Robust Hydrogels from Lanthanide Nucleotide Coordination with

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Robust Hydrogels from Lanthanide Nucleotide Coordination with Evolving Nanostructures for Highly Stable Protein Encapsulation Li Xu, Zijie Zhang, Xiaoqiang Fang, Yibo Liu, Biwu Liu, and Juewen Liu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b18005 • Publication Date (Web): 12 Apr 2018 Downloaded from http://pubs.acs.org on April 12, 2018

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ACS Applied Materials & Interfaces

Robust Hydrogels from Lanthanide Nucleotide Coordination with Evolving Nanostructures for Highly Stable Protein Encapsulation

Li Xu,ab* Zijie Zhang,b Xiaoqiang Fang,a Yibo Liu,b Biwu Liu,b and Juewen Liub*

School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan, 528458, P. R. China. E-mail: [email protected]

Department of Chemistry and Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Ave. West, Waterloo, Ontario, Canada, N2L 3G1, E-mail: [email protected]

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Abstract Metal coordination with organic ligands often produce crystalline metal-organic frameworks (MOF) and sometimes amorphorous nanoparticles. In this work, we explore a different type of material from the same chemistry: hydrogels. Lanthanides are chosen as the metal component because of their important technological applications and continously tunable properties. Adenosine monophosphate (AMP) and lanthanides form two types of coordination materials: the lighter lanthanides from La3+ to Tb3+ form nanoparticles, while the rest heavier ones initially form nanoparticles but later spontaneously transform to hydrogels. This slow sol-to-gel transition is accompanied with heat release as indicated by isothermal titration calorimetry (ITC). The transition is also accompanied with a morphology change from nanoparticles to nanofibers as indicated by TEM. These gels are insensitive to ionic strength or temperature with excellent stability. Gelation is unique to AMP since other nucleotides or other adenine derivatives only yield nanoparticles or soluble products. Entrapment of guest molecules such as glucose oxidase is also explored, where the hydrogels allow better enzyme activity and stability compared to nanoparticles. Further applications of lanthanide coordinated hydrogels might include biosensors, imaging agents, and drug delivery.

Keywords:

coordination

polymers;

hydrogels;

metal-organic

frameworks;

proteins;

encapsulation


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Introduction Metal coordination is a simple yet powerful method of building materials. Depending on the metal species and ligand geometry, a suite of structures have been demonstrated. The resulting materials are called metal-organic frameworks (MOFs) when they are porous and crystalline,1 while more generally they are called coordination polymers (CPs).2-7 CPs are useful for catalysis,8-11 sensing,12-16 drug delivery,17 energy harvesting,18 and gas adsorption.19-21 So far, most known CPs are nanoparticles, while we are interested in a different type of material: hydrogel. Hydrogels swell in water and they are extremely useful for encapsulation of guest molecules, tissue engineering, and controlled release.22-24 Using metal coordination for preparing hydrogels is still at an early stage.25-29 Compared to covalent chemical crosslinking, metal coordinated hydrogels are formed under mild conditions and may have self-healing properties. Nucleotides are interesting ligands for metal coordination. Each nucleotide contains a phosphate and a nucleobase.6, 7, 30-32 Nucleotide CPs have been used for various applications in enzyme mimicking,14, 33 drug delivery,34 sensing,35, 36 logic gates,15, 16 and encapsulation.37, 38 Lanthanides (Ln) refer to the 15 metals from La to Lu. Ln3+ ions have been used to cleave nucleic acids,39-42 prepare luminescent probes,43 and build CPs.37, 44, 45 Fundamental interactions between Ln3+ and nucleotides have also been studied and both the phosphate and the purine bases are important for metal coordination.46-50 Previous work only reported CP nanoparticles formed by Ln3+ and nucleotides. Herein, we discovered that six heavy lanthanides have a nanoparticle-to-hydrogel transition upon aging, accompanying a change in morphology from nanoparticles to nanofibers. This type of sol-gel transition has never been reported in such CPs. The application of such hydrogels for entrapping protein enzymes has also been explored.



