Trapping It Softly: Ultrasoft Zirconium Metallogels for Macromolecule

Jul 15, 2016 - Trapping nanosized drugs in ultrasoft, shear-thinning hydrogels with large pores is of particular interest, yet a persistent challenge ...
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Trapping It Softly: Ultrasoft Zirconium Metallogels for Macromolecule Entrapment and Reconfiguration Amir Sheikhi* and Theo G. M. van de Ven* Department of Chemistry, Centre for Self-Assembled Chemical Structures, and Pulp and Paper Research Centre, McGill University, Montreal, 3420 University Street, QC H3A 2A7, Canada S Supporting Information *

ABSTRACT: Trapping nanosized drugs in ultrasoft, shearthinning hydrogels with large pores is of particular interest, yet a persistent challenge in nanomedicine due to the lack of hydrodynamic confinement. Engineering molecular interactions between a macromolecule and a supramolecular gel may address this shortcoming, providing a key route to develop advanced drug carriers without compromising matrix elasticity. Here, we show that ultrasoft zirconium-based metallogels are able to trap and reconfigure model nanodrugs (e.g., dextran) through complexation and hydrogen bonding. The diffusion coefficients of dextran molecules (Mw ∼ 10−2000 kDa, a ∼ 2− 20 nm) in zirconium carbonate (ZC) metallogels (G′ < 30 Pa) were measured by pulsed field gradient nuclear magnetic resonance (PFGNMR), which revealed the coexistence of hindered and enhanced collective diffusion regimes for the first time. This work may pave the way toward designing next generation ultrasoft drug carriers and functional templates to control biomacromolecular processes, such as protein folding. an a large hotel room hinder the motion of a fly? What if sticky patches are distributed all around the room? Answering these questions may help design a system to trap small macromolecules in extremely large pores of a soft carrier for drug delivery. Recent decades have witnessed an increasing demand for shear-thinning ultrasoft hydrogels as injectable drug vehicles, which are able to gradually disintegrate in the body.1−12 On the one hand, a low elastic modulus, for example, G′ ∼ 10 Pa corresponds to a large gel mesh size ξ ∼ (G′/ kBT)−1/3 ∼ O (100 nm), where kBT is the thermal energy, and on the other, most of the drugs have a molecular radius a ∼ O (nm), preventing them from efficient entrapment in ultrasoft gels (a < ξ). To compensate the lack of physical confinement in ultrasoft gels, the molecular interactions between the drugs and host matrices should be engineered. Typically, a large portion of drugs involve potential hydrogen bond forming functional groups,13 for example, hydroxyl in cyclodextrins14,15/polyphenols16 and fluorinated molecules in anticancer and AIDS therapeutics,17 or bear decorative stealth polymers such as polyethylene glycol (PEG), a suitable hydrogen bond acceptor. 18 Dextran, a branched α(1 → 6) linked glucan polysaccharide19 with negligible protein adsorption tendency,20 has been widely used as a model nanodrug, plasma substitute,21 cell marker,22 crowding agent,23 and drug carrier.24 The dynamics of inert dextran in physiological media and tissues have shed light on a wide spectrum of bioprocesses. The hindered diffusion of dextran in microporous media,25 such as cytoplasm26,27 suggests that cells comprise a non-Newtonian

C

© 2016 American Chemical Society

crowded environment. To simulate such a crowded medium, dextran may be added in vitro to buffer solutions, inducing protein aggregation, increased metabolic activity, and molecular assembly of oligomeric structures.23 Interestingly, with dextran, it is also possible to detect diseases: tumor tissues experience a reduced glycosaminoglycan content, enabling probe dextran to adopt a less hindered motion than in healthy tissues.28,29 Enhancement in the dextran diffusion coefficient has been observed in aqueous media containing motile species, such as bacteria. As an example, at only 0.5% v/v of E. coli, dextran (Mw ∼ 77 kDa) adopted a 4-fold faster diffusion than in the absence of bacteria.30 Yet, no experimental evidence of the coexisting hindered and enhanced diffusion of dextran has been reported. In this Letter, we explore how the dynamics of a model nanodrug (dextran) are affected by the nonhydrodynamic and noncovalent interactions with metal-based hydrogels. Such interactions promote the probe macromolecules to adhere to an ultrasoft shear-thinning matrix, while overcoming the limitations of common noncovalent interactions (ionic attraction and hydrophobic interactions). Ionic attractions typically require oppositely charged surfaces,31 which are not applicable to neutral molecules, for example, dextran. Moreover, such interactions may be susceptible to salt concentration and pH, restricting conjugations near the isoelectric point of Received: June 10, 2016 Accepted: July 8, 2016 Published: July 15, 2016 904

