Shape and Mechanical Control of Poly(ethylene oxide) Based

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Shape and Mechanical Control of Poly(ethylene Oxide) Based Polymersome with Polyoxometalates via Hydrogen Bond Benxin Jing, Xiaofeng Wang, Haitao Wang, Jie Qiu, Yi Shi, Haifeng Gao, and Yingxi Zhu J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b11759 • Publication Date (Web): 25 Jan 2017 Downloaded from http://pubs.acs.org on January 31, 2017

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The Journal of Physical Chemistry

Shape and Mechanical Control of Poly(ethylene oxide) based Polymersome with Polyoxometalates via Hydrogen Bond Benxin Jing,a Xiaofeng Wang,b Haitao Wang,c Jie Qiu,c Yi Shi,b Haifeng Gao,b and Yingxi Zhua,* a

Department of Chemical Engineering and Materials Science, Wayne State University,

Detroit, MI 48202 b

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN

46556 c

Department of Civil & Environmental Engineering & Earth Sciences, University of Notre

Dame, Notre Dame, IN 46556 * Email: [email protected]

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ABSTRACT: Polymersomes are self-assembled vesicles of amphiphilic block copolymers and have been explored for wide applications from drug delivery to mirco/nanoreactors. Polymersomes are soft and highly deformable, thus their shape instability due to osmolarity difference across polymer membranes and low elasticity could conversely limit their practical use. Instead of selecting particular polymer chemical reactions to enhance the mechanical properties, we have employed inorganic polyoxometalate (POM) clusters as simple physical crosslinkers to control the shape and mechanical stability of polymersomes in aqueous suspensions. Robust spherical shape with enhanced elastic and bending moduli of POMdressed poly(ethylene oxide) (PEO) based polymersomes are achieved. We have accounted the hydrogen bonding between POM and PEO blocks for POM adsorption and stabilization of polymersomes, whose interaction strength could be also tuned by mixing solvents of hydrogen bond donors or receptors with water. The stimuli-responsive properties of POMs are introduced in POM-dressed polymersomes upon the physical crosslinking of POMs with PEO blocks in aqueous media. As POM can be used as nanomedicines, catalysts, and other functional nanomaterials, POM-dressed polymersomes with significant shape and mechanical reinforcement could open new avenues for the applications of PEO-based polymersomes and other PEO-tethered nanocolloids.


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1. INTRODUCTION

As the polymeric analogue of liposome (or lipid vesicle), polymersome (or polymer vesicle) was first developed from amphiphilic block copolymers more than 15 years ago1. Similar to liposome, polymersome could also offer a small compartment to accommodate chemicals as imaging agents, micro/nano reactors, and drugs or gene for medical therapeutics2-5. However, polymersome often encounters osmolarity difference across polymer membranes, leading to the shape transformation from a sphere to a stomatocyte, and finally to a nested vesicle with considerably reduced size6-7. Conversely, the shape stability of drug/gene carrying polymersomes for various biomedical applications is critical for their translocation through cell membrane upon circulation8, internalization pathway9, and consequently their medical efficacy10-12,13. For micro/nano reactors, the shape instability of polymersomes could adversely cause chemical leakage and result in size tightness, which could consequently affect the selectivity, controllability and rate of chemical reaction. Hence, stabilizing the shape with enhanced mechanical stability of polymersomes has been highly desired and investigated for broadening their practical applications over the past decades. One popularly adopted method to stabilize the shape of polymersomes is to crosslink either the hydrophobic or hydrophilic block of amphiphilic polymersomes14-17. Crosslinking polymer blocks by additive crosslinkers could improve the mechanical properties of polymersomes by several orders of magnitude. However, crosslinking biocompatible poly(ethylene oxide) (PEO) based polymersomes could be challenging in that common crosslinking approaches by radiation using UV18, electron beam19 or -radiation20 could damage the hydrophobic blocks as well as the encapsulated interior reagents. Alternative approaches often involve chemical crosslinking of PEO with weak polyacids, such as poly(acrylic acid) via hydrogen bonding21. Such approaches could improve the tensile strength of PEO, but not the modulus nor shape stability due to the inherent flexibility of 3 ACS Paragon Plus Environment