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Materials and Methods Chemicals. Adenine, adenosine, adenosine 5′-monophosphate (AMP) disodium salt, adenosine 5′-triphosphate (ATP) disodium salt hydrate, guanosine 5′-monophosphate (GMP) disodium salt hydrate, cytidine 5′-monophosphate (CMP) disodium salt, D-ribose 5-phosphate disodium salt, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), glucose oxidase, albuminfluorescein isothiocyanate conjugate (F-BSA) and the LnCl3 were purchased from SigmaAldrich. Acetate and 2-(N-morpholino)ethanesulfonic acid (MES) monohydrate were from Mandel Scientific Inc. (Guelph, ON, Canada). Milli-Q water was used for all the experiments to prepare buffers and solutions. ITC. Isothermal titration calorimetry (ITC) was performed on a VP-ITC microcalorimeter instrument (MicroCal). Nucleotide, nucleoside and Ln3+ solutions were prepared using the same buffer (50 mM MES, pH 6, 25 mM NaCl). The nucleotide/nucleoside loaded in the cell was 5 mM (1.4551 mL). The Ln3+ concentration in the injection syringe was 20 mM. Each titration consisted of an initial injection of 1 µL followed by 28 injections of 10 µL spaced 240 sec apart. Data from the first injection were omitted from analysis. Background heat from Ln3+ injecting into the buffer was subtracted. Unless otherwise indicated, all the tests were performed at 25 °C. Binding isotherms were fitted using the two binding site model in Origin 7.0. For the single injection ITC experiments, 20 µL of 500 mM Ln3+ was injected into the cell containing 14 mM of AMP (1.45 mL) all at once, and the reaction was followed for 2 h. Preparation of CPs. The Ln3+/nucleotide CPs were synthesized according to a previously reported method.37 Typically, 140 µL LnCl3 aqueous solution (100 mM in Milli-Q water) was added to 280 µL of AMP solution dissolved in acetate buffer (100 mM, pH 5.0) to produce a 1:2 molar ratio, and white precipitants formed immediately. The sample was then centrifuged at 4 ACS Paragon Plus Environment

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10,000 rpm for 5 min and washed with Milli-Q water to remove unreacted chemicals. The precipitants were finally dispersed in acetate buffer (100 mM, pH 5.0), which yielded a hydrogel after 6 h at room temperature. TEM and DLS. Transmission electron microscopy (TEM) was performed on a Philips CM10 microscope. A drop of Ln3+/AMP dispersion (100 µg/mL) was placed on a 230 mesh holy carbon copper grid. After 30 s, the excess solution was removed by a piece of filter paper. The gel samples were first disrupted before putting on the grid. The ζ-potential of the CPs was measured by dynamic light scattering (DLS) using a Malvern Zetasizer Nano ZS90 system with a He-Ne laser (633 nm) at 90° collecting optics at 25 °C. In a typical experiment, the CPs (100 µg/mL) were dispersed in 10 mM HEPES buffer (pH 7.6). Rheometry. Rheological tests of hydrogels were conducted on a DHR-3 rheometer (TA Instruments, DE, USA), with a 40 mm diameter cone-plate attached to a transducer. The temperature was controlled by the bottom Peltier plate at 25 °C. All tests were performed immediately after transferring 0.5 mL of a Dy3+/AMP hydrogel onto the sample stage. Frequency sweep was obtained with a strain of 0.2%. Strains sweep was obtained with a frequency of 1 Hz. Sol-gel phase transition. To study the effect of pH, the samples were adjusted from pH 2 to 13 with 0.25 M NaOH or 0.25 M HCl. To study the temperature effect, the samples were maintained at each temperature for 30 min. After treatment, each sample was centrifuged at 10,000 rpm for 5 min followed by inverting the tube for 1 min to judge if the gel formed (documented by a digital camera). The formed gel was also weighed on a balance for quantification.



