)) with LaCh. Arrows in the spectra indicate the varying DLPG/LaCh concentration or ratio of the substrate to OPE. Reproduced from ref 40. Copyright 2015 American Chemical Society.

fluorescence increase when LaCh is added to anionic S-OPE (COOEt) (a.k.a. −1S-OPE-1 (COOEt)). It was anticipated that enzyme activity could be monitored by following the timed decay of a fluorescence signal from the

complexes detected in Figure 13 upon addition of enzymes such as the phospholipases and AChE. As shown in Figure 13, the addition of phospholipases PLA1 and PLA2 to samples of SOPE-2 (COOEt) results in the decay of the signal from the J


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Figure 13. (A) Fluorescence of the S-OPE-2 (COOEt)/DLPG aggregates over the course of PLA1 activity with 1.4 μM OPE and a DLPG concentration of 7.27 μM, with enzyme added ranging from 0.5 to 5 mU of PLA1. (B) 1.4 μM S-OPE-2 (COOEt) with DLPG at a series of concentrations from 10.6 to 35.6 μM (7.5−25.4 DLPG/OPE), followed by the addition of 4 mU of PLA1. (C) Fluorescence of the S-OPE-2 (COOEt)/DLPG aggregates over the course of PLA2 activity with 1.4 μM OPE and a DLPG concentration of 7.27 μM, with enzyme added ranging from 0.5 to 5 mU of PLA2. (D) 1.4 μM S-OPE-2 (COOEt) with DLPG at a series of concentrations from 2.37 to 17.8 μM (1.7−12.7 DLPG/OPE), followed by the addition of 40 mU of PLA1. t = −1 s is the time of enzyme addition. The wavelength of excitation is 375 nm, and the wavelength of emission is 440 nm. Reproduced from ref 40. Copyright 2015 American Chemical Society.

Figure 14. (A) Absorbance at 430 nm and (B) fluorescence (ex, 370 nm; em, 440 nm) of −1S-OPE-1 (COOEt) and LaCh for 0.2, 0.4, and 0.6 U of AChE. Reproduced from ref 40. Copyright 2015 American Chemical Society.

group, releasing diacyl glycerol as a product, was found not to change the complex fluorescence in the time that PLA1 and PLA2 were reactive.40,41 The potential of using the complex between lauroyl choline and −1S-OPE-1 (COOEt) as a sensor for acetylcholinesterase activity is attractive due to the importance of AChE as a terminator of synaptic transmission by hydrolyzing the neuro-

OPE/DLPG complex. Fluorescence profiles in Figure 13 consist of a flat portion followed by a rapid decrease in fluorescence. The flat portion of the plot increases with the addition of excess DLPG and is attributed to the lipase cleavage of unbound lipid before lipid is either consumed, within the complex, or released and rapidly consumed following release. Not surprisingly, phospholipase C, which cleaves phospholipids at the phosphate K


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Figure 15. Fluorescence (λexc = 370 nm, λem = 440 nm) of the −1S-OPE-1 (COOEt)/LaCh complex (5 μM OPE, 32 μM LaCh) after addition of 0.6 U of AChE in the presence of AChE inhibitor (A) Itopride HCl, (B) Meptazinol HCl, and (C) TAE-1. Traces with inhibitor are denoted by +I, and −I indicates no inhibitor. Reproduced from ref 40. Copyright 2015 American Chemical Society.

Scheme 8. Preparation of Surface-Grafted (SG) Microspheres Where OPE-n Are Covalently Linked to Amine-Functionalized Microspheres

