Natural Polyphenol Surfactants: Solvent-Mediated Spherical Nano

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Natural Polyphenol Surfactants: Solvent-Mediated Spherical Nanocontainers and Its Stimuli-Responsive Release of Molecular Payloads Debabrata Payra, Yoshihiro Yamauchi, Sadaki Samitsu, and Masanobu Naito Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.8b03741 • Publication Date (Web): 15 Oct 2018 Downloaded from http://pubs.acs.org on October 15, 2018

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Chemistry of Materials

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Chemistry of Materials 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Natural Polyphenol Surfactants: Solvent-Mediated Spherical Nanocontainers and Its Stimuli-Responsive Release of Molecular Payloads Debabrata Payra,*1 Yoshihiro Yamauchi,1 Sadaki Samitsu,2 and Masanobu Naito*2 1

International Center for Young Scientists (ICYS), National Institute for Materials Science (NIMS), 1-2-1 Sengen, Tsukuba, Ibaraki 305-0047, Japan. 2 Data-driven Polymer Design Group, Research and Services Divison of Materials Data and Integrated System (MaDIS), National Institute for Materials Science (NIMS), 1-2-1 Sengen, Tsukuba, Ibaraki 305-0047, Japan. ABSTRACT: The self-assembly of amphiphilic building blocks represents an elegant strategy to produce (nano)structures with unique functionalities and often investigated for wide-range applications in biology and materials science. Herein, we report micron- to nanoscale vesicular assembly made of naturally abundant dendritic polyphenols, tannic acid (TA). Rich contents in several plant parts, non-toxic and inherent ability of diverse molecular interactions including H-bonding, π-π interactions, and metal coordination make such polyphenols promising class of natural building blocks for supramolecular assembly and precursor of natural surfactants. The facile modification of hydrophilic TA by introducing n-alkyl chains produced TA-based multi-arm surfactants, which facilitates molecular assembly in water. Systematic manipulations of processing parameters including amphiphile concentration, cosolvent ratio and mixing rate enabled to achieve well-defined and size-tunable spherical vesicles in the range of 0.1 to 1.0 µm, which was enclosed by a molecularly thin periphery of ca. 3-5 nm. Further, both hydrophilic and hydrophobic guest molecules could be encapsulated noncovalently into the vesicle, implying presence of hydrophilic interior and hydrophobic alkyl-chaindominated periphery in such vesicular assembly. Next, controlled disassembly of such vesicles was thoroughly examined and demonstrated high potential as nanocarriers of guest molecules. Moreover, presence of non-substituted aromatic hydroxyls due to partial modification of polyphenols offered radical scavenging or antioxidant properties of the vesicles. Present report heralds a new direction of utilizing chemically modified low-cost TA as diverse supramolecular tectons, nanocarriers, and functional natural additives in wide-range practical applications.

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INTRODUCTION

The molecular assembly of amphiphilic building blocks into a well-defined (nano)structures and functions is prevalent in numerous natural systems and synthetic manipulations.1-10 Extensive efforts have been pursued over last few decades to understand the role of molecular architecture, shape/size tunable assemblies, controlled functionality, and recognize potential uses in drug delivery, catalysis, smart interfaces, bioimaging and sensing.11-14 Hence, a myriad of natural and synthetic amphiphiles have been investigated including polymers, liposomes, dendrimers, macrocycles and continue to have significant interest ranging from biology to materials.11,15-17 In particular, surfactants based on natural resources are gaining interest due to ever-increasing environmental concern. Whereas, conventional natural surfactants based on sugars, amino acids, and lipids have been investigated widely,18-20 plant polyphenols such as epicatechin gallate (ECG), epigallocatechin gallate (EGCG), or tannic acid (TA) have recently been received more attention as precursor abundant in nature.21-23 In this report, we describe a facile chemical modification of multi-arm polyphenol TA to produce a new class of natural surfactants and solvent-mediated spherical assembly in water (Figure 1). Tannic acid is a non-toxic, hydrosoluble polyphenol and well-known to exhibit several interesting properties such as antimicrobial, radical scavenging, and metal complexation.23 Moreover, presence of excess dihydroxyphenyl (cate-