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Encapsulation and release of proteins. Encapsulation of protein was performed by mixing AMP (100 mM, 280 µL), F-BSA (10 mg/mL, 100 µL) and acetate buffer (100 mM, pH 5.0, 1570 µL) before LnCl3 (100 mM, 140 µL) was added. The amount of protein incorporated was calculated from the absorbance of the supernatant solution compared to an aqueous solution of untreated protein in the same buffer. To study release, protein loaded gels or nanoparticles were placed into 1.5 mL Eppendorf tubes, and 1.0 mL of acetate buffer (100 mM, pH 5.0) was added. At designated time points, 1.0 mL of supernatant was replaced with fresh acetate buffer (100 mM, pH 5.0), and 200 µL of the supernatant for each sample was analyzed for fluorescent intensity on a SynergyTM H1 microplate reader in duplicate. Immobilization of GOx within Ln3+/AMP hydrogels was performed by mixing AMP (100 mM, 280 µL) in acetate buffer (100 mM, pH 5.0), 1560 µL acetate buffer (100 mM, pH 5.0), and GOx (10 mg/mL, 200 µL). Then, La3+, Dy3+ or Lu3+ (100 mM, 140 µL) in water was quickly added and mixed. After 6 h, the samples were centrifuged at 8000 rpm for 10 min. The amount of encapsulated GOx was measured by the Bradford assay from the absorption intensity of the supernatant solutions. The absorption of untreated GOx was used as a reference. GOx activity assays and stability test. For activity assay, a glucose solution (5 M, 18 µL) was mixed with free GOx (1 mg/mL, 40 µL) or 40 µL of suspension of the encapsulated GOx (containing 1 mg/mL GOx) and phosphate buffer (10 mM, pH 7.6, 142 µL) for 1 h. Then, 20 µL of the sample was mixed with 5 µL Fe3O4 nanoparticles (2 mg/mL) and 2 µL ABTS (100 mM) dissolved in acetate buffer (50 mM, pH 4.0). The mixture was incubated at room temperature for 30 min, and the absorbance at 415 nm was measured by a UV-vis spectrometer. For stability test at different pH, the suspension of free GOx or the loaded materials were incubated in different


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buffers for 4 h. To test different temperatures, the samples in phosphate buffer (10 mM, pH 7.6) were incubated at 50 to 90 °C for 30 min before the GOx activity was measured.

Results and Discussion Six heavy lanthanides formed hydrogels with AMP. To gain a comprehensive understanding, we used the 14 Ln3+ from La3+ to Lu3+ but omitted the radioactive Pm3+. We mixed each Ln3+ with adenosine monophosphate (AMP) at a 1:2 ratio (Ln3+:AMP), and all the samples turned cloudy immediately, suggesting formation of CP nanoparticles.37 After overnight incubation, interestingly, the last six Ln3+ (from Dy3+ to Lu3+) all turned to hydrogels, while the rest eight lighter ones remained as nanoparticle dispersions as originally prepared (Figure 1A). For the other two rare earth metals, Sc3+ formed CP nanoparticles, while Y3+ formed hydrogels (Figure 1B). The ionic size of Y3+ is similar to that of Ho3+, and it appears that the size of Ln3+ is critical for hydrogel formation.

Figure 1. Photographs of the CPs formed by mixing (A) various Ln3+; or (B) Sc3+ and Y3+ (7 mM) with AMP (14 mM) overnight at pH 5. The vials were inverted before taking the pictures. 7 ACS Paragon Plus Environment


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(C) The weight of the final Ln3+/AMP CP products after centrifugation. (D) The swelling ratios (the mass of hydrated gel over that of dried gel) of the gels.

The weight of each CP product was individually measured after centrifugation and removal of liquid water with a pipette (Figure 1C). The last six samples were much heavier since they trapped much more water. There seemed to be a trend that the gels with a heavier Ln3+ retained more water. With 7 mM Ln3+ and 14 mM AMP, and assuming all these monomers went into the gels, the swelling ratios ranged from ~120 (for Dy3+) to ~160 (for Lu3+) (Figure 1D). Here swelling ratio was defined as the mass of the hydrated gel over the mass of the dried gel. Many organic gels can reach a swelling ratio of around 2000,51 and thus the swelling here was quite moderate. Delayed gelation with evolving nanostructures. While the same reaction was previously performed by Nishiyabu et al,37 they only reported CP nanoparticles. We initially obtained nanoparticles as well but observed gels after overnight incubation. Our results indicated that Ln3+ could form both nanoparticles and hydrogels with AMP but with a delayed gelation. We studied the kinetics of gelation with Dy3+and it took 6 h for full gelation to occur at room temperature (~22 °C, Figure 2B, inset). Another transition occurred between 1 h and 2 h, when the system became more transparent and likely the size or aggregation state of the CP nanoparticles changed after ~1 h. To quantitatively follow this interesting slow gelation, we performed a single-injection isothermal titration calorimetry (ITC) experiment. Instead of typical multiple injections, we added the Dy3+ ions all at once (Figure 2B). A sharp heat release was observed right after the


