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Self-aggregation, Antibacterial Activity and Mildness of Cyclodextrin/Cationic Trimeric Surfactant Complexes Chengcheng Zhou, Dong Wang, Meiwen Cao, Yao Chen, Zhang Liu, Chunxian Wu, Hai Xu, Shu Wang, and Yilin Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b11667 • Publication Date (Web): 31 Oct 2016 Downloaded from http://pubs.acs.org on November 3, 2016

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Self-aggregation,

ACS Applied Materials & Interfaces

Antibacterial

Activity

and

Mildness

of

Cyclodextrin/Cationic Trimeric Surfactant Complexes Chengcheng Zhou,† Dong Wang,§ Meiwen Cao,§ Yao Chen,† Zhang Liu,† Chunxian Wu,† Hai Xu,§ Shu Wang,‡,* and Yilin Wang†,* †

Key Laboratory of Colloid and Interface Science, Beijing National Laboratory for Molecular Sciences (BNLMS), Institute

of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China; University of Chinese Academy of Sciences, Beijing 100049, P. R. China ‡

Key Laboratory of Organic Solids, Beijing National Laboratory for Molecular Sciences (BNLMS), Institute of Chemistry,

Chinese Academy of Sciences, Beijing 100190, P. R. China §

Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), Qingdao 266580, P. R. China

ABSTRACT: Despite efficacious antimicrobial activity, cationic oligomeric surfactants show strong skin irritation potential due to their larger cationic charge numbers and multiple hydrophobic chains. This work reports that the incorporation of α-, β- and γ-CDs with different cavity sizes can effectively improve the mildness of cationic ammonium trimeric surfactant DTAD with a star-shaped spacer while maintaining its high antibacterial activity. Based on the different cavity sizes of CDs and the asymmetry in the spacer of DTAD, the CD/DTAD mixtures form α-CD@DTAD, 2α-CD@DTAD, β-CD@DTAD and γ-CD@DTAD complexes. Compared to DTAD, these CD/DTAD complexes show much stronger self-assembly ability with much lower critical aggregation concentrations (CAC) and form more diverse aggregates with reduced zeta potential. Just above their CACs, the CD/DTAD complexes form vesicles or solid spherical aggregates of ~50 nm, and then transform into small micelles of ~10 nm as the concentration increases. The strong self-assembly ability and the multiple sites of hydrogen bonds of the 1

ACS Paragon Plus Environment


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CD/DTAD complexes endow them with high antibacterial activity against E. coli, showing a very low minimum inhibitory concentration (2.22−2.48 µM) comparable to that of DTAD. In particular, the addition of CDs significantly reduces the abilities of DTAD in solubilizing zein (a skin model protein) and in binding with zein, and the mildness decreases in the order of 2α-CD@DTAD > β-CD@DTAD > γCD@DTAD > α-CD@DTAD. This tendency depends on their different self-assembling structures, and the formation of vesicles is approved to be in favor of the improvement of the mildness. KEYWORDS:

cyclodextrin, cationic trimeric surfactant, aggregation behavior, antimicrobial

activities, mildness

INTRODUCTION Surfactants possess both hydrophilic and hydrophobic moieties, and the amphiphilic structure endows them with unique functions as wetting agents, solubilizers, emulsifiers, etc.1-3 Generally, cationic surfactants show a broad range of biomedical applications,4-10 especially, as antibacterial agents.6-10 They exhibit bactericidal potency primarily by targeting and disintegrating bacterial cell membranes through electrostatic and hydrophobic interaction.6,7 To date, various cationic surfactants have been designed to develop highly efficient antimicrobial agents with low minimal inhibitory concentration (MIC),7,8,11-13 and thus reduce the exposure of bacteria to surfactants and curb the potential development of bacterial resistance.14-16 It has been found that the antibacterial activity of surfactants increases with increasing the amount of cationic charges and hydrophobic chains.12,13 As we reported previously, cationic oligomeric surfactants, composed of three or more amphiphilic moieties chemically connected by spacer groups, show much higher antibacterial activity over their corresponding monomeric and dimeric counterparts.13 In particular, the oligomeric surfactants have lower critical aggregation concentrations (CAC) and multiple aggregate structures.17-19 The feature enhances the local cationic charge concentration and aggregate mass, and thus leads to strong interaction between the surfactants and bacterial cell membrane, 2