chol) and trihydroxyphenyl (pyrogallol) moieties offers a rich and versatile physical and chemical manipulations including multivalent coordination, H-bonding, π-π stacking, and also functionalization of aromatic hydroxyls. From structural viewpoint, TA can be considered as a multi-arm macromolecule of pyrogallol moieties attached to a multivalent glucose unit by ester linkages. Note that, such hyperbranched or dendritic macromolecules exhibit multiple benefits as surfactants including low polydispersity, very stable assemblies, generation-dependent molecular tuning, facile functionalization, and multivalent interactions with biological/synthetic systems.24-27 Thus, TA or related polyphenols hold high potential as molecular building blocks for supramolecular aggregation or creation of multi-functional nano-/microstructures. Three major approaches exist to exploit such polyphenols as supramolecular tectons. First one exploits metal-coordination induced rapid assembly and convenient for multi-dimensional inorganic, organic, and biological particle templates.28-30 Second one utilizes supramolecular interactions such as H-bonding, π-π stacking, or electrostatic mediated layer-by-layer (LBL) assembly, which has been investigated by several groups.31-33 The last one is oxidative coupling induced aggregation of plant polyphenols in the presence of Cu2+/ Ag+ and temperature/ microwave.34,35 These approaches have demonstrated versatile applications by employing such assemblies of lowcost polyphenols including permeable/ degradable thin-film and capsules, biomedical applications, multifunctional


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Chemistry of Materials §

Figure 1. (a) Chemical structure of dendritic plant polyphenol, tannic acid (TA) with background image of Chinese gallnuts, a natural source of TA. (b) Synthetic route to partially n-alkyl substituted tannic acid (PATA) consists of a hydrophilic core and hydrophobic rim.

(nano)composites, among others.28-35 However, in general, most of these studies are template-based, multi-component aggregation and thus lack of understanding or tuning selfassembly process particularly in molecular level which may provide better design to target (nano)structures. Herein, we present self-assembly of TA based surfactants by an easy and rational molecular tuning. Interestingly, TA itself can be considered as an amphiphilic molecule having excess of hydrophobic (aromatic) and hydrophilic (polyhydroxyls) segments. However, TA alone does not produce welldefined assembly and often reported to aggregate in a random manner by strong intermolecular interactions.36,37 Two other factors can also be accounted to this phenomenon that a suitable hydrophobic-to-hydrophilic ratio and specific topology of an amphiphilic molecule play a vital role to govern the overall assembly process. Nonetheless, we envisioned TA as a potential building block owing to several structural and chemical features similar or expected in a multi-arm amphiphiles. For example, presence of aromatic units has been reported to drastically enhance the stability of such assemblies and indeed TA contains these segments in excess.26,38 On the other hand, degradation of TA by enzyme or light source is another interesting feature which could be beneficial for controlled disassembly process.39,40 Moreover, aromatic polyhydroxyls provide a platform to introduce desired functional groups and multivalent binding ability to external ions/ biomolecules. Results described herein demonstrate that the partial hydrophobization by saturated alkyl chains (PATA) enable to achieve welldefined spherical assembly in water by cosolvent mixing method. A systematic investigation by means of dynamic light scattering (DLS), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and small-angle Xray scattering (SAXS) revealed spherical assembly of PATA molecules enclosed by a molecularly thin (~3-5 nm) membrane akin to natural liposome vesicles.41,42 The stability of resulted polyphenol vesicles was revealed to be very good under physiological, thermal, and mechanical conditions. Further, encapsulation of both hydrophilic and hydrophobic guest molecules during self-assembly process was confirmed by ultraviolet-visible and fluorescence spectroscopy. Finally, disassembly of PATA vesicles and controlled release of loaded cargo molecules have been demonstrated in the presence of several chemical stimuli including surfactants, amines, or others.