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organic polymers22. In this work, we explore a facile physical crosslinking approach via hydrogen bonding to stabilize PEO-based polymersomes with significantly improved shape and mechanical stability by inorganic polyoxometalate (POM) heteropolyacids bearing rigid framework. POMs are clusters of transition metal oxides (MOx, M = Mo, W, V, U and Nb; x = 4-7) with well-defined structure at the atomic level and typically 0.8-5 nm in diameter, and can be regarded similar to other molecular complex materials such as fullerene and polyhedral oligomeric silsesquioxane (POSS). They have recently emerged as catalysts, photoelectronic/magnetic materials, redox mediator for water splitting, anti-cancer and anti-virus medicines thanks to their unique optical, magnetic, and electric properties and high reactivity23-28. Although POMs are sometimes considered as pristine nanoparticles, they are fundamentally different from nanoparticles. Similar to fullerene and POSS29, POMs can fully dissolve in polar solvents to form thermodynamically stable solutions, distinct from the suspensions of nanoparticles in liquid medium. Additionally, the charges on many POM polyanions are delocalized and mobile30-33, giving rise to specific steric effect and ionic interactions. As some POMs can self-assemble into “blackberry” in water via hydrogen bonding34-35, it makes promise to form POM-PEO complexes via hydrogen bonding. We have recently found POMs can readily adsorb on zwitterionic liposomes to improve liposome dispersion and mechanical strength in aqueous media36. Furthermore, with the selection of hydrophilic POMs, we can minimize the complication of hydrophobic interaction with the hydrophobic blocks of polymersome in aqueous media. In this work, we explore the adsorption of POM with PEO-based polymersome and examine the effect of POM content on the shape and elasticity of polymersomes. The POM selected in this work is wheel-like Na14[Mo154O462H14(H2O)70]·400H2O ({Mo154}) of 3.5 nm in diameter and 1.5 nm in thickness as schematically illustrated in Figure 1a37-38, which is the major component of natural “molybdenum blue”39. We have determined 4 ACS Paragon Plus Environment

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pKa  5.50 of {Mo154} by titration as shown in Supplemental Figure S1, confirming its weak acid nature due to the Mo-OH group40. Based on the atomic structure revealed from X-ray crystallography37-38, {Mo154} can offer total 28 hydroxyl groups as hydrogen bond donors to interact with PEO whose ethylene oxide monomer unit is a typical hydrogen bond acceptor. In this work, we use poly(ethylene oxide-b-ε-caprolactone) (PEO-b-PCL), a widely used biocompatible and biodegradable amphiphilic block copolymer, to prepare polymersomes in water. Since the Young’s modulus of PCL is reported to be an order of magnitude lower than that of polystyrene, polylactide, or other commonly used hydrophobic polymer blocks41, polymersomes consisting of PCL as hydrophobic interiors upon PEO-b-PCL microsegregation in water is expected to exhibit much weak mechanical strength and can be easily deformed. It should be noted that as the size,

d

= 3.5 nm of {Mo154} is much smaller than

typical 50-500 nm sized polymersomes, it would be “stealth” on polymersome surface without alter their geometry, which is very difficult to be achieved by plain nanoparticles 42-45. In this work, we mainly employ dynamic light scattering (DLS) and atomic force microscopy (AFM) to quantify the change in the size and elasticity of PEO-b-PCL polymersome upon {Mo154} adsorption.

2. EXPERIMENTAL

2.1 Chemicals and Materials: Sodium molybdate dehydrate (Na2MoO4·2H2O), sodium hydrosulfite (Na2S2O4), hydrochloric acid, sodium acetate, acetic acid, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), ethanol (EtOH) were purchased from Sigma-Aldrich and used directly. Poly((ethylene oxide)113-b-(ε-caprolactone)215) (PEO-bPCL, polydispersity index PDI = 1.30) was purchased from Polymer Source and used directly. Single crystal silicon wafers with one side polished were purchased from Silicon Quest