DOI: 10.1021/acsmacrolett.6b00447 ACS Macro Lett. 2016, 5, 904−908

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Figure 1. Normalized echo amplitude decay versus squared pulsed magnetic field gradient intensity G2 for dextran molecules (Mw = 110 kDa, at chemical shift ∼3.42 ppm) in an ammonium zirconium carbonate pregel solution (a) and in gelled zirconium carbonate after 4 h heating at 80 °C, obtained from PFGNMR experiments at T ∼ 25 °C. A single exponential decay (eq 1) fits the data in (a) well, yielding D0 ∼ 3.67 × 10−11 m2 s−1, with R2 ∼ 0.999, while it fails to explain a gelled system (b, dashed line). A dual exponential decay (eq 2) fits the echo amplitude versus G2 well (b, solid line), furnishing D1 ∼ 0.41 × 10−11 m2 s−1, D2 ∼ 4.59 × 10−11 m2 s−1, and f ∼ 0.45, with R2 ∼ 0.998. Note that almost half of dextran molecules adopt D1/D0 ∼ 0.11 and the rest attain D2/D0 ∼ 1.25.

⎡ ⎛ A(2τ ) δ⎞ ⎤ = f exp⎢− γ 2D1δ 2⎜Δ − ⎟G2 ⎥ + (1 − f ) ⎝ ⎣ A(0) 3⎠ ⎦ ⎡ ⎛ δ⎞ ⎤ × exp⎢− γ 2D2δ 2⎜Δ − ⎟G2 ⎥ ⎝ ⎣ 3⎠ ⎦

charged species. To benefit from hydrophobic interactions in aqueous systems, apolar interfaces (often suffering from low solubility in water) are required,32,33 which may demand chemical modifications to impart nonpolarity to the macromolecule structure. We endeavor to address these limitations using metal-based interactions with ammonium zirconium carbonate (AZC). Zr compounds, benefiting from excellent biocompatibility and biointegration,34,35 high physicochemical and mechanical endurance,36 and facile processing, are of particular interest in biomedicine and biomaterials.37,38 The time evolution of the diffusion coefficient of dextran (molecular weight Mw ∼ 10−2000 kDa, hydrodynamic radius a ∼ 2−20 nm) in a gelling ammonium zirconium carbonate solution is measured using pulsed field gradient nuclear magnetic resonance (PFGNMR) spectroscopy. This study is unique in a way that dextran can no longer be considered as an inert probe. When dextran molecules (0.5% wt) are exposed to a pulsed magnetic field gradient G (Gauss m−1) in an ammonium zirconium carbonate solution (0.5% wt), the echo amplitude decreases with increasing G (Figure S1, Supporting Information). The amplitude attenuation A(2τ)/A(0) adopts a single exponential decay according to the well-established spin diffusion formalism of Stejskal and Tanner:39 ⎡ ⎛ A(2τ ) δ⎞ ⎤ = exp⎢ −γ 2D0δ 2⎜Δ − ⎟G2 ⎥ ⎝ ⎣ 3⎠ ⎦ A(0)

(2)