EXPERIMENTAL SECTION

Materials: Synthetic manipulations were carried out under argon atmosphere employing standard Schlenk technique. Ultrapure water (resistivity=18.2 MΩ, pH = 6.8) used in all experiments and was obtained from a Millipore system. Tannic acid (TA) and potassium carbonate (K2CO3) was purchased from Wako chemicals and used as received. Alkyl (n-hexyl, n-decyl, and n-hexadecyl) iodides were purchased from Tokyo Chemical Industry Co. Ltd (TCI). Perylene, pyrene and rhodamine B (RB) dye was purchased from WAKO chemicals. Cetyltrimethyl ammonium bromide (CTAB), sodium dodecyl sulfate (SDS), Tween 40, Triton X-100, alkyl amines, aniline, methoxypolyethylene glycol amine (Mw 5000 Da), 1-hexanol and other common chemicals and solvents were purchased from commercial sources and used without further purification. Stable radical 2,2diphenyl-1-picrylhydrazyl (DPPH) was purchased from TCI and used as received. General Procedure for Self-Assembly of PATA in water: A specific amount of PATA was dissolved in tetrahydrofuran (THF) and filtered through a membrane filter (0.2 µm). The solution was placed in a beaker and excess amount of water was added by a dropping funnel to this solution under magnetic stirring. Immediately, a turbid solution was observed and allowed to stir for several hours in laboratory conditions. Finally, the solution was filtered by common gravity filtration technique to remove dust particles. Hydrophilic/hydrophobic guest encapsulation: For hydrophilic guest encapsulation, aqueous rhodamine B (RB) solution (5 µM) was added to the PATA solution in THF and allowed to encapsulate during self-assembly process. After several hours, small portion of water was mixed to maintain a fixed concentration of dye and dialysed against pure water using 12-14 kDa membrane tubing (Fisherbrand) for 24 h. For hydrophobic guests, specific amount of perylene or pyrene was added to the PATA solution in THF and encapsulation was performed in the same manner with RB. Disassembly studies: Release of guest molecules was monitored by time-dependent emission spectra after employing external stimuli. Release of hydrophilic RB and hydrophobic pyrene were respectively monitored by increase in emission intensity at 581 nm and decrease in emission intensity at 375 nm. Releasing efficiency of hydrophobic guests is calculated by I0-I/ I0 × 100, where I0 is initial emission intensity and I indicate intensity after addition of stimuli. Characterization methods and instrumentations: Dynamic light scattering (DLS): DLS measurements were carried out on a DLS 8000HAL (Otsuka electronics) instrument equipped with an ALV-SP compact goniometer, an ALV 5000 cross-correlator, and HeNe laser (λ = 632.8 nm). All measurements were performed in a cylindrical scattering cell (d = 10 mm) at a fixed angle of 90° and at 25 °C. Hydrodynamic diameter (Dh) was calculated using the StokesEinstein equation assuming spherical assembly. Zeta potential (ζ): Zeta potential was studied on an ELSZ-1000Z (Otsuka electronics) using a standard flow cell at 25 °C. UV-visible spectroscopy: UV-vis spectra were recorded on a JASCO (V-600) spectrometer. Scanning electron microscopy (SEM): Glass substrate (7 x 7 mm2) was used for this study. Substrates were cleaned thoroughly by sonication in ethanol, n-hexane, and acetone for 3 minutes each. After drying in ambient condition, substrate was further plasma treated for 2 minutes. Finally, about 50 µl of aqueous solution was drop-casted under ambient conditions. Samples were Pt coated for 30 s in all cases just before observation by a Hitachi SU8000 instrument operating at an acceleration voltage of 1.0-1.5 kV. Transmission electron microscopy (TEM): Carbon coated copper grid (200 mesh) substrate was used for this study. Substrate was plasma treated for 2 minutes before drop-casting a small amount (10 µl) of solution under ambient conditions. Bright field TEM images were recorded on a JEOL (JEM-1010) machine operating at an accelerating voltage of 100 kV and without staining of the samples. Small-angle X-ray scattering (SAXS): For this measurement, assembly solution was concentrated by removing most of the solvent under reduced pressure to a final concentration of ~10 mg ml1. SAXS measurements were performed in a standard capillary cell for liquid sample on Anton-Paar (SAXSess mc2) instrument equipped with a copper K-alpha source. Molecular structure analysis: Molecu-



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lar mechanics were performed with universal force field (UFF) in Avogadro computer program.43 Fluorescence emission spectra: Emission spectra were recorded on a JASCO (FP-6600) fluorimeter.