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which contributes to the antibacterial activity.13 Despite their efficacious antimicrobial activity, cationic surfactants are often limited in practical applications. One of the reasons is their strong skin irritation such as redness and inflammation mainly caused by the strong interactions of the surfactants with proteins or lipids in skin.20,21 Moreover, as the numbers of cationic charges and hydrophobic chains increase, the irritant potential of the surfactants increases.22-27 Thus, it is imperative to improve the mildness of cationic surfactants without sacrificing their superior antimicrobial activity. Recent studies have revealed that the incorporation of cyclodextrin (CD) is favorable for the improvement of biocompatibility of surfactants.28-32 CDs are donut-like oligosaccharides with a hydrophilic exterior and a hydrophobic cavity.33 This feature confers on CDs the ability to form inclusion complexes with a very wide range of guest species by encapsulating the hydrophobic parts of the guest molecules into the cavities.34-36 The commonly native CDs are α-, β- and γ-CDs, consisting of six, seven and eight glucoside unities, respectively, which are of different cavity size. The discrepancy in the cavity size makes each CD form inclusion complexes with specific types of guest molecules.36-38 In addition, the outer surface of CDs is covered with abundant hydroxyl groups, which provides multiple hydrogen bond sites.39 By controlling the formation of hydrogen bonds between the hydroxyl groups of CDs, CDguest inclusion complexes can self-assemble into various aggregate structures.40-42 To meet different demands, the host-guest interaction has been applied to form various CD-based amphiphiles.30,35,43-45 For examples, Luk and co-workers30 designed a CD-based surfactant, whose hydrophilic headgroup is a folded and stable self-inclusion complex of ferrocenyl-substituted β-CD. This CD-based surfactant shows strong self-assembling ability with a low CAC of about 7 µM. Unlike traditional ionic surfactants denaturing proteins, the assemblies of this CD-based surfactant can effectively retain the native folded structure of a membrane protein (bacteriorhodopsin), and thus this surfactant is suitable for the recrystallization of membrane proteins. Liu group44 constructed giant nanotubes possessing enzymatic function by using CD-based amphiphiles, where the host molecule CDs are modified with the catalytic 3



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moieties of glutathione peroxidase (GPx). In contrast to ebselen, a well-known GPx mimic, these CDbased nanotubes loaded with high peroxidase centers exhibit a remarkable enhanced activity for the reduction of H2O2. Recently, a linear-star supramolecular amphiphile with a multi-arm topological structure was fabricated by multi-arm β-CD-PLLA and Azo-PEG, which self-assembles into sphere-like, carambola-like and naan-like micelles, tube-like fiber, and shuttle-like and random curled-up lamellae by tuning the length of hydrophilic or hydrophobic chains.45 Therefore, based on the host-guest complexation, two or more distinct properties can be easily incorporated into one molecule. Our previous studies found that cationic ammonium trimeric surfactant DTAD with a star-shaped asymmetric spacer (Scheme 1a) has a CAC value of 0.20 mM, and displays a unique aggregation behavior, i.e., forming vesicles at low concentration and transforming into small micelles accompanied with the molecular conformational transition as the concentration increases.18 Moreover, DTAD can efficiently kill Gram-negative E. coli with a very low MIC value of 1.70 µM.13 However, DTAD may show strong skin irritation potential due to its larger cationic charge number and multiple hydrophobic chains. Thus, in this work, α-, β- and γ-CDs with different cavity sizes (Scheme 1b) are incorporated to improve the mildness of DTAD. The self-assembly behavior of the CD/DTAD inclusion complexes, the interaction of the CD/DTAD complexes with a skin model protein zein as well as the antimicrobial activity against E. coli have been studied. It is anticipated to understand the effects of CDs on the self-assembly of novel star-shaped oligomeric surfactants and combine the mildness of CDs and the antimicrobial activity of oligomeric surfactants in the CD/DTAD inclusion complexes.

Scheme 1. Chemical structures and the schemes of (a) cationic trimeric surfactant DTAD with 1H NMR signal assignments and (b) Cyclodextrins, α-CD (n = 6), β-CD (n = 7), and γ-CD (n = 8). 4