where D1 and D2 are the hindered and enhanced diffusion coefficients, respectively, and f denotes the dextran immobile fraction (number of hindered or trapped dextran divided by the total dextran molecules). Note that eq 2 reduces to (1) when f → 1 or 0 in which cases D1 ∼ D0 or D2 ∼ D0. To explain the bimodal distribution of diffusion coefficients, the interaction between zirconium carbonate (ZC) and dextran should be understood. When ZC crystals Zr(OH)α(CO3)β· nH2O (α ∼ 3.2, β ∼ 0.4, and n ∼ 6.9)40 are dissolved in water, through a mild polymerization, a low molecular weight polymer is obtained. In our study, the ammonium zirconium carbonate concentration was ∼0.16 mM (Zr ∼ 13−22%, provided by vendor), and dynamic light scattering (DLS) yielded a diameter d ∼ 5.2 ± 0.1 nm, which corresponds roughly to a degree of polymerization ∼12, assuming a Zr−O bond length ∼0.22 nm.40 Upon heating at 80 °C, AZC partially decomposes to zirconium hydroxide by releasing carbon dioxide and ammonia and forms a supramolecular network according to the following reaction:41,42Small amplitude oscillatory shear experiments (Figure S2a, Supporting Information) show that reaction 1 is time-dependent, and at an AZC concentration of 0.5% wt, the elastic modulus increases from ∼0 to ∼30 Pa in 4 h, corresponding to a sol−gel thermo-transition. This transformation provides a versatile infrastructure for binding OHrich molecules to Zr through oxo complexation and/or hydrogen bonding. As a model system, dextran, a branched polysaccharide comprising α-linked D-glucopyranosyl monomers, is studied here. In reaction 1, when X is a dextran molecule, and Y represents a Zr species cross-linked to a sufficiently large number of zirconium molecules, a soft, sticky network of zirconium carbonate is formed to which dextran molecules are adhered; thus, their mobility is reduced, as evidenced by the hindered diffusion coefficient in Figure 1b. When Y corresponds to a limited number of Zr molecules (e.g., at low reaction time or AZC concentration), no effective network is formed, and dextran molecules with negatively charged patches of zirconium carbonate are produced. The association of ZC molecules (ζ ∼ −14 ± 4 mV at 0.5% wt

(1)

yielding a single diffusion coefficient D0, where 2τ denotes the required time for signal attenuation as a result of diffusion, A is the echo amplitude, γ ∼ 8515.2π s−1 Gauss−1 is the 1H gyromagnetic ratio, and δ and Δ represent the pulsed field gradient duration (s) and lag time between the gradient pulses (s), respectively (Figure 1a, normalized echo amplitude decay versus squared magnetic field strength). However, when dextran molecules (Mw > 10 kDa) are incubated in a heatinitiated gelling AZC system, the echo amplitude diverges from a single exponential decay (Figure 1b). Interestingly, a linear superposition of two exponential decays, corresponding to two diffusion coefficients fits A(2τ)/A(0) well, furnishing coexisting hindered and enhanced diffusion coefficients: 905

DOI: 10.1021/acsmacrolett.6b00447 ACS Macro Lett. 2016, 5, 904−908

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rotational diffusion coefficients, respectively. Accordingly, for a sphere, eq 3 yields 3

kT a 2(1 − e−(2ΔkBT /8πηa )) D2 = B + 6πηa 3Δ

(4)

and for a rigid rod, D2 =

kBT

{ ( ) − 0.3}

3πηL 1/ln

L a

⎣

+

⎦

L2(1 − e−{2ΔkBT / ⎡πηL /3ln(L / a)⎤}) 36Δ 3

(5)

Dextran-zirconium carbonate is likely neither a perfectly spherical macromolecule nor a completely uncoiled rigid rod. For a sphere or rod with nanosized characteristic dimensions, the effect of the second term in the right-hand side of eqs 4 and 5 at experimentally plausible Δ (e.g., >1 ms) is negligible. For example, for the largest dextran molecule used in this work, the contribution of normalized rotational diffusion coefficient is in O(10−16 m2 s−1), which is 6 orders of magnitude smaller than the dextran translational diffusion coefficient. The independency of the PFGNMR diffusion coefficients from Δ is confirmed experimentally (Figure S3, Supporting Information). Enhanced diffusion of dextran has been previously observed in the presence of swimming bacteria as a result of hydrodynamic interactions.30 This is less likely to be the governing phenomenon in our case, because even if the selfcross-linking of zirconium carbonate molecules during the reaction yields a hydrodynamic coupling with dextran, no reaction takes place at room temperature, where the diffusion measurements have been conducted. To understand the origin of diffusion enhancement, the effect of dextran molecular weight on the polymer dynamics is investigated.