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RESULTS AND DISCUSSION

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Formation and Characterization of PATA Assembly: The synthesis of partially n-alkyl substituted tannic acid (PATA) was carried out by one-pot chemical modification, following a reported method by our group.37 The degree of substitution on each TA molecule can be varied in between 125 due to aromatic hydroxyls contributed from both catechol and pyrogallol subunits (Figure 1). However, controlled synthesis and characterization with particular number of alkyl substitutions is difficult due to the presence of multiple polyphenolic components in such commercially available TA. Nonetheless, in the present study we mainly focused on decasubstituted hexadecyl-modified TA, TA(C16)10 unless otherwise mentioned and the substitution number is based on feeding molar ratio between TA and n-alkyl units. Meanwhile, the reason behind selecting deca-substitution is owing to good balance between hydrophobic and hydrophilic segments suitable for systematic study on self-assembly process, which was preliminarily observed during our previous study.37 The PATA molecules are insoluble in water but readily dissolved in THF, resulting in a transparent solution. When water was added to the THF solution, instant assembly of PATA molecules was detected by Tyndall effect (Figure 2a). Eventual evaporation of THF by exposing the bulk solution to laboratory atmosphere for about 24 h produced an opaque solution of PATA assembly in pure water (Figure S1). We further performed a series of dynamic light scattering (DLS) measurements on the evaporation process to unveil aggregation behavior and size distribution quantitatively. At an early stage of the evaporation, size distribution was relatively broad and the peak hydrodynamic diameter (Dh) is slightly large suggesting swollen hydrophobic fatty segments due to the presence of THF (Figure S2a). After 10 h exposure, DLS measurement exhibited a unimodal distribution of Dh in the range of 150 ± 30 nm (Figure 2b). Further, surface charge density of PATA aggregates was measured as ζ-potential close to -54 mV (Figure 2c). This high negative potential can be attributed to the presence of unsubstituted aromatic hydroxyls of TA on the outer surface,28,31,34 facilitating good dispersion stability of PATA assembly. Direct observation of the self-assembled structure of PATA molecules was performed after solvent evaporation in ambient conditions and high vacuum by employing scanning electron microscopy (SEM), and transmission electron microscopy (TEM). As shown in figure 2d, SEM study clearly revealed spherical morphology of PATA with approximate size in well agreement by DLS observation. Next, we performed TEM studies to obtain additional information about the nature of PATA assemblies after drying about 20 µl solution on a copper grid by slow evaporation of solvent under ambient conditions. Spherical morphology of about 300 nm was confirmed as shown in figure 3a, and a careful observation indicated clear contrast between (semi)transparent interior and darker periphery, which is consistent with a typical vesicular structure.44 The thickness of such periphery was estimated to be ~5 nm for TA(C16)10 from their TEM images (Figure 3a and S8). However, little variation of vesicle size was noticed in some cases possibly due to the flattening during solvent stripping

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Figure 2. (a) The comparison of Tyndall effect for PATA in good solvent (THF) and assembly in water. (b) Aggregation size distribution of PATA in water by dynamic light scattering (DLS) measurement. (c) Zeta potential distribution of assembly in distilled water (pH = 6.8). (d) Scanning electron microscopy (SEM) image of PATA assembly after drop-casting on a glass substrate.

process but partial or complete collapse was rarely observed indicating mechanically robust nature of the vesicle wall. Further, to gain more insight and verify TEM observations about molecular arrangements of discrete PATA molecules during self-assembly, small-angle X-ray scattering (SAXS) was carried out for PATA assembly in water. This study was performed for PATA assembly with different alkyl chain lengths (hexyl, decyl, and hexadecyl) and the final concentration was always adjusted to ~10 mg ml-1 to get sufficient scattering intensity. The SAXS profiles have been shown in figure 3b and interlayer distance (d) was calculated employing the equation d = 2 π / q, where q is scattering vector in nm-1. Considering hollow vesicular assembly, d is directly related to the wall thickness and indeed a significant change was observed with variation of alkyl chain length (Figure 3b). For example, d for TA(C16)10 (Figure 3b, blue line) and TA(C10)10 (Figure 3b, black line) was estimated to be ~5.2 nm and ~3.4 nm, respectively. Obviously, the molecular size of TA(C16)10 is bigger than TA(C10)10 for longer hexadecyl chains and led to longer interlayer distance. Nonetheless, SAXS measurements were consistent with TEM observation and provide valuable information to predict possible molecular orientation during selfassembly process. Finally, the optimized molecular structure of PATA molecules were determined by molecular mechanics to conclude our hypothesis regarding molecular arrangements during self-assembly process. The most stable molecular structures for different PATA molecules have been shown in figure S9 and average diameter was 3.5 nm, 4.3 nm, and 5.3 nm for TA(C6)10, TA(C10)10, TA(C16)10, respectively. Further, a careful observation reveals that vesicle wall thickness was close to or slightly shorter than extended molecular diameter. Considering hydrophilic environment on both sides of the wall typical for a vesicular assembly, it is more likely that PATA


Effects of Processing Parameters on PATA Assembly: Since self-assembly of such TA based dendritic amphiphiles have rarely been reported previously, we examined the effect of various processing parameters such as PATA concentration, volume ratio of co-solvents (water:THF), or rate of poor solvent addition. By varying PATA concentration, critical aggregation concentration (CAC) was estimated from the intersec-

