Sequence-Dependent Peptide Surface Functionalization of Metal

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Biological and Medical Applications of Materials and Interfaces

Sequence Dependent Peptide Surface Functionalization of Metal-Organic Frameworks Gang Fan, Christopher Dundas, Cheng Zhang, Nathaniel A. Lynd, and Benjamin Keith Keitz ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b05148 • Publication Date (Web): 15 May 2018 Downloaded from http://pubs.acs.org on May 16, 2018

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ACS Applied Materials & Interfaces

Sequence Dependent Peptide Surface Functionalization of Metal-Organic Frameworks Gang Fan†‡, Christopher M. Dundas†, Cheng Zhang† §, Nathaniel A. Lynd†‡, Benjamin K. Keitz†﹡

† McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, Texas, 78712, United States ‡ Center for Dynamics and Control of Materials, University of Texas at Austin, Austin, Texas, 78712, United States KEYWORDS: Peptides, Metal-Organic Frameworks, Surface Functionalization, Phage Display and Drug Delivery.

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ABSTRACT

We report a non-covalent surface functionalization technique for water-stable metal organic frameworks (MOFs) using short peptide sequences identified via phage display. Specific frameworks binding peptides were identified for crystalline Zn(MeIM)2 (MeIM = 2methylimidazole, ZIF-8), semi-amorphous Fe-BTC (BTC = 1,3,5-benzene-tricarboxylate) and Al(OH)(C4H2O4) (MIL-53(Al)-FA, FA: fumaric acid) and their thermodynamic binding affinities and specificities were measured. Electron microscopy, powder X-ray diffraction, and gas adsorption analysis confirmed that the peptide functionalized frameworks retained similar characteristics compared to their as-synthesized counterparts. Confocal Laser Scanning Microscopy demonstrated that peptide was localized on the surface of the frameworks, while surface area measurements showed no evidence of pore blockage. Finally, we measured the pH-dependent release of fluorescein from peptide-functionalized frameworks and discovered that peptide-binding can attenuate fluorescein release by improving framework stability under low pH conditions. Our results demonstrate that phage display can be used as a general method to identify specific peptide sequences with strong binding affinity to water-stable metalorganic frameworks and that these peptides can alter drug release kinetics by affecting framework stability in aqueous environments.

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INTRODUCTION Metal-organic frameworks (MOFs) are two or three-dimensional arrays of organic ligands linked together through inorganic nodes that have shown promise in a variety of applications including gas separations, 1 gas storage, 2-4 catalysis, 5-7 sensing, 8,9 and drug delivery. 10 These materials are particularly promising for biological applications due to their high surface areas, which allow for record loadings of diagnostic and therapeutic agents, including Methotrexate (MTX),11,12 Doxorubicin (DOX)13 and Fluorouracil (5-FU).14 For biomedical applications, functionalization of the framework surface is extremely important since this interface controls the stability of the framework, the rate of drug release, cell uptake, and the overall biological response.10 However, in contrast to mesoporous silicas and metal nanoparticles, 15-19 there are few general techniques for surface functionalization of metal-organic frameworks,20 which results in part from a fundamental lack of knowledge on the surface chemistry and interfacial interactions of these materials. Several covalent methods for metal-organic framework surface modification have been reported. For example, post-synthetic exchange of surface-exposed ligands with functionalized alternatives enabled surface modification via standard coupling chemistry.21-26 Core-shell materials containing a metal-organic framework core and a grown shell of silica or polymer is another popular surface functionalization strategy that takes advantage of well-developed chemistries for the shell materials.27-29 In conjunction with these covalent strategies,30 milder, non-covalent methods for functionalizing framework surfaces using polymers31-33 or lipid bilayers12,30 have recently been reported. These approaches are applicable to a wide range of frameworks and their mild nature limits the formation of undesirable structural features, such as defects, that negatively may affect material performance. Nevertheless, further development of non-covalent surface functionalization techniques for metal-organic frameworks is warranted to prevent pore blockage and to accentuate desirable framework properties.32