AZC) with neutral dextran (ζ ∼ −5.1 ± 1.5 mV, Mw ∼ 2000 kDa) results in a negative ζ-potential (∼−32 ± 1 mV at 0.5% wt AZC). A negatively charged dextran−zirconium carbonate complex may readily uncoil and stretch, transforming from a globular shape to a rod-like polyanion. Such deviation from a spherical structure affects the diffusion coefficient:43 D2 = Dt +

r 2(1 − e−2ΔDr) CΔ

(3)

where r is the characteristic length (sphere radius a or rigid rod length L), C is a constant (C = 3 and 36 for spheres and rigid rods, respectively), and Dt and Dr are the translational and

Figure 2. Time evolution of dextran (0.5% wt) normalized diffusion coefficient in AZC (0.5% wt) gelling solutions, obtained from PFGNMR spectroscopy. The blue and black symbols represent hindered (D1) and enhanced (D2) diffusion coefficients, respectively, measured from fitting the echo amplitude attenuations to eq 2. In panel (a), the dynamics of dextran (Mw ∼ 10 kDa) were well prescribed by eq 1. The fraction of macromolecules adopting hindered diffusion f (immobile fraction) is shown with red symbols. The dashed lines are to guide the eyes. Note that at t = 0, dextran undergoes diffusion in pregel solutions (1011 × D0 ∼ 10.19 ± 0.26, 5.98 ± 0.39, 3.54 ± 0.10, 3.75 ± 0.10, 3.20 ± 0.16, and 2.31 ± 0.08 m2 s−1 in panels a−f, respectively, obtained from fitting eq 1 to A(2τ)/A(0) of 5−10 dextran chemical shifts in the range of 3.3−3.8 ppm with R2 > 0.99, also see Figure S1, Supporting Information). 906

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anchor) cross-linking. At a lower AZC concentration (∼0.1% wt), no significant gel network is obtained and the ZCanchored dextran is solely affected by the charge-mediated reconfiguration and complex morphology. At this condition, the diffusion coefficient is well-established by a singleexponential decay of echo amplitude, which increases with time as dextran binds to zirconium carbonate (Figure S5, Supporting Information). This supports the general mechanism proposed in this work. The dynamics of dextran molecules while contacting AZC is presented schematically in Figure 3. In an AZC pregel solution

Time evolution of the diffusion coefficient of dextran molecules (Mw ∼ 10−2000 kDa, radius a ∼ 2−20 nm, 0.5% wt) in ammonium zirconium carbonate (0.5% wt) solutions is presented in Figure 2. Before the cross-linking reaction kicks off (t = 0), regardless of the dextran molecular weight, a single exponential decay (eq 1) fits the echo amplitude attenuation well, yielding free diffusion coefficients similar to the literature.44 When the dextran size (Mw ∼ 10 kDa, a ∼ 2 nm) is comparable to its persistence length lp (e.g., lp ∼ 0.5−1.8 nm obtained from single molecule force spectroscopy or smallangle X-ray scattering45−47), its dynamics in the metallogel (t > 0) is similar to the pregel solution (Figure 2a), suggesting that ZC is unable to trap or reconfigure extremely small macromolecules. An ∼10% decrease in the diffusion coefficient may be the result of a slight increase in the dextran size due to the complexation with zirconium carbonate. Note that the bulk viscosity (Figure S2a, Supporting Information) increases by a factor of ∼5000 after 4 h. Compared to the pore viscosity, this suggests that nanosized molecules in the large gel pores experience no dissipative evolution of the network (e.g., percolation-driven clustering). Increasing the size of dextran molecules beyond Mw ∼ 40 kDa gives rise to a bimodal distribution of diffusion coefficients (similar to Figure 1b) at t > 0. At short times (t ≤ 0.3 h), a significant portion of macromolecules exhibits an enhanced diffusion (Figure 2b-f, black symbols). The larger the dextran size, the more pronounced is the diffusion boost, e.g., D/D0 reaches ∼5 when Mw ≥ 500 kDa after ∼20 min. At this time, the reaction attains its maximum rate (Figure S2b, Supporting Information), yet the network is not fully developed. When the reaction proceeds, enhanced diffusion coefficients level off, adopting values close to the pregel solution (Mw = 40−110 kDa) or 2−3 times larger than the pregel solution (Mw = 500− 2000 kDa). Such trend is likely arisen from the gradual increase in the dextran-zirconium carbonate size as a result of Zrmediated coclustering. The diffusion enhancement by a conformation transformation from a sphere to a rod-like particle is shown in Figure S4 (Supporting Information). When the aspect ratio of a rod is small, the diffusion coefficient adopts values close to the diffusion coefficient of a sphere with an equivalent hydrodynamic radius. By increasing the particle length, a significant diffusion enhancement is observed. The lower the particle cross-sectional area (at a constant length), the larger the enhancement. When the dextran size is small, for example, a/lp ∼ 1 (Mw ∼ 10 kDa), the ZC association does not significantly change the diffusion coefficient, because dextran is unable to undergo reconfiguration. The larger the a/lp, the more pronounced is the effect of dextran-zirconium carbonate binding. According to the hydrodynamic theory of diffusion, depending on the dextran aspect ratio and L, eq 5 may predict larger diffusion coefficients for rods (D) than for coiled (Ds) polymers. As an example, for dextran with Mw ∼ 2000 kDa, L ∼ 50 nm, and a ∼ 4.3 nm, enhanced diffusion D/Ds ∼ 4. Simultaneously, at short times (t ≤ 0.3 h), a population of dextran molecules (immobile fraction) adopts a hindered motion (Figure 2b−f, blue symbols), which progressively becomes arrested as the gel structure is developed (e.g., plateaued D/D0 ∼ 0.1 at t ∼ 4 h). The immobile fraction increases by increasing the dextran size (e.g., up to f > 50% after 4 h). This implies that Zr metallogels are more effective in arresting larger macromolecules, likely because of more available binding sites per molecules and branched (multi-