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International and used as substrates for AFM experiments after being cleaned in a heated piranha solution (30% H2O2 and 70% H2SO4) at T = 120 °C for 1 hr. {Mo154} POM was synthesized by strictly following the procedure developed by Achim Müller et al38. 2.2 Preparation of PEO-b-PCL Vesicle: PEO-b-PCL polymersome was prepared by a modified nano-precipitation method as shown in Figure 1b46. Briefly, under sonication, 8.0 mL 0.02 M sodium acetate/acetic acid aqueous buffer (pH = 4.00) was added into 2.0 mL 2.0 g/L PEO-b-PCL solution in DMF in droplet wise at the speed of 5 µL/s by springe pump (NE300, New Era Pump System). During this process, the vial was suspended in the bath center of Branson 1800 Ultrasonic Cleaner to achieve the most vigorous mixing. Then the polymersomes were dialyzed overnight to remove DMF. By this method, fresh polymersome with PDI < 0.15, which was measured by dynamic light scattering (DLS) immediately after the polymersome prepared, were achieved. POM dressed polymersome was prepared by simply adding POM with desired concentration to PEO-b-PCL polymersome aqueous suspension and incubated 30 min before characterization. 2.3 Characterization: The size and zeta potential of polymersome added with {Mo154} in liquid media was measured by integrated DLS and zeta potential analyser (ZetaPlus, Brookhaven Instruments). For the size measurement of polymersomes in mixed solvents, the refractive index and viscosity of medium were corrected by the fraction of organic solvent in the mixture with water based on the following literatures on water-acetonitrile mixture47-48, water-DMA mixture49-50, and water-ethanol mixture51-52. The morphological structure of {Mo154}-dressed polymersomes deposited on a silicon wafer in acetate buffer was characterized by AFM (Multimode, Nanoscope IV Controller, Brucker Nano) operated in the tapping mode with a silicon nitride probe (NP, Brucker Nano), whose spring constant, k ~ 0.33 N/m was determined by the thermal-tune method53, and a water-proof scanner (J scanner, Bruker Nano) at room temperature. The tapping-mode fluid 6 ACS Paragon Plus Environment

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cell (MTFML, Bruker Nano) with O-ring was cleaned with copious ethanol and blow-dried in a stream of nitrogen. For high quality image acquisition, the resonance frequency of AFM probe in aqueous solution was fixed between 9 kHz to 10 kHz. The membrane stiffness, 𝑘𝑚𝑒𝑚 of {Mo154}-added polymersomes was determined by AFM under the contact mode. The morphology of {Mo154}-added polymersomes was also characterized by TEM (Titan 80–300 microscope, FEI, Hillsboro, OR). The sample was prepared by simply depositing a droplet of 50 mg/L polymersomes with or without added POMs in aqueous suspension on a TEM grid (PELCO® Silicon Dioxide Support Films, TED PELLA) and drying in air before TEM experiments without any metal staining.

3. RESULTS AND DISCUSSION We start with examining the change in the size and zeta potential of PEO-b-PCL polymersomes with added {Mo154} in aqueous suspensions by DLS. As shown in Figure 2, the size of PEO-b-PCL polymersome decrease rapidly with increasing {Mo154} concentration at POM-to-polymer molar concentration ratio, 𝑐

𝑐𝑃𝑂𝑀 𝑃𝑜𝑙𝑦𝑚𝑒𝑟

> 0.2 and reach a plateau at 𝑐


≥

2.0. Similarly, the measured zeta potential decreases from ~-10 mV to ~-55 mV with increasing {Mo154} concentration when a higher onset concentration ratio, 𝑐


 0.6 is

exceeded. As PEO-b-PCL is electrically neutral, the increased negativity of the polymersome with added {Mo154} strongly suggests the adsorption of {Mo154} clusters on the polymersome, which is accompanied with reduced polymersome size and increased surface charge density. The higher onset 𝑐


for zeta potential change than that for size change of polymersomes

suggests that a good fraction of POMs are buried in the PEO layer of polymersomes. It is noted that the size change of polymersomes is not monotonic with POM concentration, but increases first and is followed by size shrinkage to be smaller than the original size. The initial size increase is clearly resulted from the polymersome aggregation due to the “bridging” 7 ACS Paragon Plus Environment