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EXPERIMENTAL SECTION Materials and Sample Preparation. Cationic trimeric surfactant DTAD was synthesized and purified as we reported previously.18 α-CD (≥ 98%), β-CD (> 99%) and γ-CD (Vetec™ reagent grade) were purchased from Sigma-Aldrich Company. Purified zein was obtained from Acros Organics. Ampr Escherichia coli (E. coli) was purchased from Beijing Bio-Med Technology Development Co., Ltd. Ultrapure water was used throughout the experiment. Phosphate buffered saline (1× PBS, pH 7.4) was used in the assessment of antibacterial activity. The CD/DTAD solutions were prepared and thermostatically incubated at 25 ºC (for at least 24 h) to allow the CD/DTAD system to self-assemble sufficiently. Isothermal Titration Microcalorimetry (ITC). The calorimetric measurements were conducted on a TAM 2277-201 microcalorimetric system (Thermometric AB, Järfȧlla, Sweden) with a stainless steel sample cell of 1 mL at 25.00 ± 0.01 °C. Each ITC curve was repeated at least twice with a deviation of ±4%. While studying the binding processes of CDs with DTAD, the sample cells were initially loaded with 600 µL water or 0.10 mM DTAD solution, and then CD solutions (0.80 mM α-CD, 0.30 mM β-CD and 0.30 mM γ-CD, respectively) was injected consecutively into the stirred sample cell in portions of 10 µL via a 500 µL Hamilton syringe controlled by a 612 Thermometric Lund pump until the end of the interaction. The system was stirred at 60 rpm with a gold propeller. To monitor the interaction of DTAD or CD/DTAD complexes with zein, the sample cell was initially loaded with 600 µL water or 5.0 mg zein/water mixed systems. Then 10 mM DTAD or CD/DTAD complexes were injected consecutively into the stirred sample cell in each portion of 10 µL until the interaction process was completed. NMR Measurements. 1H NMR and ROESY spectra were recorded on an AVANCE 600 MHz NMR (Bruker, Switzerland) at room temperature (25 ± 2 °C). Deuterium oxide (99.9%) was used to prepare stock solutions of CD/DTAD complexes. All the proton signals were calibrated with HDO signal at 5



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4.790 ppm. While studying the stoichiometric ratio of CD/DTAD and the molar fraction of complexed DTAD (xcDTAD), the variations in chemical shifts (∆δ) of DTAD were monitored with the addition of CD by keeping the constant DTAD concentration. Assuming the fast exchange on NMR time-scale, the molar fraction of complexed DTAD, xcDTAD (its counterpart is free DTAD, xcDTAD + xfDTAD = 1) can be quantified by the observed chemical shift (δ), i.e. δ = xcDTADδc + xfDTADδf or equivalently ∆δ = δ − δf = (δc − δf)xcDTAD, where δc and δf are the proton chemical shifts of complexed and free DTAD, respectively.36 δc and δf values of DTAD can be determined by the titration plots of CD/DTAD mixtures. To monitor the variation of the chemical shifts of CD/DTAD mixture against the surfactant concentration, 1H NMR spectra were recorded with a Bruker AV400 FT-NMR spectrometer operating at 400.1 MHz. ESI-MS Measurements. ESI-MS measurements were carried out on 9.4T Solarix FT-ICR-MS (Bruker, USA). The operating conditions of the ESI source: positive ion mode; capillary voltage -3500 V, dry temperature 200 °C; skimmer 25.0 V; nebulizer pressure 1.0 bar; dry gas 4.0L/min. 0.1 mM CD/DTAD sample was diluted 10 times by methanol and introduced via direct infusion at a flow rate of 2.00 µL/min. Surface Tension Measurements. Surface tension measurements were conducted using the drop volume method46 at 25.00 ± 0.01 °C. Every drop was kept for about half an hour, and each surface tension value (γ) was determined from at least five consistent measured values. The surface tension curve was repeated at least two times. Electrical Conductivity Measurements. The conductivity of CD/DTAD mixtures as a function of concentration was measured by a JENWAY model 4320 conductivity meter at 25.0 ± 0.1 ºC. The molar conductivity Ʌ = (κ − κ0)/CDTAD, where κ is the specific conductivity of CD/DTAD mixed solution, κ0 is the specific conductivity of water, and CDTAD is the concentration of DTAD. ζ-Potential Measurements. The surface charge property of CD/DTAD aggregates was studied by ζpotential measurement at a scattering angle of 173° with Nano ZS (Malvern Instruments) equipped with 6


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a thermostatted chamber and a 4 mW He-Ne laser (λ = 632.8 nm) at 25 °C. Disposable capillary cells were used for the measurements. Dynamic Light Scattering (DLS). Dynamic light scattering (DLS) measurements were carried out on an LLS spectrometer (Model ALV/SP-125), which was equipped with a 22 mW He-Ne laser (632.8 nm wavelength) and a refractive index matching bath of filtered toluene at 25 °C surrounding the cylindrical scattering cell. The samples were filtered by 450 nm filters. The scattering angle was 90°. Cryogenic Transmission Electron Microscopy (Cryo-TEM). The CD/DTAD mixtures were embedded in a thin layer of vitreous ice on freshly carbon-coated holey TEM grids by blotting the grids with filter paper and then were plugged into liquid nitrogen. Frozen hydrated specimens were imaged by an FEI Tecnai 20 electron microscope (LaB6) operated at 120 kV in low-dose mode. For each specimen area, the defocus was set to 1–2 µm. Images were recorded on Kodak SO 163 films and then digitized by a Nikon 9000 with a scanning step of 2000 dpi corresponding to 2.54 Å/pixel. Fourier Transform Infrared (FT-IR). FT-IR measurements were performed on Nicolet Magna IR 750 equipped with an infrared microspectrography (Thermo Scientific Co., USA). The CD/DTAD mixtures were frozen in liquid nitrogen and subsequently lyophilized for 48 h before FT-IR measurements. Assessment of Antibacterial Activity. The antimicrobial activity of DTAD, CD and CD/DTAD mixtures against E. coli was evaluated using traditional surface plating method.47 Certain concentrations of DTAD, CD or CD/DTAD mixtures were separately added into E. coli PBS solution with the concentration of about 2 × 107 CFU/ml, and the mixtures were incubated for 30 min at 37 °C. Next, the E. coli suspensions were serially diluted by 104-fold with PBS. 100 µL diluted E. coli was spread on the solid agar plate (LB) with 100 µg/mL ampicillin and then incubated for 14–16 h at 37 °C. All the experiments were performed in triplicate. The effects of DTAD, CD or CD/DTAD complexes on the bacteria were assessed by the reduction ratio of E. coli colonies. E. coli colonies on the agar plates were counted and the reduction ratio was calculated by [(A − B)/A] × 100%,48 where A is the mean number of E. coli col7