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molecules adopt a folded state in aqueous media facing hydrophobic segments (alkyl substituted hydroxyls) inward the vesicle wall and hydrophilic units (unsubstituted hydroxyls) at outer-layer of membrane. Note that, we can expect such folding of PATA molecules in aqueous media possibly due to the conformational flexibility of individual arm connected to a small glucose core. For example, average distance from core to periphery for TA(C16)10 molecule is ~2.6 nm and the membrane thickness is about 5.2 nm indicating bilayer structure just like a natural liposome vesicles (Figure 3c and 3d).41,42 On the other hand, membrane thickness was ~3.4 nm for TA(C10)10 molecule slightly lower than twice of molecular radius (~2.1 nm) possibly due to interpenetrated or interdigitated bilayer assembly.7 Along with this, the formation of bilayer structure can also be rationalized with the estimation of critical packing parameter (Cpp = V/A.l, where V is the tail volume, A is the head area, and l is tail length).45-47 Although, there is slight variation of hydrophobic chain lengths but, considering multiple alkyl substitutions total area of tail sections is nearly same with the TA core (1/2 ≤ Cpp ≤ 1), which is known to exhibit bilayer structure like vesicle or lamellar. Nonetheless, together with TEM, SAXS, and molecular mechanics, we propose a bilayer or interdigitated bilayer membrane formation enclosed by an aqueous interior during water addition to the THF solutions of PATA.

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Figure 3. (a) Transmission electron microscopy (TEM) image of PATA vesicles on a copper grid obtained after drying under ambient conditions. (b) SAXS profiles of different PATA assembly in aqueous solution with final concentration of ca. 10 mg ml-1. For clarity, each profile is multiplied by an arbitrary intensity factor. (c) Geometrical structure of TA(C16)10 optimized by molecular mechanics. The average distance from core to periphery was ~2.5 nm for TA(C16)10 molecule. (d) Schematic depiction of vesicular assembly of PATA, showing possible arrangements of each molecular component.

tion of two distinct regimes in a concentration dependent transmittance (at 350 nm) plot as shown in figure 4a. The CAC for TA(C16)10 was determined to be ca. 0.20 mg ml-1 and the amount was slightly higher for shorter chain length (decyl or hexyl) in the range of 0.25-0.30 mg ml-1 (Figure 4a and S3). In this case, CAC was not influenced significantly with the variation of alkyl chain length in particular, when number of aliphatic substitution was identical (deca- for present study). Further, concentration above CAC exhibited to increase the aggregation size with broad dispersity accompanying unintentional partial precipitation (Figure 4b and S4). Next, we examined the role of initial volume ratio of cosolvents (water:THF) by rapid addition of water. Initial water content above 75 vol. % was found to be crucial for smaller aggregation (ca. 150 nm) with narrow size distribution while larger assembly was formed with less water content (below 66 vol. %) in the range of 1 ± 0.4 µm (Figure 4c and S2b). Further, we observed a gradual increase in average aggregation size and particle dispersity with slower addition rate of water. By changing addition rate of water, slow addition (ca. 2 ml min-1) of water led to particle size in the range of 650 ± 300 nm while an instant addition (ca. 600 ml min-1) produced well-defined aggregation close to 150 nm (Figure 4d). Along with the DLS studies, we verified SEM morphology of PATA assembly under aforementioned processing conditions. PATA concentration above CAC produced spherical assembly with larger size in the range of 500-900 nm (Figure S5). On the other hand, random aggregation was observed below CAC due to the insufficient number of surfactants to form a well-defined morphology. Further, initial volume ratio of water and THF was revealed

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Figure 4. (a) Critical aggregation concentration (CAC) of TA(C16)10 estimated from concentration-dependent optical transmittance at 298 K. (b) Comparison of DLS profiles with variation of initial PATA concentrations in good solvent (THF). (c) Role of initial water content (vol. %) in tuning average aggregation size and distribution, observed by DLS measurements. (d) Effect of water addition rate in PATA solution of THF to control average aggregation size and distribution. In this case, amphiphile concentration was fixed at CAC (0.2 mg ml-1) and initial water content at 91 vol. %.