Meptazinol. However, for TAE-1, red-shifted absorption and strongly red-shifted green fluorescence were recorded for the mixture, but they do not interfere with the operation of the sensor.40 The sensor formed from the association of the anionic OPE with lauroyl choline successfully detected the activity of human acetylcholinesterase. This application demonstrates that OPE has the ability not only to detect enzyme activity but also to sense the inhibition of enzyme activity inhibitors. These results suggest that OPE, or oligomers similar to it, may be used and developed as sensors for chemical and biological agents ranging from applications in the detection of pollutants, weaponized toxins, or other disease agents. In related recent work (not reviewed in this Feature Article), we have found that the carboxyester OPE derivatives can also be used to sense intermediates in protein misfolding events related to the amyloid fibrils formed in neurological diseases such as Alzheimer’s and Parkinson’s diseases.48,49 We also have found that the quenching of fluorescence that occurs with these compounds in aqueous solution is also accompanied by a lack of

transmitter acetylcholine. Lauroyl choline was chosen as a substitute for acetylcholine due to its having a sufficiently long hydrocarbon chain that is anticipated to form a strong complex with −1S-OPE-1 (COOEt). The complex has strong absorption and fluorescence (quantum efficiency close to 1), and as shown in Figure 14, the AChE-catalyzed cleavage can be monitored by either absorption or fluorescence decay. It is clear from Figure 14 that the rate of complex disappearance correlates with the amount of enzyme added (U). As indicated above, AChE is responsible for the termination of nerve signals. Inhibiters of AChE are often highly neurotoxic and potential insecticides or nerve agents. Our sensor was tested against three compounds: TAE-1, Itopride, and Meptazinol, all of which have been shown to be AChE inhibitors.43−47 These compounds are less volatile than nerve agents or pesticides and thus can be tested against the present sensor. As shown in Figure 15, all three compounds attenuate the destruction of the complex by AChE, presumably due to inhibition of the enzyme. The potential reaction of the three inhibitors with the sensor, −1S-OPE-1 (COOEt), was checked, and no aggregates were observed for Itopride or L


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Figure 16. Biocidal study of E. coli with SG-OPE-1, SG-OPE-2, and SG-OPE-3 after 15, 30, and 60 min of irradiation followed by staining with live/ dead stain: green for live and red for dead. The excitation wavelengths were 488 and 543 nm. The selected area was enlarged at the same magnification and inserted into the top left corner.

mentioned elsewhere, we see similar photochemical activation with detergent association.51

oxygen activation through triplet sensitization, thus the inactivation by fluorescence quenching correlates with a lack of photosensitization.50 However, the detergent activation of fluorescence by removal of the interfacial water offers a controllable and localized way to turn on the photosensitization of singlet oxygen and its characteristic photochemical reaction paths.50 It is interesting to review the results seen in the initial study of antibacterial activity of OPE-1, OPE-2, and OPE-3 vs S. epidermidis and E. coli after irradiation with UV light absorbed by the OPE-n.51 For example, for OPE-1 at a concentration of 0.01 μg/mL with S. epidermidis there is very little killing on irradiation for 30 min (0.6%) or 60 min (2.5%) of irradiation. However, after 2 h of irradiation the killing is 25.5%, which is significantly higher. For S. epidermidis at 0.05 μg/mL, the numbers are 2.3, 24.4, and 80.1% for 30, 60, and 120 min, respectively. A similar trend is seen for OPE-2, where there is relatively little killing over the first 30 min and an accelerating increase for the second and third intervals. Initially, we did not consider that there was probably a slow, dark association of the OPE-n with the bacteria. However, once the OPE-n associate with the bacteria and shed some interfacial water, they become photochemically active due to less quenching by water. As

8. BACTERICIDAL ACTIVITY OF OPE-n ON MICROSPHERE SUPPORTS For the penultimate section, we return to the original idea that led to our synthesis of the first three OPE-n’s. Our goal was to make a bactericidal surface with the OPE-n covalently bound to a surface that would likely be simpler and more ordered than the surface grafted (from) microspheres with PPE.51 We anticipated that it should be straightforward to take microspheres and react them to link the OPE-n to the surface (Scheme 8). The procedure outlined in Scheme 8 worked smoothly for all three OPE-n’s, and the three microspheres-bound OPEs were easily isolated and detected by confocal fluorescence microscopy.52 Two bacteria were examined in this study, which were Gramnegative E. coli and Gram-positive S. aureus. The concentration of bacteria was kept at around 3.0 × 10−7 cells/mL, while the ratio of bacteria to SG-OPE-n was 10:1. The suspensions containing bacteria and SG-OPE were kept in the dark or irradiated with near-UV light in a photochamber. After exposure, propidium iodide was used for the dead stain, while SYTO 9 and SYTO 24 were used for the live stain in E. coli and S. aureus, respectively. The results are summarized in Figure 16 for E. coli M