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onies in the control sample (without DTAD, CD or CD/DTAD complexes), and B is the mean number of E. coli after treated with the DTAD, CD or CD/DTAD complexes. The results were repeated three times. Solubilization of Zein by DTAD or CD/DTAD Mixtures. 5.0 mg/mL zein was separately added to DTAD or CD/DTAD mixed solutions at the DTAD concentration of 5.0 mM, and then the mixtures were stirred for 48 h. The undissolved zein was separated by centrifugation, and UV-vis absorbance of the supernatants was made at 25 °C with a Jasco UV-550 spectrophotometer. RESULTS AND DISCUSSION CD/DTAD Inclusion Complexes with Different Binding Ratios. Firstly, ITC was employed to investigate the association process of DTAD with three kinds of CDs. Figure 1 shows the variation of the observed enthalpy (∆Hobs) against the CD/DTAD molar ratios when α-, β- and γ-CD were separately titrated into 0.10 mM DTAD solution. The ITC curves are approximately sigmoidal in shape, and ∆Hobs values change gradually from exothermic value to zero, reaching the saturation of interaction between CD and DTAD. These ITC curves are analyzed by the model of single set of binding sites described in Supporting Information. The binding constant (Kb), the binding ratio (N), and the binding enthalpy (∆Hb) of CD with DTAD are obtained. Then the binding Gibbs free energy (∆Gb) is calculated from ∆Gb = −RTln(Kb), and the binding entropy change (∆Sb) is derived from T∆Sb = ∆Hb − ∆Gb. The obtained complexation parameters of CD with DTAD are listed in Table 1. As shown, α-CD forms 2 : 1 complexes with DTAD while β-CD and γ-CD form 1 : 1 complexes with DTAD, which is caused by the different cavity size of these three CDs and the resulting different steric hindrance effect. The binding constants of α-CD/DTAD, β-CD/DTAD and γ-CD/DTAD indicate that the binding ability of CD with DTAD is stronger than that with the corresponding monomeric surfactant,36,49,50 suggesting that the multiple chains promote the binding potential of DTAD with CD and the hydrogen bonds may be formed between the amide groups of the DTAD spacer and the hydroxyl groups on the rim of the CD cavity. This kind of hydrogen bonds was previously observed between lauryl sulfobetaine and β-CD.51 Considering 8


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the experimental and fitting errors, the binding constants for α-CD/DTAD, β-CD/DTAD and γCD/DTAD are close with each other. Additionally, the negative ∆Hb values indicate that the associations of three kinds of CDs with DTAD are all exothermic, while the entropy change (∆Sb) is different for the three CDs. Considering that ∆Hb is of large negative value while T∆Sb is of comparable positive value for α-CD, the complexation of α-CD with DTAD is an enthalpy–entropy double driven process. Given that T∆Sb ≈ 0 for β-CD and T∆Sb < 0 for γ-CD, the complexations of β-CD and γ-CD with DTAD are all enthalpy–driven. Therefore, the interaction mode of CDs with DTAD significantly depends on the types of CDs, which is similar to the inclusion behavior of didecyldimethylammonium bromide or didecyldimethylammonium chloride with different types of CDs.31,52 0

∆ Hobs (kJ/mol)

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-7 -14 -21

α-CD/DTAD β -CD/DTAD γ -CD/DTAD

-28 -35 0

1

2

3

4

5

nCD/nDTAD

Figure 1. The variation of observed enthalpy changes (∆Hobs) against CD/DTAD molar ratio by titrating 0.80 mM α-CD, 0.30 mM β-CD and 0.30 mM γ-CD into 0.10 mM DTAD solution, respectively. The dilution enthalpy of the CD solution has been deducted. Table 1. Thermodynamic Parameters of the Binding of CD with DTAD Derived from the ITC Curves in Figure 1.