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injection (at 2 min), and then the system became stable with no more heat released in the next few minutes. We assigned this initial heat to the binding of Dy3+ to AMP. About 10 min later, a broader heat release was observed spanning ~30 min, and this second transition could be related to the delayed gelation. The faster gel transition during ITC than that shown in the photograph is likely due to the higher temperature for ITC (vide infra). To understand the morphology of these CP materials before and after gelation, we prepared TEM samples at the two time points marked by 1 and 2 in Figure 2B. At time 1 (Figure 2A), we observed aggregated irregular nanoparticles consistent with previous reports.37 At time point 2, interestingly, the same sample transformed to a nanofiber (Figure 2C). Such fiber structures are typically seen in hydrogels and this TEM result also supports the sol-gel transition. Therefore, the second ITC peak was associated with the transformation of morphology of the CPs. We then measured the ζ-potential of the samples. All the CP products were negatively charged right after preparation (Figure 2D), and the charge was more negative for the heavier Ln3+. The first pKa of Ln3+ bound water decreases from 9.3 (for La3+) to 8.2 (for Lu3+), making hydrated Lu3+ more acidic than hydrated La3+, which might explain the trend of surface charge. After gelation, the product become less negatively charged (Figure 2E), and this shift in surface charge suggests a change in the coordination environment.



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Figure 2. TEM micrographs of the CPs formed by mixing AMP with Dy3+ at (A) time point 1; and at (C) time point 2 of (B). (B) An ITC trace of a single injection of Dy3+ (20 mM) into AMP (5 mM) in MES buffer (50 mM, pH 6, 25 mM NaCl) at 25 °C. (D) ζ-potential of the CP products formed right after mixing AMP with the 14 Ln3+ ions after washing in 10 mM HEPES buffer (pH 7.6). (E) ζ-potential values of the CPs before and after forming hydrogels. The gels were disrupted and re-dispersed before measurement. To further understand the gelation process, we studied the effect of temperature. At 4 °C, it took 8 h for the gel to form, while at a higher temperature (60 °C), gelation was faster (Figure 3A, B). The temperature effect was also followed using single-injection ITC (Figure 3C). Compared to the transition at 25 °C, the one at 30 °C occurred faster, consistent with the visual inspection result. The requirement on temperature suggested that the gelation is an energydependent process and an activation energy barrier needs to be overcome.


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Taken together, we believe a partial dissolution of the CP nanoparticles must have occurred since the gel fibers were in general smaller in diameter than that of the particles (Figure 2A, C). This was consistent with the suspension became less cloudy before gelation (inset of Figure 2B). Full dissolution did not occur since the system was not completely transparent. The change in ζ-potential, temperature-dependent gelation and release of heat all supported a change in the coordination environment during gelation.

Figure 3. Photographs of Dy3+ and AMP mixtures at (A) 4 °C, and (B) 60 °C at different time points after mixing. Single injection ITC traces of (C) Dy3+ titrating into AMP at two temperatures; and (D) three different Ln3+ titrating into AMP at 25 °C.

Heavier lanthanides favor gelation. In addition to the delayed gelation, another interesting observation was that gels only formed with the last six Ln3+ (Figure 1A). To better understand this, we then performed single-injection ITC on different Ln3+ (Figure 3D). La3+ showed only



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one peak right after injection, consistent with its only forming nanoparticles. Lu3+ had a quite broad second transition, and compared to that of Dy3+, its transition was further delayed. It might be that a heavier lanthanide needs more activation energy for the sol-gel transition. To further understand the reactions, we then performed traditional multi-injection ITC experiments (Figure 4A-C). To avoid gelation, we also lowered the metal and AMP concentrations. By fitting these ITC traces, all the thermodynamic parameters can be obtained (the bottom panels and Table S1). We observed a large heat release with La3+, the heat dropped significantly with Tb3+, while barely any heat was released with Lu3+. All these Ln3+ had a similar binding affinity (e.g. similar Kd values or ∆G, Table S1), suggesting an increased contribution of entropy as the atomic number of Ln3+ increases.46 It is likely that more water molecules were released during the reaction for Lu3+ than for La3+ upon coordination with AMP. This trend is similar to that for titrating Ln3+ into GMP.46 With decreasing the size of Ln3+ (e.g. Lu3+ being the smallest), the number of inner-sphere coordinated water or other ligands is decreased due to steric effects, and it is more difficult for Lu3+ to loss water.46 Therefore, increased water release for Lu3+ (i.e. more entropy increase) would indicate a very strong AMP coordination to over compensate the energy loss for releasing water. All these three samples showed a binding stoichiometry of 0.5 to 0.6 for Ln3+:AMP. Therefore, a fixed 1:2 ratio was used in the study for preparing CPs. When Lu3+ was titrated into D-ribose 5-phosphate (R5P, without the base but with the phosphate and ribose, Figure 4D), a large amount of heat absorption was observed, suggesting phosphate binding is accompanied with heat absorption.46 Therefore, for all of these lanthanides, they must also bind to the adenine base part to explain the negative enthalpy of the reaction. The