Figure 3. Mechanism of dextran reconfiguration and entrapment using an ultrasoft gel-forming solution of zirconium carbonate (ZC). Note that the ammonium counterions are not shown.

(Figure 3, left panel), dextran has insignificant interactions with ZC molecules and adopts a globular conformation. At the beginning of the cross-linking reaction, heat-activated ZC molecules through the partial decomposition according to reaction 1 form complexes with dextran molecules, increasing the dextran surface charge. Negative patches of ZC on the dextran tend to increase the intramolecular electrostatic repulsion, uncoiling dextran (Figure 3, middle panel). This process is comparable with the deionization of a polyanion suspension, where a screened double layer is expanded by removing ions from the bulk (e.g., by ion exchange resins), stretching the polyanion. Further (ZC)n-dextran cross-linking arrests dextran molecules by incorporating them in the ZC metallogel (Figure 3, right panel). In conclusion, we have addressed one of the key challenges of cargo delivery in nanomedicine, that is, macromolecular entrapment in ultrasoft, porous materials, hinging on the physicochemical fundamentals of Zr-assisted complexation and hydrogen bonding. PFGNMR spectroscopy attested to two distinguished groups of dextran molecules inside Zr metallogels; one adopting a diffusion coefficient higher than the bulk value likely as a result of structural reconfiguration, and the other exploring a hindered dynamics due to the incorporation in the gel structure. This work paves the first steps toward designing cost-effective ultrasoft nanodrug carriers as well as motifs to reconfigure macromolecules. Future endeavors should seek the potential of metallogels in engineering protein folding at the cell level to prevent or control proteopathy.

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EXPERIMENTAL METHODS

PFGNMR spectroscopy was conducted on preheated AZC solutions (0.5% wt) at room temperature using a 500 MHz NMR instrument (Varian INOVA) equipped with room temperature 1H−13C−15N triple-resonance probe and vertical pulsed field gradients. To obtain the diffusion coefficient of dextran in metallogels, the echo amplitude decay was registered as a function of gradient strength (∼1.9−45 G cm−1) using a H2O-suppressed LED pulse sequence.48 The size and ζ907

DOI: 10.1021/acsmacrolett.6b00447 ACS Macro Lett. 2016, 5, 904−908

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ACS Macro Letters potential of ZC and dextran were measured using dynamic light scattering in disposable cuvettes and calculated from electrophoretic mobility (electrophoretic light scattering ELS, conducted in the universal dip cell kit using Zetasizer NanoZS equipped with a 4 mW633 nm He−Ne solid-state laser, Malvern Instruments, U.K.), respectively. Viscoelastic properties (elastic G′ and loss G″ moduli) of gelling AZC solutions were registered with time upon heating at 80 °C through small-amplitude oscillatory shear (SAOS) rheology. Extended Experimental Methods are provided in the Supporting Information. The dynamics of AZC gel viscoelastic evolution, frequency sweeps, and LVE tests are presented in Figure S2, Supporting Information.