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One promising class of molecules for the functionalization of metal-organic framework surfaces are short peptides,34-38 which are a popular class of ligands for binding to metals, metal oxides, and other inorganic materials. Peptide sequences that bind to a specific material can be identified through phage display, which relies on a large library of random peptide sequences that are down-selected to consensus sequences with strong binding affinity to the material of interest (Figure 1).42 Using this technique, peptide sequences that bind to specific crystal facets of palladium, gold, and many other materials have been identified.43-45 These peptides were subsequently leveraged to functionalize material surfaces,46 control crystal growth and orientation,47-50 and direct material formation in photovoltaic and electrochemical devices.51-53 In the case of metal-organic frameworks, dipeptides have been used as ligands in framework synthesis while longer peptides have been covalently attached to the interior and exterior of frameworks via post-synthetic modification.39-40 Larger biomolecules, including proteins and nucleic acids, have also been incorporated into the pores of metal-organic frameworks.41 Finally, larger proteins, such as the tobacco mosaic virus (TMV) coat protein, have been used to direct framework synthesis.54 Despite these advances, the study of non-covalent and sequencedependent binding of peptides to metal-organic frameworks is relatively unexplored. Here, we demonstrate that phage display can be used to identify peptide sequences with strong binding affinity to the water-stable metal-organic frameworks, Zn(MeIM)2 (MeIM = 2methylimidazole, ZIF-8), semi-amorphous Fe-BTC (BTC = 1,3,5-benzene-tricarboxylate), also known as Basolite F300, and Al(OH)(C4H2O4) (MIL-53(Al)-FA, FA: fumaric acid). Consensus peptide sequences with strong binding affinity to each framework were obtained and their thermodynamic binding affinities and specificities were characterized. We also investigated the localization of adherent peptides and determined that their presence does not adversely affect framework properties. Finally, we demonstrate that peptide functionalization augments ZIF-8 performance in controlled release of a model small molecule, Fluorescein (FITC), by improving metal-organic framework stability under acidic conditions. Overall, our results demonstrate that

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specific peptide sequences can exhibit strong and selective binding to metal-organic frameworks and suggest that these sequences can be leveraged to modify framework surfaces or control framework nucleation.

Figure 1. Phage display for identification of MOF-binding short peptide sequences. METHODS Chemicals and Reagents: All chemicals were analytical grade and used without further purification unless otherwise stated. Zinc nitrate hexahydrate (Zn(NO3)2•6H2O, 98%), 2methylimidazole (99%), copper(II) nitrate hemi(pentahydrate) (Cu(NO3)2•2.5H2O, 98%) and trimesic acid were purchased from Sigma-Aldrich. Sodium formate (98%), fumaric acid (99%) and Fluorescein were purchased from Alfa Aesar. Ferric chloride hexahydrate (FeCl3•6H2O) and methanol were purchased from Fisher Scientific. Aluminum sulfate octadecahydrate (Al2(SO4)3•18H2O, ACS grade) and urea were purchased from VWR International. Ultrapure Water was generated from a Milli-Q Integral Water Purification System. Sodium hydroxide was purchased

from

EMD

Millipore

Corporation

(Germany).

NHS-Fluorescein

(5/6-

carboxyfluorescein succinimidyl ester) was purchased from ThermoFisher Scientific. The framework-binding peptides were synthesized using solid phase peptide synthesis (SPPS)

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technique and purchased from Bio-Synthesis Inc. The purity of peptide is higher than 95% according to HPLC analysis (Onyx™ Monolithic C18, Flow rate: 1.0 ml/min) and matrix-assisted laser desorption/ionization (MALDI-TOF) test (Applied Biosystems Voyager System 1099, Calibration Matrix: α-Cyano-4-hydroxycinamic acid). Thermogravimetric Analyzer (TGA): Thermogravimetric analysis (TGA) was performed using a Perkin Elmer TGA 7 with a nitrogen atmosphere and a flow rate of 30 mLmin-1. The temperature was ramped from 25 to 800 °C at 5 °C min-1. X-ray diffraction (XRD): X-ray diffraction (XRD) was performed on a Rigaku R-Axis Spider diffractometer with an image plate detector using Cu Kα radiation (λ=1.54 Å) and a graphite monochromator. XRD samples were prepared by mixing a small amount of dried framework with a droplet of mineral oil followed by mounting on a cryoloop. Transmission

Electron

Microscope

(TEM):

Low-resolution

transmission

electron

microscopy (TEM) images were acquired on a FEI Tecnai Spirit Bio Twin operated at 80 kV. High-resolution transmission microscopy (HRTEM) images were acquired on a field emission JEOL 2010F TEM operated at 200 kV. TEM samples were prepared by drop-casting 5 μL of dilute framework dispersion in water onto a 200 mesh carbon-coated copper TEM grid (Electron Microscopy Science). Dynamic Light Scattering (DLS): DLS measurements were performed at 25 °C on a Zetasizer Nano ZS, Malvern, using a 25 mW helium-neon laser (632.8 nm). Low-Pressure Gas Adsorption: Gas adsorption isotherms in the range 0.00-1.01 bar were measured volumetrically using a Micromeritics ASAP2020 instrument. All gases were 99.998% purity or higher. Isotherms at 77 K were measured using liquid nitrogen baths. Langmuir and BET surface areas of ZIF-8, Fe-BTC and MIL-53(Al)-FA were consistent with literature reports.55-57