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gelation transition, which is accompanied with heat release cannot be assigned to more phosphate binding, but instead less contributions from phosphate binding. The Kd’s from ITC were very similar for different Ln3+, indicating that forming CP nanoparticles or gels was not governed by binding affinity. Most Ln3+-size dependent transitions happen at Gd3+ (so called Gd break),52-56 while in our case here, the transition occurred between Tb3+ and Dy3+. This suggests that more than one factor is contributing to our nanoparticle-to-gel transition, and the water retain ability might be an important reason. The morphology of the CP products was further characterized using transmission electron microscopy (TEM) (Figure 4E-G). After overnight incubation, La3+/AMP formed aggregated nanoparticles with the individual particle size around 30 nm, while the mixtures of AMP with Dy3+ and Lu3+ formed fibers consistent with their hydrogel properties. The fibers were longer with Lu3+ than with Dy3+, which may explain Lu3+/AMP’s retaining more water in Figure 1D.



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Figure 4. ITC traces of titrating (A) La3+, (B) Tb3+, (C) Lu3+ into AMP; and (D) titrating Lu3+ into R5P in MES buffer (50 mM, pH 6, 25 mM NaCl) at 25 °C. Panel (D) is reproduced with permission from reference 46. Copyright 2018 Elsevier. Background heat of titrating Ln3+ into the same buffer was subtracted. TEM micrographs of the CPs formed by mixing AMP with (E) La3+, (F) Dy3+, and (G) Lu3+ after overnight incubation.

Only AMP supports gelation. All of our above studies used AMP. We then tried other nucleosides and nucleotides. Interestingly, GMP and CMP failed to formed gels with Dy3+ after overnight incubation (Figure 5A), indicating adenine coordination is critical for gelation. We then tested the importance of the phosphate part by using adenine and its derivatives (Figure 5B).


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Again, only AMP promoted gel formation for Dy3+, while clear solutions were formed with the rest. Therefore, it is important to have just one phosphate linked to the nucleotide. We also varied the ratio of metal and AMP by keeping their total concentration at 21 mM. It appeared that the system is quite tolerate to excessed AMP, while if Tm3+ was in excess, the yield of the gel could be lower (Figure 5C). To further guide the synthesis of gels, we varied the concentrations of Dy3+and AMP but keeping their 1:2 ratio. Below 3 mM Dy3+, little gel formed (Figure 5D). The gel weight reached the maximum with 7 mM Dy3+. Further increasing of the concentrations, however, decreased the gel weight likely due to the lack of sufficient water. Finally, we carried out rheological experiments to estimate the mechanical properties of the Dy3+/AMP gels. In the frequency sweep experiment, the storage modulus (G′) was much larger than the loss modulus (G′′) with a linear response observed over a wide frequency range from 0.1 to 100 Hz (Figure 5E). The changes in G′ and G′′ under shear strain were also recorded at a constant frequency of 1 Hz. The strain sweep showed a roughly linear regime below the critical strain value of ~3%, above which both moduli gradually decreased to very low values indicating a partial break of the gels (Figure 5F).



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Figure 5. Photographs of the products formed between Dy3+ with different (A) nucleotides, or (B) adenine and its derivatives in acetate buffer (100 mM, pH 5.0). (C) Varying the ratios while keeping the sum of Tm3+ and AMP concentrations at 21 mM. (D) The final product weight of Dy3+/AMP prepared at different concentrations by retaining a 1:2 ratio of these two species. (E) Dynamic frequency sweep rheometry data for Dy3+/AMP gel at 25 °C (strain kept at 0.2%). (F) Strain sweep rheometry data (storage modulus G' and loss modulus G˝ versus strain) for the gel.