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(12) Vermonden, T.; Jena, S. S.; Barriet, D.; Censi, R.; van der Gucht, J.; Hennink, W. E.; Siegel, R. A. Macromolecules 2010, 43 (2), 782− 789. (13) Desiraju, G. R. Acc. Chem. Res. 1996, 29 (95), 441−449. (14) Del Valle, E. M. M. Process Biochem. 2004, 39 (9), 1033−1046. (15) Szejtli, J. Chem. Rev. 1998, 98 (97), 1743−1753. (16) Haslam, E. J. Nat. Prod. 1996, 59 (2), 205−215. (17) Park, B. K.; Kitteringham, N. R.; O'Neill, P. M. Annu. Rev. Pharmacol. Toxicol. 2001, 41, 443−470. (18) Boddé, H. E.; Lehr, C. M.; De Vries, M. E.; Bouwstra, J. A.; Junginger, H. E. Biofouling 1991, 4 (1−3), 163−169. (19) Sloan, J. W.; Alexander, B. H.; Lohmar, R. L.; Wolff, I. A.; Rist, C. E. J. Am. Chem. Soc. 1954, 76 (17), 4429−4434. (20) Perrino, C.; Lee, S.; Choi, S. W.; Maruyama, A.; Spencer, N. D. Langmuir 2008, 24 (16), 8850−8856. (21) de Jonge, E.; Levi, M. Crit. Care Med. 2001, 29 (6), 1261−1267. (22) Wang, D. N.; Liu, S. Y.; Trummer, B. J.; Deng, C.; Wang, A. L. Nat. Biotechnol. 2002, 20 (3), 275−281. (23) Ellis, R. J. Trends Biochem. Sci. 2001, 26 (10), 597−604. (24) Liu, Z.; Jiao, Y.; Wang, Y.; Zhou, C.; Zhang, Z. Adv. Drug Delivery Rev. 2008, 60 (15), 1650−1662. (25) Bohrer, M. P.; Patterson, G. D.; Carroll, P. J. Macromolecules 1984, 17 (6), 1170−1173. (26) Luby-Phelps, K.; Castle, P. E.; Taylor, D. L.; Lanni, F. Proc. Natl. Acad. Sci. U. S. A. 1987, 84 (14), 4910−4913. (27) Verkman, A. S. Trends Biochem. Sci. 2002, 27 (1), 27−33. (28) Nugent, L. J.; Jain, R. K. Cancer Res. 1984, 44 (1), 238−244. (29) Jain, R. K. Cancer Res. 1987, 47 (17), 3039−3051. (30) Kim, M. J.; Breuer, K. S. Phys. Fluids 2004, 16 (9), 1−5. (31) Ciferri, A.; Perico, A. Ionic Interactions in Natural and Synthetic Macromolecules; John Wiley & Sons, Inc.: NJ, 2012. (32) Reed, A. E.; Curtiss, L. a; Weinhold, F. Chem. Rev. 1988, 88 (6), 899−926. (33) Blokzijl, B. W.; Engberts, J. B. F. N. Angew. Chem., Int. Ed. Engl. 1993, 32 (11), 1545−1579. (34) Lee, D. B. N.; Roberts, M.; Bluchel, C. G.; Odell, R. A. ASAIO J. 2010, 56 (6), 550−556. (35) Wenz, H. J.; Bartsch, J.; Wolfart, S.; Kern, M. Int. J. Prosthodont. 2008, 21 (1), 27−36. (36) Sherepo, K. M.; Red’ko, I. A. Biomed. Eng. 2004, 38 (2), 77−79. (37) Tang, S.; Huang, X.; Chen, X.; Zheng, N. Adv. Funct. Mater. 2010, 20 (15), 2442−2447. (38) Denry, I.; Kelly, J. R. Dent. Mater. 2008, 24 (3), 299−307. (39) Stejskal, E. O.; Tanner, J. E. J. Chem. Phys. 1965, 42 (1), 5. (40) Takasaki, F.; Fujiwara, K.; Nakajima, Y.; Nishikawa, T.; Masu, H.; Imanari, M.; Hidaka, Y.; Ogawa, N. Dalt. Trans. 2015, 44 (2), 645−652. (41) Sako, R.; Sakai, J. Surf. Coat. Technol. 2013, 219, 42−49. (42) Song, D.; Breedveld, V.; Deng, Y. J. Appl. Polym. Sci. 2011, 122 (2), 1019−1029. (43) Baldwin, A. J.; Christodoulou, J.; Barker, P. D.; Dobson, C. M.; Lippens, G. J. Chem. Phys. 2007, 127 (11), 114505. (44) Jowkarderis, L.; van de Ven, T. G. M. Soft Matter 2015, 11, 9201−9210. (45) Rief, M.; Oesterhelt, F.; Heymann, B.; Gaub, H. E. Science 1997, 275 (5304), 1295−1297. (46) White, J. A.; Deen, W. M. Biophys. J. 2002, 82 (4), 2081−2089. (47) Garg, S. K.; Stivala, S. S. J. Polym. Sci., Polym. Phys. Ed. 1978, 16 (8), 1419−1434. (48) Altieri, A. S.; Hinton, D. P.; Byrd, R. A. J. Am. Chem. Soc. 1995, 117 (9), 7566−7567.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.6b00447. Extended Materials and Methods, echo amplitude decay of dextran PFGNMR spectra, rheological properties of AZC (0.5% wt) metallogels, PFGNMR-based diffusion coefficient of dextran as a function of pulse lag, theoretical diffusion coefficient of rod-like particles, and the diffusion coefficient of dextran upon reaction with AZC (0.1% wt) (PDF).