α-CD/DTAD

2.0

Kb (105 M1 ) 1.73

-20.02

9.88

β-CD/DTAD

1.0

1.36

-29.04

0.27

-29.31

γ-CD/DTAD

0.93

1.57

-37.14

-7.49

-29.65

N

∆Hb (kJ/mol)

T∆Sb (kJ/mol)

∆Gb (kJ/mol) -29.82

9



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Figure 2. (a)–(c) 1H NMR spectra and proton assignments of CD/DTAD mixtures in D2O versus CD/DTAD concentration ratios, i.e., CD/DTAD mixing molar ratio (CDTAD = 0.10 mM). (d)–(f) The changes of chemical shifts (∆δ) of Ha or Hc in DTAD and molar fraction of complexed DTAD (xcDTAD) against the CD/DTAD concentration ratios. ROESY spectra and the scheme of the CD/DTAD complexes for (g) α-CD/DTAD mixture at the mixing molar ratio of 2 : 1, (h) α-CD/DTAD mixture at the mixing molar ratio of 6 : 1, (i) β-CD/DTAD mixture at the mixing ratio of 5 : 1, and (j) γ-CD/DTAD mixture at the mixing molar ratio of 5 : 1. Next, to determine the structures of CD/DTAD complexes formed in the three CD/DTAD mixtures, NMR and ESI-MS measurements were carried out. All the results are shown in Figure 2 and Figure S1 (Supporting Information). In Figure 2a–2c, with the addition of CDs into DTAD solution, all proton signals of the alkyl chain of DTAD shift toward downfield, indicating the inclusion of the alkyl chain into the hydrophobic cavity of CDs. Moreover, upon adding α-CD or β-CD into DTAD solution, the singlet peak of N-methyl groups (Hf) connected to two symmetric ammoniums of DTAD splits into a doublet, indicating that the Nmethyl groups (Hf) are in two different electronic environments. This suggests that both α-CD and β-CD are selectively threaded onto one of the symmetric alkyl chains of DTAD. In the case of γ-CD, the peak 10


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shape of the N-methyl groups (Hf) keeps unchanged, which means that γ-CD is threaded onto the asymmetric alkyl chain of DTAD. Furthermore, the variations in chemical shifts (∆δ) of the representative protons in the hydrocarbon chain of DTAD against the CD/DTAD ratios are shown in Figure 2d–2f for more clear observation. For the α-CD/DTAD mixture (Figure 2d), as the α-CD/DTAD mixing molar ratio (Cα-CD/CDTAD) increases from 0 : 1, ∆δ (Ha) of the methyl protons (Ha) in the alkyl chain end of DTAD gradually increases, and then reaches a flat between the mixing molar ratios of 2 : 1 and 3 : 1. Beyond the α-CD/DTAD mixing ratio of 3 : 1, ∆δ (Ha) continuously increases until it reaches the mixing ratio of 6 : 1, and afterwards keeps constant. The two plateaus mean that two types of α-CD/DTAD complexes form with varying the α-CD/DTAD mixing ratio. Given that the binding ratio of α-CD with DTAD is 2 : 1 from the ITC results, the two types of α-CD/DTAD complexes are probably α-CD@DTAD and 2α-CD@DTAD. The ESI-MS peaks of the α-CD/DTAD mixture at Cα-CD/CDTAD = 2 show the presence of [αCD@DTAD]3+ (m/z = 612.72803, theoretical value m/z = 612.72435) (Figure S1a), and the mixture at Cα-CD/CDTAD = 6 : 1 shows the existence of [2α-CD@DTAD]3+ (m/z = 937.16640, theoretical value m/z = 937.16445) (Figure S1b). Thus, when Cα-CD/CDTAD ≤ 3, the complexes formed are mainly αCD@DTAD, but the DTAD molecules are nearly completely complexed into α-CD@DTAD only at 2 ≤ Cα-CD/CDTAD ≤ 3 (Figure 2d). When Cα-CD/CDTAD is beyond 3, the α-CD/DTAD complexes start to transform into the 2α-CD@DTAD complexes, and all the complexes exist as 2α-CD@DTAD at Cα-CD/CDTAD ≥ 6 (Figure 2d). Additionally, the α-CD molecules present a truncated cone rather than a perfect cylinder, where the wider rim of the cone is usually called “head” while the narrower rim is “tail”.53 The proton H3 of CD is close to its wider head while H5 and H6 are in the narrower tail, and all these protons are located in the interior cavity of CD.54 To determine the mutual direction of α-CD and DTAD, ROESY technique was used. For the α-CD@DTAD complexes at the mixing molar ratio of 2 : 1, the cross-peak exists between H5 located on the narrower tail of α-CD and Hb in the tail of the alkyl chain of DTAD 11