Highly robust coordination gels. We further tested the stability of the CP gels in different conditions. The gel weight was independent of the salt concentration with up to 1 M NaCl (Figure 6B), suggesting that electrostatic interaction might not be important for gelation and such gels can withstand high salt. The effect of pH was then tested. The sol-gel transition occurred between pH 2 and 9, and the highest gel yield was at pH ~5 (Figure 6C). We reason that when the pH was too high, Ln3+ was hydrolyzed and thus could not bind to AMP anymore; while at pH lower than 2, adenine was fully protonated (pKa = 3.5), which also disrupted metal binding. 16 ACS Paragon Plus Environment

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Overall, the gel is more susceptible to base, suggesting that OH- can compete with AMP for metal coordination and hydrolyze lanthanides. The above pH test was for gel formation. We further tested pre-formed gels and then added HCl or NaOH. At pH 2, most of the gel disappeared and only a small fraction left after centrifugation (Figure 6D). With a final of 1 M HCl, the gel fully dissolved and formed a clear solution. At pH 9, the gel also dissolved becoming a cloudy suspension (Figure 6E). After centrifugation, only a small volume of white pellet was obtained, and these precipitants were likely lanthanide hydroxide. Further adding NaOH to reach pH 14 again yielded a clear solution. Urea is a hydrogen bond disruptor. We added a final of 4 M urea, which led to disruption of the gel (Figure 6F). However, after centrifugation, the sample formed a gel again. Therefore, urea could disrupt some interactions responsible for forming bulk gels (e.g. connecting small gel pieces together), but could not disrupt the core structure of the gels. Finally, the effect of temperature was studied and the gel was stable at even 100 °C (Figure 6G). Combining the data on urea and heating, it appears that hydrogen bonding is not important, and metal coordination is likely to be the main contributor. Overall, this type of gel is quite robust despite the fact that it is not covalently crosslinked.



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Figure 6. (A) A schematic illustration of Ln3+/AMP coordination. Gel weights (B) in different salt concentrations and (C) at various pH values. Photographs of the gel stability assay in (D) acidic; (E) basic; and (F) 4 M urea conditions.(G) Temperature effect on the Dy3+/AMP gels, and the gels remained stable even at 100 °C.

Mechanism of gelation. With the above characterization, we now have a better picture on the gelation process. From ITC, it is known that phosphate binding absorbs heat, while gelation releases heat. Based on this, we reason that the heavier lanthanides are initially coordinated mainly with the phosphate of AMP, forming a kinetically stable but thermodynamically less stable structure. With thermal energy, the system gradually transformed to a thermodynamically more stable structure by replacing some of the phosphate binding with base binding, thus freeing some phosphate groups. For GMP, the contribution of its phosphate binding to the lanthanides is likely to be larger than that for AMP, which is reflected from the positive enthalpy for the heavy


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lanthanides and thus GMP is less likely to free its phosphate.46 This can explain why GMP cannot form gels. The way AMP and GMP coordinate to lanthanide is quite different. For example, the Tb3+/GMP complex is highly luminescent while Tb3+/AMP is not. A similar transformation of coordination geometry in CPs has been previously reported in Au3+ coordination to adenosine.57 In that case, the energy can be from UV light or heat. After the transformation, the product became luminescent. Adenosine does not have a phosphate group and thus it is solely related to the change in the coordination in the base part (with the N9 position blocked by the ribose). This Au3+ example also indicates the possibility of changing coordination geometry in CPs to yield different properties. With the above discussion, we could only conclude that both phosphate and the adenine base contributed to Ln3+ binding. Hydrogels are amorphous and cannot be studied by X-ray crystallography. We did powder XRD on the dried La3+/AMP and Dy3+/AMP samples but did not observe well-defined diffraction peaks, suggesting that the dried materials were amorphous. Without higher resolution structural information, it is difficult to know the exact coordination geometry. Figure 6A showed a proposed structure of the Ln3+/AMP complex. Overall, a heavy Ln3+ and AMP are required for forming such gels and the adenine base and phosphate of AMP both contribute to metal coordination. Retaining encapsulated enzyme activity. After understanding the physical properties of these novel gels, we then explored their application for molecular encapsulation. Typically, a catalyst (e.g. sol-gel transition in silica), or initiator (e.g. radical polymerization) is needed for making gels. An advantage of the CP gels is that gelation is spontaneous and no UV light or chemical initiators are needed, and thus the reaction can be performed under mild and physiological conditions.37, 44, 58-60 19 ACS Paragon Plus Environment