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AUTHOR INFORMATION

Corresponding Authors

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

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from a NSERC Discovery Grant and from the NSERC Innovative Green Wood Fibre Products Network are gratefully acknowledged. A.S. cordially thanks Dr. T. Sprules, Quebec/Eastern Canada High Field NMR Facility, for the PFGNMR spectroscopy training, and Prof. P. Carreau and Dr. A. Saffar, École Polytechnique de Montréal, for providing the rheometer and training.

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REFERENCES

(1) Lin, C. C.; Metters, A. T. Adv. Drug Delivery Rev. 2006, 58 (12− 13), 1379−1408. (2) Branco, M. C.; Pochan, D. J.; Wagner, N. J.; Schneider, J. P. Biomaterials 2009, 30 (7), 1339−1347. (3) Brandl, F.; Kastner, F.; Gschwind, R. M.; Blunk, T.; Tessmar, J.; Göpferich, A. J. Controlled Release 2010, 142 (2), 221−228. (4) Cruise, G. M.; Scharp, D. S.; Hubbell, J. A. Biomaterials 1998, 19 (14), 1287−1294. (5) Guvendiren, M.; Lu, H. D.; Burdick, J. a. Soft Matter 2012, 8 (2), 260−272. (6) Lu, H. D.; Charati, M. B.; Kim, I. L.; Burdick, J. A. Biomaterials 2012, 33 (7), 2145−2153. (7) Hoare, T. R.; Kohane, D. S. Polymer 2008, 49 (8), 1993−2007. (8) Altunbas, A.; Lee, S. J.; Rajasekaran, S. A.; Schneider, J. P.; Pochan, D. J. Biomaterials 2011, 32 (25), 5906−5914. (9) Yan, C.; Altunbas, A.; Yucel, T.; Nagarkar, R. P.; Schneider, P.; Pochan, D. J.; Schneider, J. P.; Pochan, D. J. Soft Matter 2010, 6 (20), 5143−5156. (10) Appel, E. a.; del Barrio, J.; Loh, X. J.; Scherman, O. a. Chem. Soc. Rev. 2012, 41 (18), 6195−6214. (11) Byrne, M. E.; Park, K.; Peppas, N. A. Adv. Drug Delivery Rev. 2002, 54 (1), 149−161. 908

DOI: 10.1021/acsmacrolett.6b00447 ACS Macro Lett. 2016, 5, 904−908