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effect of POMs across polymersomes at low coverage of POMs on polymersomes. The decreased size of polymersomes at higher POM concentration is possibly the combined result from {Mo154}-induced PEO layer shrinkage and dissociation of polymersome aggregates due to enhanced electrostatic repulsion between {Mo154}-dressed charged polymersomes. Similar to POM stabilized liposomes36, PEO-b-PCL polymersomes achieve excellent colloidal stability at a constant diameter of ~132 nm while the zeta potential of POM-dressed polymersomes decrease to -55 mV. Similar POM adsorption on polymersomes and the resulting size change of POM-dressed polymersomes are also observed with different POMs such as {Mo176} as well as different PEO-based polymersomes as shown in Supplemental Figure S2. Furthermore, we have compared the morphology of PEO-b-PCL polymersome before and after adding {Mo154} clusters by AFM in water. Bare polymersome is too soft to be clearly revealed by AFM even under tapping mode as only smeared morphology of PEO-b-PCL polymersomes deposited on a silicon wafer is observed in Figure 3a-i, which is similar to the case of liposome morphology in a fluid phase as revealed by tapping-mode AFM36. As such, the morphology of bare polymersomes could be only revealed by cryo-TEM, but not regular TEM.46,

54

In sharp contrast, we observe in Figure 3a-ii that {Mo154}-dressed PEO-b-PCL

polymersomes clearly show stable and well-defined spherical shape with repeated AFM scans. Interestingly, {Mo154}-dressed PEO-b-PCL polymersomes could even maintain the spherical shape under disturbing contact-mode AFM (see Figure 4a and 4b below) or under air purging and drying (see Figure 3b-ii and Supplemental Figure S3), which is clearly different from the collapse and fusion of bare polymersomes upon air drying as shown in Figure 3b-i. Hence, it is strongly suggested that the adsorption of {Mo154} on PEO-b-PCL results in mechanically strong and stable PEO-b-PCL polymersomes. We confirm the presence of {Mo154} clusters embedded in polymersomes by TEM, for which a droplet of {Mo154}-dressed PEO-b-PCL polymersomes in aqueous suspension is cast on TEM grid 8 ACS Paragon Plus Environment

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without any metal decoration. As shown in Figure 3b-ii, the adsorption of {Mo154} into polymersomes is confirmed by the dark rim contrast from the spherical polymersome contour by TEM while bare polymersomes cannot be seen by regular TEM in vacuum. To quantify the mechanical strength of PEO-b-PCL polymersome, we analyze the morphological change of the polymersome with different amounts of added {Mo154} by varying the loading force in the contact-mode AFM. As shown in Figure 4b, the height of PEO-b-PCL polymersomes decreases with increasing loading through the AFM tip. We thereby estimate the stiffness, 𝑘𝑚𝑒𝑚 of the polymersome from the measured deformation, δ by contact mode AFM with the following equation 55-56, 𝐹 = 𝑘𝑚𝑒𝑚 𝛿 (1). 𝑘𝑚𝑒𝑚 is used to estimate the apparent Young’s modulus, E and bending modulus, 𝑘𝑏 of polymer vesicle membrane by following the equations, 𝑘𝑚𝑒𝑚 =

4𝐸ℎ2 𝑅√3(1−𝜈 2 )

(2)

𝐸ℎ3

𝑘𝑏 = 12(1−𝜈2 ) (3) where h, R and v are membrane thickness, vesicle curvature radius and Poisson ratio (v = 0.5 in this work), respectively. With the measured bilayer thickness h = 32 nm by TEM (Figure 3b-ii), we estimate the E and 𝑘𝑏 of PEO-b-PCL polymersomes decorated with {Mo154} of increased amounts as summarized in Table 1, which are also compared to those reported of some well-known liposomes and polymersomes55-57. The apparent Young’s modulus of {Mo154}-dressed PEO-b-PCL polymersomes is measured to be ~ 200 MPa, in close approximation to that of dry PCL bulk polymer41, suggesting enhanced mechanical property though water could be a plasticizer of PCL58. Additionally, the obtained E and 𝑘𝑏 of {Mo154}dressed PEO-b-PCL polymersomes appear to be 1-2 orders of magnitude higher than those of liposomes even in the gel phase57. More importantly, the mechanical properties of {Mo154}dressed polymersomes are still 4-5 folds higher than those of polystyrene-based 9 ACS Paragon Plus Environment