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Figure 17. Biocidal study of S. aureus with SG-OPE-1, SG-OPE-2, and SG-OPE-3 after 15, 30, and 60 min of irradiation followed by staining with live/ dead stain: green for live and red for dead. The excitation wavelengths were 488 and 543 nm. The selected area was enlarged at the same magnification and inserted into the top left corner.

and Figure 17 for S. aureus. In samples with E. coli and SG-OPE1, bacteria are dispersed and live because they appear as single green dots. There is little evidence of bacterial attachment to OPE-1-bound microspheres. Note that in all images the microspheres are not observed. This lack of fluorescence from the microspheres is expected because there is no more than a monolayer of the oligomer in each case. In contrast, in E. coli samples with SG-OPE-2 and SG-OPE-3, clusters of mixed live and dead bacteria are seen, indicating bacterial attachment to the microspheres and bactericidal activity exerted by the OPEgrafted microspheres. The dark space in the centers of these clusters are likely the 5-μm-diameter microspheres with OPE attached. Both the number of bacteria and the proportion of dead (red) bacteria are higher for SG-OPE-3 than for SG-OPE2. Also, more dead bacteria than live (green) bacteria are present. For the samples with S. aureus (Figure 17), the results are even more striking. For the three images with SG-OPE-1, there are mostly live bacteria, but they appear to be clustered around the SG-OPE-1 microspheres and the number of attached bacteria increases with irradiation time. For the sample with SGOPE-2, bacterial attachment and clustering are clearly visible, and it is also clear that bacteria are dying (yellow-orange) after 30 min of irradiation. After 60 min of irradiation, attached bacteria are dead. Finally, for SG-OPE-3, a large number of dead

bacteria around the microspheres are visible, and there are significantly more dead bacteria. Furthermore, these dead bacteria appear to be surrounded by a halo of red haze that is likely cytoplasmic material extruded from the dead or dying bacteria coating the microspheres. Interestingly, for studies of both E. coli and S. aureus, there seems to be little capture or killing of either bacteria in the dark under the conditions employed (data not shown). The results of this study lead to several inferences and conclusions. First, compared to the studies with the previous surface-grafted polymers, we can see significant differences between both the Gram-negative E. coli and Gram-positive S. aureus. It is easier for the shorter SG-OPE to apprehend the S. aureus than the E. coli. Although we cannot determine the orientation of the more-or-less rigid OPE with respect to the microsphere surface, it is reasonable to infer that the ends of the longer OPE-2 and OPE-3 are on average farther away from the microsphere surface and better able to intercept the bacteria. It also appears that while the surface-bound OPE are shorter than the PPE grown from the surface, they are also more effective at capturing and killing bacteria under UV irradiation, especially for the SG-OPE-3. The images from these confocal fluorescence studies of the SG-OPE are actually much more informative than the earlier studies with polymeric PPE grown from microN


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spheres23,24 in that we can see the binding and killing through several steps and the difference in binding and killing from OPE1 through OPE-3. Without the dominant fluorescence from these OPE-covered microspheres, the attachment of the bacteria to the microspheres is clearly seen, and the effect of the antimicrobial OPEs correlates well with what we learned in our earlier antimicrobial studies via TEM.27,53 It is remarkable to see that SG-OPE-2 and SG-OPE-3 are very efficient in capturing and killing bacteria despite the fact or perhaps because they are shorter and absorb much less light than does SG-PPE.

family of S-OPE-5s or S-OPE-7s. These pure compounds should be water-soluble and strongly fluorescent (except for COOEt derivatives). From our earlier studies on the interaction of PPE and OPE with membranes, it would be useful to determine how these molecules compare in reactivity and property with corresponding low-molecular-weight polymers.