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We first chose a protein (fluorescein-labeled bovine serum albumin, F-BSA, pI = 4.7) as a model guest molecule. This protein was mixed with Ln3+ and AMP during CP formation. The inset of Figure 7B shows that most of the proteins were in the gel while the water phase was clear, indicating a high loading efficiency. We then used excess amount of protein and quantitatively measured the loading in each CP (Figure 7B). Compared to the La3+/AMP CP nanoparticles, the hydrogels formed by AMP with Dy3+or Lu3+ had a slightly higher loading efficiency. Overall, the F-BSA protein was readily encapsulated by both CP nanoparticles and hydrogels. Following this, we explored the release of F-BSA from the CP nanoparticles and hydrogels (Figure 7F). The CP nanoparticles and hydrogels exhibited a similar release profile releasing ~40% after the first day. The release then showed down and another 20-30% was released in the next five days. There was not much difference between CP nanoparticles and hydrogels in this aspect. We then wanted to test whether the function of proteins was affected by encapsulation. For this purpose, we used glucose oxidase (GOx). GOx can convert glucose to gluconic acid and H2O2, and the H2O2 product was reacted with iron oxide nanozymes to oxidize ABTS for color production (see Figure 7A for the reaction scheme). Using this assay, we found that the La3+/AMP nanoparticles had only ~20% of the activity of the free enzyme, but the gels with Dy3+ or Lu3+ both had nearly 100% of the original activity (Figure 7C). Therefore, although the CP nanoparticles and gels had a similar loading capacity, the gels enabled high enzyme activity. This is easy to understand since the gels had a large fraction of water and are highly porous with all the pores connected to retain water, allowing proteins to be in their native conformation and also efficient substrate diffusion. 20 ACS Paragon Plus Environment

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To further evaluate the stability of gel encapsulated enzymes, we tested the activity as a function of temperature (Figure 7D) and pH (Figure 7E). In both cases, the gels showed a similar activity as the free enzyme, while the activity of GOx in La3+/AMP nanoparticles dropped much more. Encapsulating enzymes in inorganic matrix can often improve their stability by hindering denaturation.61,

62

Therefore, compared to the previously reported CP nanoparticles, these CP

hydrogels have much better performance.

Figure 7. (A) A scheme of the reactions for measuring GOx activity using a colorimetric assay. (B) Incorporation of GOx into the CP products. An image of F-BSA in Lu3+/AMP gel is also shown. (C) Relative activity of the GOx enzyme in the CP materials compared to that of the free enzyme. Stability of the GOx@Ln3+/AMP compared with the equivalent free enzyme at different (D) temperatures; and (E) pH values at 25 °C. The same concentrations of the free enzyme and encapsulated enzyme were used for each assay.



Page 22 of 29

Conclusions In conclusion, we have demonstrated CP hydrogels formed by AMP and the six heavy Ln3+ ions, while the rest lighter Ln3+ formed CP nanoparticles. These gels were formed via a unique sol-gel transition, where the morphology of the initially produced CP nanoparticles turned to nanoscale fibers. The reactions were monitored using single and multiple injection ITC and ζ-potential measurement. The base structure, monophosphate, and lanthanide species are all critical as building blocks of the CP gels. The CP gels are the most stable under slightly acidic pH. High ionic conditions, concentrated urea and temperature did not disturb the gels, suggesting that electrostatic attraction or hydrogen bonding were not important for gelation. This unique nanoparticle-to-gel transition has fundamental implications in CP chemistry showing the interplay of kinetics and thermodynamics in forming CP materials. The supramolecular CP networks display good ability for protein inclusion, and the encapsulation can be achieved under mild conditions with a simple mixing step. Compared to CP nanoparticles, the CP gels allowed better stability of encapsulated GOx enzyme. So far, we have not taken advantage of the chemical and physical properties of Ln3+, such as luminescence, magnetic property and catalytic activity. The lanthanides were only used as a structural element to form CPs. Further exploring the chemistry of lanthanides in such gels will be a logic future direction to prepare functional soft materials.

Supporting Information Available This information is available free of charge via the Internet at http://pubs.acs.org/. Binding thermodynamic parameters from ITC (PDF). 22 ACS Paragon Plus Environment

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Acknowledgement This work is supported by the Natural Sciences and Engineering Research Council of Canada (NSERC), the National Natural Science Foundation of China (No. 21301034), and the National Science of Foundation of Guangdong Province (S2013040014083). L. Xu was supported by a Chinese Scholarship Council (CSC 201608440087) Scholarship to visit the University of Waterloo.

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