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(Figure 2g), indicating that one of the symmetric hydrocarbon chains of DTAD is preferably included into the cavity of α-CD from the wider rim of α-CD (see the schematic illustration in Figure 2g). For the 2α-CD@DTAD complexes at the mixing molar ratio of 6 : 1, the cross-peaks exist in the proton pairs of H5-Ha and H5-Hc. This suggests that two α-CD molecules are aligned in a head-to-head fashion to maximize the formation of hydrogen bonds as illustrated in the scheme of Figure 2h. For both the β-CD/DTAD and the γ-CD/DTAD mixtures, the situations are similar but they are different from that of the α-CD/DTAD mixture. Upon increasing the β-CD/DTAD or γ-CD/DTAD mixing molar ratio, ∆δ (Hc) of the methylene protons (Hc) of the alkyl chain of DTAD in β-CD/DTAD mixture or ∆δ (Ha) of the methyl protons (Ha) of the alkyl chain of DTAD in γ-CD/DTAD mixture gradually increases until it reaches a maximum at the mixing molar ratio of 5 : 1, and afterwards almost keeps unchanged (Figure 2e and 2f). The ESI-MS spectra show the presence of [β-CD@DTAD]3+ (m/z = 667.07651, theoretical value m/z = 667.07641) at the β-CD/DTAD mixing ratio of 5 : 1 (Figure S1c), and [γ-CD@DTAD]3+ (m/z = 721.09447, theoretical value m/z = 721.09402) at the same ratio (Figure S1d). So the complexes formed in both β-CD/DTAD and γ-CD/DTAD mixtures are mainly in the form of β-CD@DTAD and γ-CD@DTAD, which is consistent with their binding ratio of 1 : 1 determined by ITC. Only at Cβ-CD/CDTAD ≥ 5 and Cγ-CD/CDTAD ≥ 5, the DTAD molecules can be completely complexed by β-CD and γ-CD (Figure 2e and 2f). In addition, similar to α-CD@DTAD complexes, the cross-peaks of H5-Hb, H6-Hb, H6-Ha and H3-Hc (Figure 2i) reveal that β-CD is also preferably threaded onto one of the symmetric hydrocarbon chains of DTAD from its wider rim. For the γ-CD/DTAD complexes, the NMR cross-peaks of H6-Hb and H6-Ha shows that γ-CD is threaded onto the asymmetric alkyl chain of DTAD from its wider rim (Figure 2j). In general, upon changing the type of CDs, CD/DTAD mixtures form the inclusion complexes with different host-guest ratios and interaction modes, i.e. α-CD@DTAD, 2α-CD@DTAD, β-CD@DTAD

12


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and γ-CD@DTAD. These different complexes will show distinct aggregation behaviors as discussed in the following text. Critical Aggregation Concentrations and Critical Aggregate Transition Concentrations (CACs) of CD/DTAD Mixtures. The formation of the inclusion complexes between CDs and DTAD is expected to alter the aggregation behavior of DTAD. According to the results above, the α-CD/DTAD mixtures at mixing molar ratios of 2 : 1 and 6 : 1, and the β-CD/DTAD mixture and the γ-CD/DTAD mixture at mixing molar ratio of 5 : 1 are chosen to be studied. At these mixing ratios, the three systems reach relative equilibrium states as shown in Figure 2d–2f. Figure 3 shows the surface tension and molar conductivity curves of these CD/DTAD mixtures, and the CAC values are determined from the clear breakpoints of and summarized in Table 2. The zeta potential values of the corresponding mixtures are also included in Figure 3. As to DTAD without CDs, the CAC, defined as C0, is 0.21 mM, taking the average of 0.20 or 0.22 mM obtained from the surface tension and molar conductivity curve, respectively. The zeta potential indicates that the DTAD aggregates carry a very large positive charge density and the charge density slightly decreases with the increase of the DTAD concentration. With the additions of α-, β- and γ-CDs, the aggregation behavior of DTAD exhibits significant changes as discussed below.