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to have significant influence in assembly formation (Figure S6). In general, initial water content below 66 vol.% produced giant particles with random aggregation in a wide range of 110 µm (Figure S6a). On the other hand, very uniform spherical assembly of ca. 150-200 nm was obtained when initial water content was above 75 vol.% (Figure S6b). We can expect such significant role of water, as it drives aggregation of hydrophobic alkyl segments, generates an interfacial tension and eventually led to a particular morphology. We believe, water content above 75 vol.% generates effective interaction energy to form spherical assembly both rapid and well-defined manner. Whereas, water content below 66 vol.% is not sufficient to propel the assembly instantly, which causes bigger and random aggregation due to the slow assembling process or fusion of smaller aggregates during evaporation of THF. Next, we investigated effect of water addition rate on vesicle size and observed a significant size variation, which supports our DLS observation (Figure 5). The PATA vesicle size was ca. 750 nm, 360 nm, 275 nm, and 175 nm for water addition rate of 2, 12, 45, and 600 ml min-1, respectively (Figure 5 and S7). Here, we speculate that the shape of PATA assembly is mainly governed by the fundamental molecular architecture, whereas size depends more on nonequilibrium aspects of the formation process like cosolvent ratio, addition rate of poor solvent, evaporation rate of good solvent, or others. Further, we envisage that a wide variety of (nano)structures of TA building blocks could be ensued by subtle manipulations of various parameters including degree of TA substitution, different cosolvent combinations, and self-assembly method (direct mixing, liquid-liquid interface, vapor diffusion etc.) in future studies.48 Guest Encapsulation Ability and Stability of PATA Vesicles: The noncovalent guest encapsulation by supramolecular nanostructures and stimuli-responsive release is important for diverse applications such as drug delivery, biosensors, and catalysis.49-52 Thus, we explored such properties of PATA

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vesicles regarding both hydrophilic and hydrophobic guests in aqueous environment. Encapsulation of a hydrophilic guest rhodamine B (RB) was examined by adding dye solution (5 µM) to the PATA solution in THF, followed by removal of free RB by dialysis for 24 h. The RB molecules were successfully encapsulated during self-assembly process, which caused an absorption peak shifted to longer wavelength and emission intensity significantly quenched due to the confinement effect of free dye molecules inside such nano-container (Figure 6a).4, 53 Similarly to a hydrophilic RB, hydrophobic small molecule perylene was encapsulated in PATA vesicle, which was verified by characteristic emission spectrum of perylene observed only with PATA assembly (Figure 6b, blue line), and was absent in pure water and water containing tannic acid (Figure 6b, black and red line). These results are consistent with a vesicle structure because a hydrophobic environment exists inside PATA bilayer and hydrophilic interior is formed inside the vesicle. Easy-controlled size in the range of 0.1-1.0 µm and facile encapsulation ability of PATA vesicle indicates high potential as a nanocarrier of active substances (e.g. drugs, fragrances, and flavor additives). Good stability of such nanocarrier is desired to avoid unexpected release during transportation.54,55 Therefore, we investigated stability of guest-loaded PATA vesicle under several conditions simulating practical use including buffered solutions (pH 5.5, 7.4, or 9.0), sonication, and thermal treatment (Figure 6c and S10). The emission intensity of pyrene-loaded vesicles was monitored because release of pyrene to the aqueous environment decreases the emission intensity drastically as previously reported.56,57 There was no significant decrease of emission intensity indicating good stability of loaded vesicles. Minor change was observed because pH-induced (de)protonation or

Figure 6. (a) Absorption (red) and emission (blue) spectra of free rhodamine B (RB) dye and encapsulated dye in assembly represented by dashed line and solid line, respectively. Dye concentration was maintained at 5 µM for all cases. (b) Comparison of emission spectra using a hydrophobic guest (perylene, 2 µM) among only in water (red), tannic acid (black), and PATA assembly (blue). Inset drawings are guest encapsulated vesicle structure. Normalized emission intensity of pyrene-loaded PATA assembly under (c) different pH conditions, and (d) thermal treatment.


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thermal treatment of PATA molecules can affect the local environment of pyrene enriched periphery temporarily and consequently the emission intensity.58 While a pyrene loaded PATA solution exhibited about 29% decrease in emission intensity at 70 °C, the solution recovered almost same intensity, when it was allowed to cool down to room temperature (Figure 6d). Furthermore, no release of pyrene was confirmed against one-hour sonication (~40 kHz), indicating excellent mechanical stability of guest loaded PATA vesicles (Figure S10d). Controlled Release of Guest Molecules from PATA Vesicles: Next, we investigated controlled release of encapsulated guest molecules through disassembly process by external stimuli. Two types of stimuli can be used for such disassembly process; exogenous (light, temperature, magnetic/electric fields etc.) and endogenous stimuli (pH, redox potential, specific enzyme, proteins or analytes).59-66 In the present study, we focused binding induced disassembly due to the presence of unsubstituted aromatic hydroxyl (catechol) units in the outer-layer of PATA assembly, as confirmed by high negative ζpotential (Figure 2c). The overall process has been schematically depicted in figure 7a. Cetyltrimethyl ammonium bromide (CTAB) was chosen due to cationic head group, which is expected to interact with negatively charged PATA vesicle. When CTAB solution (ca. 200 µM) was injected to the RBloaded PATA vesicle solution, emission intensity gradually increased with elapsed time up to 25 h while no release was observed without stimuli (Figure 7b). The significant increase in emission intensity indicates release of dye molecules from vesicle interior to the bulk solution. Note that, CTAB amount was fixed much lower than critical micelle concentration (CMC, ~900 µM) intentionally, to avoid possible recapture of