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polymersomes of similar bilayer thickness56 , which is typically about one order of magnitude higher than that of PCL bulk polymer. To the best of our knowledge, {Mo154}-dressed PEO-bPCL polymersomes exhibit the highest elastic moduli of polymersomes as reported so far. The improvement of the mechanical properties of PEO-b-PCL polymersome by POM clusters is significant and promising. With much enhancement of mechanical stability and strength by adsorbed {Mo154} clusters on PEO-b-PCL polymersome, it becomes critical to examine and understand the underlying interaction between {Mo154} and PEO-b-PCL. Considering neutral hydrophilic PEO block at the exterior polymersome aqueous interface and abundant hydroxyl groups exposed at the exterior surface of {Mo154} cluster, we expect the hydrogen bonding between PEO block and {Mo154} responsible for the adsorption of {Mo154} clusters on the polymersome membrane. However, it remains a great challenge to directly determine the hydrogen bonding between POM and PEO blocks in this work as well as inorganic nanoparticle-polymer assembled systems in general due to the low density of functional groups that results in insufficient signal in spectroscopic or other characterization methods. Specifically in this work, {Mo154} could carry a maximum of 28 hydroxyl groups in contrast to more than 400 Mo=O bonds; even if all the hydroxyl groups could form hydrogen bonds with PEO, it is too weak to modify the absorption spectrum of Mo-O by FT-IR or other spectroscopic characterization. Additionally, the absorption spectrum of {Mo154} at the wavelength of 955 cm-1, corresponding to the asymmetric stretching vibration mode of Mo=O38, 59 will be masked by the absorption spectrum of CH2 groups in PEO60-61 upon PEO{Mo154} assembly. Thus, it is difficult to apply trational spectroscopy methods, such as FT-IR, to examine the hydrogen bonding between {Mo154} and PEO blocks. Instead, we use solvent additives to tune the possible hydrogen bonding in aqueous suspension, which is widely adopted in examining the hydrogen bonding in nanoparticle and block copolymer assembled systems as reported in recent literatures62-64. 10 ACS Paragon Plus Environment

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To examine the intermolecular hydrogen bonding between PEO and {Mo154}, we selectively add several different solvents to the aqueous medium and thereby tune the hydrogen bonding strength. Among them, solvents like dimethylformamide (DMF), dimethylacetamide (DMA), and acetonitrile could only work as hydrogen bond acceptor, but not as hydrogen bond donor, in water due to their lack of hydrogen atom directly bound with the highly electronegative atoms like oxygen and nitrogen. Because these solvents as hydrogen bond acceptors could compete with PEO to interact with {Mo154} clusters via hydrogen bonding, adding these solvents to polymersome aqueous suspensions could conversely weaken the PEO-{Mo154} interaction. In contrast, other solvents like alcohol could work both as hydrogen bond donors and acceptors. As alcohol can form hydrogen bonds with {Mo154}, the active hydrogen atoms could still interact with PEO to form hydrogen bonds, thereby adding such solvents to aqueous suspensions could facilitate the PEO-{Mo154} interaction. To verify this speculation, DMA, acetonitrile and ethanol are added to aqueous suspension to alter the strength of hydrogen bonding between PEO blocks and {Mo154} clusters. As shown in Supplemental Figure S4, adding organic solvents could also alter the size of bare polymersomes, hence the reported sizes in Figure 5 are normalized by the size of bare polymersomes in corresponding mixed solvent of water and added miscible organic solvents. When DMA is added to the polymersome aqueous suspension with a resultant molar fraction great than 4.5 mol%, no size change of PEO-b-PCL polymersome is observed with added {Mo154} (Figure 5a). Similar behavior that constant polymersome size, instead of shrinkage, is maintained with added {Mo154} is observed in mixed acetonitrile and water solvent at an acetonitrile molar fraction greater than 10.5 mol%. In sharp contrast, adding ethanol to the aqueous suspension could cause the size shrinkage of PEO-b-PCL polymersome with added {Mo154} at an ethanol molar fraction up to 19.8 mol% (Figure 5b). Furthermore, we have excluded the possible electrostatic origin for the interaction between {Mo154} and PEO blckas, which is inversely proportional to medium relative 11 ACS Paragon Plus Environment