Table 2. CAC and Aggregation Ionization Degree (α) of CD/DTAD Complexes in Aqueous Solution at 25.0 °C. DTAD α-CD : DTAD = 2 : 1

α-CD : DTAD = 6 : 1 β-CD : DTAD = 5 : 1

γ-CD : DTAD = 5 : 1

C0 C1 C2 C3 C1 C2 C1 C2 C3 C1 C2 C3

CAC (mM) Surface Tension Conductivity 0.20 0.22 — 0.0074 — 0.045 0.25 0.13 — 0.0061 0.22 0.14 — 0.010 — 0.040 0.22 0.14 — 0.010 0.15 0.10 0.31 0.28

α 0.63 0.98 0.94 1.1 1.0 1.1 0.93 0.89 1.1 0.90 0.89 0.97

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ACS Applied Materials & Interfaces 70

C0

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0.01

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100 80

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60 40 20 0 0.01

CDTAD(mM)

0.1

1

10

CDTAD(mM)

Figure 3. Variations of surface tension γ versus the DTAD concentration CDTAD, molar conductivity Ʌ against CDTAD0.5, and ζ potential against CDTAD for (a) α-CD/DTAD mixture (column a), (b) β-CD/DTAD mixture (column b), and (c) γ-CD/DTAD mixture (column c) at 25.0 °C.

For the α-CD/DTAD mixture at the mixing molar ratio of 2 : 1, at which DTAD is completely complexed into α-CD@DTAD, the breakpoint in the surface tension curve is 0.25 mM, while three breakpoints at 0.0074, 0.045 and 0.13 mM are found in the molar conductivity Ʌ-CDTAD0.5 curve (Figure 3a). The third inflection point on the Ʌ-CDTAD0.5 curve is close to the CAC value obtained by the surface tension curve considering the experimental error. So it is concluded that α-CD@DTAD complexes display three critical concentrations, defined as C1, C2 and C3. That is to say, the α-CD@DTAD complexes form aggregates beyond C1, and then experience two aggregate transitions at C2 and C3. Moreover, the surface tension does not become constant even beyond the C3 and still decreases significantly (Figure 3a), indicating that the aggregates may still keep changing. The former two critical points C1 and C2 are not found in the surface tension curve, probably because the concentrations are too low, where the surface tension values are close to that of pure water. Compared to the CAC value of DTAD, α-CD@DTAD complexes show much lower CAC. This may be attributed to the hydrogen bonds between the hydroxyl groups of α-CD and the weakened electrostatic repulsion between the headgroups of the α-CD@DTAD 14


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complexes, as proved by the obviously decreased ζ potential (Figure 3a). However, the surface tension value of α-CD@DTAD is larger than that of DTAD due to the reduction in the number of the hydrocarbon chains. In addition, the values of the aggregation ionization degree (α) of three aggregation processes characterized by C1, C2 and C3 can be estimated from the electrical conductivity curve (Figure S2), which are calculated by α1 = (dκ/dC)C1 α-CD@DTAD > γCD@DTAD > β-CD@DTAD > 2α-CD@DTAD, which is consistent with their different solubilization ability to zein (Figure 7). Weak ability in solubilizing zein and weak interaction with zein are supposed to mean weak skin irritation, thus it can be concluded that the addition of CDs improves the mildness of DTAD, and the mildness decreases in the order of 2α-CD@DTAD > β-CD@DTAD > γ-CD@DTAD > α-CD@DTAD > DTAD.

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Considering that all the CD/DTAD complexes carry the same number of hydrocarbon chains and similar cationic charge density, the obvious differences among the interaction of these CD/DTAD complexes with zein are proposed to rely on their different aggregate structures. As proved by the DLS and cryoTEM results (Figure 4), above C1, all the CD/DTAD complexes form larger aggregates with the similar size (~50 nm), which is in favor of their mildness due to the large steric repulsion between the large aggregates and zein. But the detailed situations of these complexes are different. The 2α-CD@DTAD complexes form the vesicles with a closed bilayer and an entrapped water compartment. Besides the hollow vesicles, the β-CD@DTAD and γ-CD@DTAD complexes self-assemble into solid spheres with a loose packing structure through hydrophobic interaction among a large number of molecules. As to the α-CD@DTAD complexes, only solid spherical structures are formed. When the size of the aggregates is similar, the solid spherical structures possess much more hydrophobic domains compared to the vesicles. As a consequence, zein is more easily solubilized in spherical structures due to the strong hydrophobic interaction of the hydrophobic domains of spherical structures with the hydrophobic moiety of zein. Thus, the α-CD@DTAD complex with the solid spherical structure exhibits the strongest capability in solubilizing zein, while 2α-CD@DTAD complex with hollow vesicles is the weakest. The βCD@DTAD and γ-CD@DTAD complexes are in between them. Compared with the γ-CD@DTAD complex, β-CD@DTAD complex forms vesicles at lower C2, thus displays the weaker ability in solubilizing zein. In addition, according to the literature,29 the toxicity of surfactants is correlated with their surface tension values, where the toxicity decreases as the surface tension values increases. For these CD/DTAD complexes, their surface tension values decrease in the order of 2α-CD@DTAD > βCD@DTAD > γ-CD@DTAD > α-CD@DTAD just beyond the critical points of the surface tension curves. The surface tension difference may also affect the interactions of these CD/DTAD complexes with zein.