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Metal organic framework Synthesis: (i) ZIF-8 was synthesized in water according to apublished procedure:55 Zn(NO3)2•6H2O (744 mg, 2.50 mmol) was dissolved in 10 mL of deionized water and added to a solution consisting of 2-methylimidazole (2-MeIm) (8.2 g, 0.10 mol) in 90 mL of deionized water. The final molar composition of the synthesis solution was Zn2+: 2-MeIm: water = 1: 40: 2228. The mixture was stirred at room temperature and quickly became cloudy. After 24 h, the suspension was centrifuged at 8000g for 10 min and washed with methanol three times. The products were then dried for 24 h under reduced pressure at room temperature. (ii) Fe-BTC was synthesized in water according to a published procedure:56 Two solutions were prepared: Solution 1 was prepared by dissolving H3BTC (0.263 g, 1.25 mmol) and NaOH (0.150 g, 3.75 mmol) in H2O (10 mL). Solution 2 was prepared by dissolving FeCl3•6H2O (0.508 g, 1.874 mmol) in water (10 mL). Solution 2 was added dropwise to solution 1 under magnetic stirring, resulting in the immediate appearance of a brownish orange solid. The resulting suspension was stirred at room temperature for 24 h. The final molar composition of the synthesis solution was Fe3+: BTC: NaOH: water = 1.5: 1.0: 3.0: 880. The solids were recovered by centrifugation, washed three times with deionized water, washed three times with ethanol, and then dried under reduced pressure at room temperature. (iii) MIL-53(Al)-FA was synthesized according to a published procedure:57 Al2(SO4)3•18H2O (0.513g, 0.77 mmol), fumaric acid (0.179g, 1.54 mmol) and urea (0.092g, 1.54 mmol) were dissolved in H2O (5.0 mL). The solution was then transferred to a Telflon lined steel Parr autoclave at 110 °C for 32 hours. The obtained white powder was washed with ethanol for three times and further dried under reduced pressure at room temperature. (iv) Fluorescein-encapsulated ZIF-8 Synthesis was synthesized in water according to a published procedure:58 Zn(NO3)2•6H2O (0.15 g, 0.50 mmol) and 2-MeIm (0.33 g, 4.00 mmol) were weighed and each dissolved in a separate volume of methanol (7.15 mL). Subsequently, a fluorescein (200 μL of a 2 mg/mL) containing methanol solution was added to the Zn(NO3)2

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solution. The 2-MeIm solution was then added and the reaction stirred for 24 h. The turbid solution was centrifuged at 8000 x g for 10 min to obtain the dye-loaded ZIF-8 after the reaction. The nanoparticles were washed three more times with methanol prior to use. Selection of peptide sequence (Bio-panning): The selection of the frameworks binding peptide sequences was done with M13 phage display (Ph.D.) library using a standard biopanning procedure. Bio-pannings were carried out using a Ph.D.-12mer peptide library (New England Biolabs) with corresponding frameworks according to the general procedure below. 1.0 × 1011 pfu of phage were incubated with frameworks (0.8 mg) that had been pre-equilibrated in 200 μL of Tris-buffer saline (TBS; pH=7.5) containing 0.1% polyoxyethylene sorbitan monolaurate (Tween 20, Sigma) for one hour at room temperature with gentle rocking. The frameworks were then washed eight times with TBS containing incremental amount of Tween 20 (0.1% to 0.5%). After each wash, the frameworks were isolated by centrifugation (RCF 10000 x g, 4 °C) for 10 minutes and the supernatant was discarded. Bound phages were eluted from the frameworks by incubation in 1.0 mL of 0.2 M glycine-HCl (pH=2.2) for 10 min at room temperature with gentle rocking. After neutralizing the supernatant (containing the eluted phage) with 150 μL of 1.0 M Tris-HCl (pH=9.1), the number of eluted phages was estimated by counting plaques formed by infected Escherichia coli (E. coli) ER2738 on serially diluted agar plates. The eluted phages were amplified by transduction in an E. coli ER2738 culture and grown in 20 mL lysogeny broth (LB) for 4.5 h in an incubating shaker at 37 °C. The resulting phages were then purified and used in the following round. After the fourth round of bio-panning, the elution was plated and 10 plaques were randomly collected and sequenced to determine the binding peptide sequence. Determination

of

Peptide-binding

Langmuir

Adsorption

Parameters:59

Peptide

sequences AHPHSDKLVPPR (Z1), TLGLRPVPVATT (F1), and TPTNQGGQARGM (M1) were selected using the bio-panning approach for ZIF-8, Fe-BTC, and MIL-53(Al)-FA, respectively. Additional consensus sequences are located in Table S1. The binding affinity of free peptide