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permittivity, εr. Apparently, adding miscible solvents to water could alter εr, yet we find no clear correlation between {Mo154}-induced polymersome size change and the medium relative permittivity of mixed solvents of varied molar fraction of organic solvents in water. For instance, the εr of 4.5 mol% DMA/water mixture is 78.3, nearly the same with that of pure water65; yet no size change of {Mo154}-added polymersomes is observed in the DMA/water mixed suspension, distinct from the shrinkage {Mo154}-added polymersomes in pure water. In contrast, the εr of 19.8 mol% ethanol/water mixture is about 55.9 66 and much lower than that of pure water, yet similar shrinkage of {Mo154}-added polymersomes is observed in the ethanol/water mixutre. Additionaly, we also exclude the possiblity of chemical reaction between PEO blocks and {Mo154} clusters to form covalent bonds by NMR because no difference in the 1H NMR spectrum of PEO/{Mo154} mixture from that of pure PEO in D2O is observed (Supplemental Figure S5). Put all together, the strong interaction between PEO-bPCL polymersome and {Mo154} cluster is of hydrogen bonding in origin. As each {Mo154} could carry up to 28 hydroxyl groups, it could form hydrogen bonds with different PEO blocks in one polymer and across different polymers. Thus, {Mo154} can crosslink PEO layer of polymersomes to enhance the mechanical strength of its dressed polymersomes. Last, we demonstrate the stimuli-responsive characteristics of {Mo154}-dressed PEO-bPCL polymersomes in aqueous media due to the presence of {Mo154}. As {Mo154} is a weak polyacid, it could render PEO-b-PCL polymersomes both pH and salt responsive feature upon adsorption. As shown in Figure 6, the size and dispersity of {Mo154}-dressed PEO-b-PCL polymersomes can be greatly altered by solution pH (Figure 6a) and salt concentration (Figure 6b): lowering solution pH, which enhances the protonation {Mo154}, or adding salt, which screens the charge of {Mo154}, could cause significant aggregation of {Mo154}-dressed polymersome due to reduced net charge density of {Mo154}-dressed polymersome, Yet such pH and salt responsive behaviors are not observed with bare PEO-b-PCL polymersomes in aqueous suspension. 12 ACS Paragon Plus Environment

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4. CONCLUSIONS

In this work, we have examined the interaction of inorganic POM cluster, {Mo154} with PEO based polymersomes to significantly enhance the shape stability and mechanical strength of diblock polymer formed soft and deformable polymersomes. We have accounted the hydrogen bonding for the adsorption of {Mo154} clusters on polymersomes to crosslink the PEO blocks. As a result, {Mo154}-dressed polymersomes can maintain their spherical shape with significantly enhanced elasticity and bending moduli. To the best of our knowledge, {Mo154}dressed PEO-b-PCL polymersomes exhibit the highest mechanical elastic moduli as reported so far. The stimuli-responsive properties of {Mo154} clusters are introduced and preserved in {Mo154}-dressed polymersomes upon the crosslinking of {Mo154} with PEO blocks in aqueous media. As POM clusters can be used as nanomedicines, catalysts, and other functional nanomaterials, POM-dressed polymersomes with significant shape and mechanical reinforcement could open new avenues for the applications of PEO-based polymersomes and other PEO-tethered nanocolloids.

Acknowledgement We acknowledge the financial support from the National Science Foundation (NSF CMMI1129821) for this work.

SUPPORTING INFORMATION AVAILABLE: Figure S1, titration curve of {Mo154}; Figure S2, size change of polymersomes and micelles added with other POMs measured by dynamic light scattering; Figure S3, morphology of dried {Mo154} dressed polymersomes by AFM; Figure S4, solvent effect on {Mo154}–dressed polymersomes in acetate buffer; Figure S5. 1H NMR spectroscopy of bare PEO and PEO/{Mo154} mixture in D2O. 13 ACS Paragon Plus Environment


Table 1. The Mechanical Properties of {Mo154}-dressed PEO-b-PCL Polymersomes at 𝒄𝑷𝑶𝑴 = 5 in Comparison to These of Some Well-Studied Polymersomes.a 𝒄 𝑷𝒐𝒍𝒚𝒎𝒆𝒓

Material

h/nm

E/MPa

kb/10-19 J

DPPC (gel phase)

5

28.1

23.4

PDMS68-b-PMOXA11

16 ± 2

17

± 11

70 ± 50

PS182-b-PAA19 29 56.5 ± 8.7 1530 ± 235 {Mo154} dressed PEO113-b-PCL215 32 199 ± 65 7200 ± 2300 a The data of DPPC, PDMS68-b-PMOXA11, PS182-b-PAA19 are adopted from published results.55-57

a)

b) PEO-b-PCL

3.5 nm

1.8 nm

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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{Mo154} Figure 1. a) Molecular structure of PEO-b-PCL and {Mo154}; b) schematic illustration of the modified nanoprecipitation method for polymersome preparation.