25



∆ Hobs (kJ/mol)

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2 γ-CD@DTAD

1 β-CD@DTAD 2α-CD@DTAD

0

Figure 8. (a) The variation of observed enthalpy changes (∆Hobs) against the DTAD concentration (CDTAD) by titrating 10 mM DTAD or CD/DTAD complexes into 5.0 mg zein/water solution, respectively (The Raw data are shown in Figure S5). ∆Hobs values are expressed in kJ/mol of surfactant. The dilution enthalpy of DTAD or CD/DTAD complexes has been deducted. (b) The binding constants (Kb) of the interaction of DTAD or CD/DTAD complexes with zein.

CONCLUSION In summary, α-CD, β-CD and γ-CD have been used to form complexes with a star-shaped cationic trimeric surfactant DTAD, and alter the aggregation behavior and the mildness of this surfactant while maintaining its high antibacterial activity. Upon adding CDs with different cavity size, the αCD@DTAD, 2α-CD@DTAD, β-CD@DTAD and γ-CD@DTAD complexes are fabricated. Compared to DTAD itself, these CD/DTAD complexes show much lower critical aggregation concentrations, and form more diverse aggregate structures with varying the concentration, larger vesicles or spherical solid aggregates of ~50 nm first, and then smaller micelles of ~10 nm. The aggregate transitions are controlled by the discrepancy in the intensity of hydrogen bonds and the hydrophobic interaction, and the changes of molecular configuration. Despite the decrease in the cationic charge density and the number of hydrophobic chains, these CD/DTAD complexes are still highly active against Gram-negative E. coli.

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Their minimal inhibitory concentration (MIC) values are 2.22−2.48 µM, whose activity is comparable to that of DTAD. This result is caused by the following reasons. On one hand, the incorporation of CDs significantly improves the self-assembling abilities of the CD/DTAD complexes, and the formation of self-assemblies makes them strongly interact with the cell membrane. On another hand, the hydrogen bonds of the hydroxyl groups of CDs with E. coli may synergistically act with the electrostatic interaction between cationic ammonium of DTAD and the negatively charged bacterial surface of E. coli, allowing the CD/DTAD complexes to efficiently target the surface of E. coli. In particular, the aggregates of these CD/DTAD complexes exhibit much weaker ability in solubilizing zein and in interacting with zein than DTAD. The stronger self-assembling abilities of the CD/DTAD complexes reduce the monomer concentration in solution, and they form large aggregates just beyond the CACs, enhancing the steric repulsion of the complexes to zein backbone. Meanwhile, the decreased hydrophobic chain numbers and reduced surface charge density weaken the hydrophobic interaction and electrostatic attraction of the CD/DTAD complexes with zein. These features of the CD/DTAD complexes endow them with better mildness than DTAD, and the mildness of the CD/DATD complexes decreases in the order of 2αCD@DTAD > β-CD@DTAD > γ-CD@DTAD > α-CD@DTAD. It is also found that the formation of vesicles is in favor of the improvement of the mildness. These studies provide a simple and effective way to improve the mildness of oligomeric surfactants without sacrificing their high antibacterial activity. The approach may be also useful in improving biocompatibility of other antibacterial agents or drugs. ASSOCIATED CONTENT Supporting Information The ITC analysis process, ESI-MS spectra and conductivity curves of CD/DTAD mixtures, calculation of the size of the CD@DTAD complexes and the ITC raw data and the observed enthalpy curves of DTAD or CD/DTAD mixtures being titrated into zein or water. This material is available free of charge via the Internet at http://pubs.acs.org 27



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AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Note The authors declare no competing financial interest. ACKNOWLEDGMENT This work was supported by the Chinese Academy of Sciences and National Natural Science Foundation of China (21025313, 21321063) REFERENCES (1) Luk, Y.-Y.; Abbott, N. L. Applications of Functional Surfactants. Curr. Opin. Colloid Interface Sci. 2002, 7, 267-275. (2) Shi, L.; Miller, C.; Caldwell, K. D.; Valint, P. Effects of Mucin Addition on the Stability of Oil– Water Emulsions. Colloids Surf., B 1999, 15, 303-312. (3) Kitamoto, D.; Morita, T.; Fukuoka, T.; Konishi, M.-a.; Imura, T. Self-Assembling Properties of Glycolipid Biosurfactants and Their Potential Applications. Curr. Opin. Colloid Interface Sci. 2009, 14, 315-328. (4) McGregor, C.; Perrin, C.; Monck, M.; Camilleri, P.; Kirby, A. J. Rational Approaches to the Design of Cationic Gemini Surfactants for Gene Delivery. J. Am. Chem. Soc. 2001, 123, 6215-6220.

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