Figure 7. (a) Schematic illustration of encapsulation process and controlled release of guest molecules in the presence of chemical stimuli. (b) The emission intensity change of RB-loaded (5 µM) PATA assembly after adding CTAB (200 µM) with different time intervals (λexcitation = 523 nm). Inset plot is time dependent release of RB molecules from PATA vesicle without stimuli (red) and with CTAB (black) by monitoring emission intensity at 580 nm. (c) Comparison of pyrene released from loaded vesicles in the presence of cationic (CTAB), anionic (SDS), and nonionic surfactants (Tween 40 and Triton X-100).

released guest molecules. In case of hydrophobic guests, emission intensity of pyrene loaded PATA vesicles gradually decreased by adding CTAB solution in the range of 10-200 µM concentration (Figure S11). After six hours, the releasing efficiency was estimated to be about 77% with 200 µM of CTAB (Figure 7c). In contrast with CTAB, anionic surfactant (SDS) and nonionic surfactants (Tween 40 and Triton X-100) did not change emission pattern significantly indicating no release of payloads (Figure 7c and S11). This result suggests nonionic or anionic surfactants cannot interact with PATA molecules and exhibit disassembly of PATA vesicles. On the other hand, cationic molecules can strongly interact with negative vesicle surface by dipolar interactions, which promotes disassembly of PATA vesicles. In fact, PATA molecules are associated in the vesicle by hydrophobic and alkyl-alkyl interactions (~50 kJ mol-1) which is much weaker than the dipolar interactions (~50-250 kJ mol-1).2 Therefore, interactions between ammonium group of CTAB and aromatic hydroxyls of PATA is strong enough to overcome the major driving force behind such assembly and gradually release encapsulated guests. This feature could be beneficial when time dependent release of payloads is necessary like in drug delivery. Considering the disassembly process by CTAB, we examined disassembly of pyrene-loaded vesicle in the presence of various amino derivatives including aliphatic primary, secondary, tertiary amines, aromatic amine, amine containing hydrophilic chain, and ammonium salt having short alkyl chains (Figure 8a). The aliphatic amines exhibited relatively high efficiency of 50-80%, in which n-hexyl amine was the best probably due to longest alkyl chain length (Figure 8a and S12). On the other hand, aromatic amine (aniline) resulted in releasing efficiency lower than aliphatic amines investigated

Figure 8. (a) Comparison of pyrene released from loaded vesicles (10-5 M) after 6 h addition time and various amount of chemical stimuli. List of chemicals used in this investigation have also been shown in the right panel. Comparison of TEM images of (b) an unloaded vesicle, (c) hydrophilic dye RB loaded vesicle, and (d) partially disassembled vesicle in the presence of CTAB. Unloaded vesicle was completely transparent but interior became intensely dark for RB loaded vesicle. Further, partial collapse of vesicle wall was observed as indicated by arrows during disassembly process.


Chemistry of Materials due to the absence of alkyl chain. Further, amine attached to a hydrophilic polymer (methoxypolyethylene glycol amine) gave releasing efficiency less than 18%, indicating no ability to promote disassembly event (Figure 8a, S13). The results indicate importance of aliphatic side chains in the disassembly event. In contrast with aliphatic amines, aliphatic alcohol (1hexanol) showed releasing efficiency less than 10%, which again confirms the critical role of amine functionality to interact with vesicle wall in the disassembly process (Figure 8a, S13). Further, we confirmed the hydrophilic guest loading and disassembly event by TEM observation. The unloaded vesicle is transparent but interior becomes completely dark after RB dye loading. Moreover, partial or complete disruption of vesicle wall and release of RB dye molecules outside membrane was observed after adding suitable amount of CTAB (Figure 8b-d and S14). Thus, we conclude here that small molecule amines or ammonium salts with aliphatic side chains are most efficient in PATA disassembly process. However, we envision that stimuli such as enzyme, protein or light source of specific wavelength might be effective as well for PATA disassembly and would be an interesting topic of investigation. Moreover, benefits of present assembling and disassembly events for specific application yet to be explored but, we envision broad scopes owing to ubiquitous presence of amine/ammonium functional groups in numerous biological systems (lipids, proteins, enzymes, etc.). One of the major advantages of present synthetic approach is that it does not completely diminish the inherent features of TA. For example, PATA coatings have been demonstrated to exhibit excellent antibacterial properties against several bacterial colony in our previous report.37 Therefore, unsubstituted catechol or pyrogallol units are easily available to maintain and exhibit diverse functionalities of TA building block. Consequently, we envisioned that PATA vesicles should exhibit radical scavenging or antioxidant properties in solution, which is useful for many practical applications. Radical scavenging property was evaluated using a stable radical assay based on 2,2-diphenyl-1-picrylhydrazyl (DPPH).67 The intense violet color of DPPH solution turned to yellow with increasing injection amount of PATA vesicle solution indicating successful quenching of radical species (Figure 9a). Further, scavenging of DPPH radical was also confirmed by decrease of characteristic peak at 520 nm with increasing overall injection amount of PATA vesicle in the range of 0.08-1.25 µg µM-1 (b)