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AUTHOR INFORMATION

ORCID

David G. Whitten: 0000-0002-6305-9494 Yanli Tang: 0000-0002-9979-6808 Patrick L. Donabedian: 0000-0003-3636-4378

9. CONCLUSIONS AND PROSPECTS Our decision to synthesize the oligomeric phenylene ethynylene electrolytes 10 years ago has led our group on a major scientific adventure and to many unforeseen yet useful results involving both fundamental science and important potential applications. In the following text, we briefly summarize the properties thus far developed and future areas for investigation. 9.1. OPEs as Antimicrobials. While one of our goals in synthesizing the unsymmetrical OPEs with one carboxyester end was to examine them as antibacterial agents and compare their activities with those of the PPE, it was initially a big surprise that in solution their activity against different strains of bacteria was comparable or in some cases even better than that of the PPE, particularly the end-only OPE-1 compounds shown in Figure 1. The OPEs have also been found to be very effective antivirals54 and antifungal agents55,56 as well as being capable of limiting and eradicating bacterial biofilms.57 The end-only OPE containing the thiophene moiety (compound C in Figure 1) is potentially quite useful in commercial applications. 9.2. OPEs as Biological and Chemical Sensors. S-OPE and OPE-n with carboxyester end groups show surprisingly low fluorescence efficiencies in water as outlined in Sections 2 and 4. However, they become strongly fluorescent when associated with organic compounds and biomacromolecules including proteins and amino acids. We have shown recently that the quenching of excited singlet states in water is also accompanied by triplet-state deactivation and the loss of efficient generation of singlet oxygen.50 This seems to be a highly promising means of controlling reactivity in complex biological systems in which indiscriminate photodynamic activity can produce unwanted damage to beneficial cells as well as cancer cells and other targeted diseases. 9.3. OPEs as Theranostic Reagents. As mentioned above but not described in detail, the OPEs with carboxy ester groups and in particular an OPE with negative charges and a longer OPE bind selectively to protein aggregate intermediates formed in the development of Alzheimer’s disease and to several protein misfolding diseases. Since they are almost nonfluorescent in water and selectively associate with certain protein conformations, they should be able to selectively oxidize the targeted proteins without producing much damage to other cells. 9.4. Synthesis and Study of New OPEs and OPE-like Reagents. We have mainly focused on positively charged OPE in our studies thus far. Many areas such as negatively charged OPE have been little explored except in the above paragraph. Given the propensity of many biomolecules and materials to have an overall negative charge, negatively charged OPE can be more selective and more likely to be useful in theranostic applications. More molecules and materials with waterinactivated fluorescence properties should be especially useful. 9.5. Synthesis and Study of Larger OPEs. For the OPEs with side arms, it should be possible to synthesize fairly easily a

Notes

The authors declare no competing financial interest. Biographies

David G. Whitten received his A.B. degree in chemistry at the Johns Hopkins University and continued his graduate work at JHU, obtaining his Ph.D. in organic chemistry. After 2 years spent doing research at the Jet Propulsion Laboratory as an officer in the U.S. Army, he spent a postdoctoral year with George Hammond at Caltech. His academic career has involved stays of 17 years at the University of North Carolina, Chapel Hill, 14 years at the University of Rochester, and an ongoing career as Distinguished Professor in two departments at the University of New Mexico, now approaching 14 years. His current research involves the synthesis and study of new oligomer and polymer polyelectrolytes and their involvement in interactions on the nanoscale with bacteria, viruses, fungi, and mammalian cells.

Yanli Tang received her B.S. degree in chemical engineering from the Department of Chemistry and Chemical Engineering, Henan University, in 2001 and her M.S. degree in chemistry from Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, in 2004. She received her Ph.D. degree in organic chemistry under the O


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supervision of Professor Shu Wang at the Institute of Chemistry, Chinese Academy of Sciences, in 2007. Following three years as a postdoctoral researcher in Professor David G. Whitten’s group at the Center for Biochemical Engineering, Department of Chemical and Nuclear Engineering, University of New Mexico, she became an associate professor in the School of Chemistry and Chemical Engineering, Shaanxi Normal University. In October 2014, she became a full professor in chemistry. Her current research interests include the design and synthesis of functional conjugated polymers materials, biosensors, and biochemical analysis.