 of bare vesicle

160 155

-10 -20

Size of bare vesicle

dH (nm)

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


150

-30

145

-40

 (mV)

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140 -50 135 -60 130 0.02

0.2

2

20

cPOM/cPCL-b-PEO Figure 2. Measured size (left side y-coordinate axis) and zeta potential (right side ycoordinate axis) of 0.05 g/L PEO-b-PCL polymersomes added with {Mo154} of increased concentration in acetate buffer by DLS. The dash lines are the size (black) and zeta potential (red) of bare PEO-b-PCL polymersome in the same buffer suspension.



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a)

40

i

ii

200

i

200

0

0

b)

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ii

0

Figure 3. a) Morphology of PEO-b-PCL polymersomes in aqueous suspension (i) without and (ii) with added {Mo154} at 𝑐


= 5 by AFM. b) Morphology of air-dried PEO-b-PCL

polymersomes (i) without added {Mo154} by AFM, Inset: featureless morphology by TEM and (ii) with added {Mo154} at

𝑐𝑃𝑂𝑀 𝑐𝑃𝑜𝑙𝑦𝑚𝑒𝑟

= 5 by TEM without any metal staining. Inset:

magnified TEM micrograph of {Mo154}-dressed PEO-b-PCL polymersomes. All of scale bars are 500 nm. The unit of height scale bar is nm.


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a)

40

b)

40 35

0

Height (nm)

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


30 25 20 15 10 5 0 -5 0

50

100

150

200

250

300

Distance (nm) Figure 4. To determine the membrane stiffness, 𝑘𝑚𝑒𝑚 of {Mo154}-dressed PEO-b-PCL polymersomes at 𝑐


= 5, contact-mode AFM characterization was conducted in aqueous

media. a) Morphology of polymersomes under AFM tip loading force of 14.2 nN. The scale is 1 µm. The unit of height scale bar is nm. b) Height profile of one single polymersome under varied loading force of14.2 nN (squares) and 24.1 nN (circles). The solid lines are the fitting results of spherical shape.



a)

1.02

b)

1.00 0.98

1.00 0.95

0.96

dH/dH0

dH/dH0

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

Page 18 of 28

0.94 0.92

0.90 0.85

0.90 0.88

0.80

0.86 0.2

2

20

cPOM/cPCL-b-PEO

0.02

0.2

2

20

cPOM/cPCL-b-PEO

Figure 5. Effect of mixed solvents on the normalized size of {Mo154}-dressed PEO-b-PCL polymersomes in acetate buffer: a) adding 4.5 mol% acetonitrile (squares), 10.5 mol% acetonitrile (circles), 2.6 mol% DMA (diamonds), and 4.5 mol% DMA (triangles) as hydrogen bond acceptors to the aqueous buffer suspension, b) adding ethanol of 4.5 mol% (squares), 10.5 mol% (circles), and 19.8 mol% (triangles) the to the aqueous buffer suspensions. The effect of added DMA and ethanol on the formation of hydrogen bonding formed between PEO blocks and {Mo154} is schematically illustrated below panel a) and b), respectively.


Page 19 of 28

a)

b) 2500

280 260

2000

dH (nm)

240

dH (nm)

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


220 200 180

1500 180 160

160

140

140

120

120 0.02

0.2

2

20

0.02

0.2

2

20

cPOM/cPCL-b-PEO

cPOM/cPCL-b-PEO

Figure 6. Salt and pH-responsive behaviors of {Mo154}-dressed PEO-b-PCL polymersomes in aqueous suspensions. a) Size of {Mo154}-dressed PEO-b-PCLpolymersome in aqueous suspensions without NaCl (squares) and with added NaCl of 10 mM (circles), 40 mM (triangles), and 200 mM (diamonds). b) Size of {Mo154}-dressed PEO-b-PCLpolymersome in aqueous suspensions of varied pH = 3.75 (squares), 2.97 (circles), 2.55 (triangles), and 2.02 (diamonds).



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TOC GRAPHIC


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Shape and Mechanical Control of Poly(ethylene oxide) Based

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