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C0 C1 C2 C3 C4 C5

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Control (C0) 0.08 µg/µM (C1) 0.15 µg/µM (C2) 0.31 µg/µM (C3) 0.62 µg/µM (C4)

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I / I0 (at 520 nm)

(a) Absorbance (a.u.)

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1.25 µg/µM (C5)

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400

500

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! / nm

700

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(Figure 9a). Time dependent activity profile was monitored with specific PATA addition (0.31 µg µM-1) and about three hours is necessary to complete the scavenging of DPPH (Figure 9b). This result clearly supports our hypothesis and the presence of unsubstituted catechol or pyrogallol units on the vesicle surface. Thus, present study opens a new direction of utilizing chemically modified TA as nanocarriers and functional natural additives in many practical applications. §

CONCLUSIONS

In summary, a facile molecular tuning of dendritic natural polyphenols, tannic acid (TA) has been demonstrated to produce a new type of natural surfactants and achieve solventmediated vesicular assembly in water. Diverse chemical and physical interactions ability of such multifunctional polyphenols make them unique and promising for supramolecular assembly. Although, template-based or multi-component aggregation induced assembly with such natural building blocks have been investigated earlier but self-assembly of chemically modified single-component tecton have never been carried out, to best of our knowledge. Present study unveils that partial hydrophobization of TA by n-alkyl chains help to produce well-defined spherical assembly in water, enclosed by a molecularly thin (~3-5 nm) membrane akin to natural liposome vesicles. Further, size of such (nano)capsules can be tuned in a broad range from ~100 nm to several µm scale by tuning several parameters including amphiphile concentration, addition rate of poor solvent, and initial volume ratio of cosolvent. In the present study, we investigated only deca-substituted TA(Cn)10 amphiphile by direct mixing of cosolvent but speculate that present study would further encourage to design various TA-based (nano)structures by simple manipulations of degree of substitution, choice of cosolvents, or self-assembly techniques. Further, encapsulation ability of both hydrophilic and hydrophobic payloads, and controlled release properties of guest molecules demonstrate potential applications as smart stimuli-responsive nanocarriers. Several chemical species including cationic surfactants and aliphatic amines are effective in PATA disassembly process. Further, we speculate the possibility of biomolecules triggered on-demand release of payloads using such PATA vesicle systems. Nonetheless, in light of the facile gram-scale synthesis, utilizing renewable biomass and multifunctional polyphenols present strategy would further encourage molecular tuning of TA building block to achieve supramolecular (nano)structures useful for wide-range applications.

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Supporting Information

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Figure 9. Radical scavenging activity of PATA vesicles using a stable radical assay based on 2,2-diphenyl-1-picrylhydrazyl (DPPH). (a) Change of absorption spectra in the presence of variable PATA concentration with 50 µM DPPH and after 1 h addition time. (b) Time dependent activity profile monitored by absorption intensity at 520 nm with final vesicle concentration of 0.31 µg µM-1.

The Supporting Information is available free of charge on the ACS Publications website. Self-assembly method, Characterizations, SEM and TEM images, Molecular mechanics, Stability and guest release studies

AUTHOR INFORMATION Corresponding Author * [email protected] * [email protected]


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ORCID Debabrata Payra: 0000-0002-4147-6166 Yoshihiro Yamauchi: 0000-0003-3611-5638 Sadaki Samitsu: 0000-0002-4139-1656 Masanobu Naito: 0000-0001-7198-819X

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS A part of this work was conducted by Nanotechnology Platform Program (Molecule and Material Synthesis) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. The authors are also grateful to the support by Council for Science, Technology, and Innovation, “Cross-ministerial Strategic Innovation Promotion Program (SIP), infrastructure maintenance, renovation and management”

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Natural Polyphenol Surfactants: Solvent-Mediated Spherical Nano

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