Ying Wang received a B.S. degree in chemistry from Jilin University in China in 2005 and an M.S. degree in physical chemistry from the Institute of Theoretical Chemistry at Jilin University in 2008. He received his Ph.D. in chemistry from the University of New Mexico in 2013 under the supervision of Prof. David G. Whitten. He is now a scientist at Regeneron Pharmaceuticals, Inc.

Zhijun Zhou received his B.S. in chemistry from Lanzhou University in China and his Ph.D. in organic chemistry with Professor David Whitten from the University of New Mexico, where his dissertation was on biosensing and biocidal activities of oligo(phenylene-ethynylenes). He was a professor at the China Academy of Engineering Physics (2012− 2017) and now is the president of Chengdu Tianhe Biotechnology Co. Ltd. His research interests include (1) the photophysical and photochemical properties of neutral oligo(phenylene-ethynylenes) and applications to biosensing and (2) the study of peptide-receptor radiopharmaceutical imaging and therapy by introducing functional motifs to optimize the in vitro and in vivo properties of peptide ligands.

Eric H. Hill received his B.S. in chemistry at Southern Oregon University, his Ph.D. at the University of New Mexico (David Whitten and Debi Evans), and completed postdoctoral appointments at CICBiomaGUNE in San-Sebastian, Spain (Luis Liz-Marzán) and the University of Texas at Austin (Yuebing Zheng). His background spans colloidal chemistry, computational chemistry, and microbiology. He has broad, multidisciplinary interests in both experimental and computational avenues of research related to life sciences and materials. He is currently a research group leader focusing on colloidal routes toward materials for photocatalysis at the Institute for Advanced Ceramics at the Hamburg University of Technology.

Jianzhong Yang was born in Hunan, but he grew up in Guangdong, China. He got his bachelor’s degree in chemistry at Shantou University in 2011. After his graduation, he came to the U.S. to pursuit his Ph.D. degree at the University of New Mexico, and he obtained his PhD in chemistry in 2016. Then, he joined a startup company called Biosafe Technologies, LLC as a research scientist for the development of lightactivated antimicrobials. In 2017, he began working at the University of New Mexico as a research assistant professor in the Center for Biomedical Engineering. His research interests lie in the synthesis of conjugated small molecules and polymers for biomedical and electronic device applications.

Harry C. Pappas earned his B.S. in mechanical engineering from the University of Massachusetts, Amherst in 2010 before traveling crossP


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country to attend graduate school at the University of New Mexico. In 2016, he graduated with a Ph.D in nanoscience and microsystems engineering under the advisement of David G. Whitten and Aaron K. Neumann. His research efforts focused on the use of flow cytometry for the evaluation of antimicrobials and, in particular, their effect on the immunogenicity of infectious pathogens. He currently works as a research assistant professor in the University of New Mexico’s Department of Chemical & Biological Engineering.


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Patrick L. Donabedian grew up in New York and received his B.A. from St. John’s College, Santa Fe in 2012 and M.S. from the University of New Mexico advised by Dr. David Whitten and Dr. Eva Chi in 2016. He is currently in the M.D.−Ph.D. program at the University of Florida. His master’s thesis applied the photoproperties of phenylene ethynylenes for sensing and perturbing pathological protein aggregates. He is interested in using medicinal chemistry and radiation−matter interactions to understand, interpret, and treat human disease.

Eva Y. Chi received her B.S. degrees in chemistry and chemical engineering from the University of California at Berkeley and a Ph.D. in chemical engineering from the University of Colorado. She is the recipient of the NSF Graduate Research Fellowship, NIH Ruth L. Kirschstein Postdoctoral Individual National Research Service Award, and the NSF CAREER award. She is currently an associate professor and Regents’ lecturer in the Department of Chemical & Biological Engineering at the University of New Mexico. Her research interests lie within soft condensed matter and include physical, self-assembly, and functional properties of proteins, polymers, and biomembranes.

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ACKNOWLEDGMENTS We thank the Defense Threat Reduction Agency for supporting this work through grant HDTRA1 08 1 0053. We thank the National Science Foundation for support through grant DMR 1207362. We thank the U.S. Department of Energy through grant number 100000276. Q


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