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with ZIF-8, Fe-BTC, and MIL-53(Al)-FA was determined by the Langmuir absorption method. The binding of the indicated concentrations of peptide to ZIF-8 or Fe-BTC particles (4 mg) was carried out for 2 h at room temperature in buffer containing 50 mM HEPES-NaOH (pH 7.0) and 150 mM NaCl. After removing the frameworks by centrifugation (RCF 10000 x g, 4 °C) for 10 minutes, the concentration of corresponded peptide in the supernatant (unbound peptide) was determined using fluoraldehyde (Pierce). Confocal Laser Scanning Microscope (CLSM): Confocal fluorescence images were recorded on a Zeiss LSM 710 confocal laser-scanning microscope (CLSM) (Jena, Germany). The excitation was performed by Ar lase at wavelengths of 488 nm and the emission was monitored at 493-556 nm. Fluorescein(FITC)-labeled ZIF-8 coated with frameworks binding peptides was washed with water and centrifuged five times, diluted and added to a confocal microscope dish before observation. For surface imaging, larger ZIF-8 particles were prepared according to a literature procedure.60 Peptide was conjugated with NHS-Fluorescein, purified through dialysis, and further purified using size-exclusion chromatography. Dye-functionalized peptide was then incubated with ZIF-8 for 2 h at room temperature. An aqueous solution of gelatine (1.0 mg/mL) was added into the ZIF-8 suspension at 40 ºC and cooled to room temperature. The resultant viscous mixture was dropcast on untreated glass substrates for observation. In-vitro ZIF-8 Fluorescein Releasing: Dye-loaded ZIF-8 samples were suspended in framework-binding peptide solution (1.0 mg/mL) at saturation coverage for two hours, centrifuged and washed with phosphate buffered (pH 7.4) solution for three times. The nanoparticles were dried under reduced pressure at room temperature overnight. Peptide treated ZIF-8 (1.0 mg) was weighed and suspended in phosphate buffered pH 6.0 solution. Two other dye-encapsulated ZIF-8 samples (1.0 mg) from the same batch without peptide treatment were suspended in phosphate buffered pH 6.0 and pH 7.0 solution, respectively. At specific time points, the samples were spun down and the fluorescence of the supernatant was measured.

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ZIF-8 samples were re-suspended in the previous supernatant balanced with fresh buffer to the same solution volume.

RESULTS AND DISCUSSION We first synthesized several metal-organic frameworks with high reported stability under aqueous conditions. ZIF-8, and Fe-BTC were successfully prepared in water under ambient conditions.55-56 MIL-53(Al)-FA was hydrothermally synthesized under autogenous pressure.57 After washing and drying under vacuum overnight, each framework was characterized by powder X-ray diffraction (PXRD), transmission electron microscope (TEM), and gas adsorption analysis. The diffraction pattern, size, morphology and surface area of these frameworks were consistent with literature reports.55-57 Robust stability of each framework during the phage display process is necessary to ensure binding and selection of sequences specific to the target material instead of a potential decomposition product. Therefore, we examined the stability61 of ZIF-8, Fe-BTC, and MIL-53(Al)-FA under bio-panning conditions and in other physiologically relevant buffers. After immersion in 1X tris-buffer saline (TBS, pH 7.5), 50mM 4-(2hydroxyethyl)-1-piperazineethanesulfonic acid-NaOH (HEPES-NaOH, pH 7.5, 150mM NaCl) and 1X phosphate buffered saline (PBS, pH 7.5), ZIF-8, Fe-BTC and MIL-53(Al)-FA showed no significant morphological changes in transmission electron micrographs or PXRD patterns, confirming their stability under these conditions (Figure S1-3). Thus, we proceeded with our phage display experiments using ZIF-8, Fe-BTC and MIL-53(Al)-FA.

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Figure 2. Structures of ZIF-8, Fe3X(H2O)2(BTC)2 • nH2O (iron carboxylate, MIL-100, an analogue to the semi-amorphous Fe-BTC structure is shown), MIL-53(Al)-FA, and their corresponding MOF-binding peptide sequences. We initiated phage display and bio-panning experiments starting from a commercially available phage library (New England Biolabs) of 12-peptide repeats with ca. 109 distinct library members. Phages were incubated with the target framework, after which phages with nonbinding peptides were removed through repeated washing. Phages with peptides sequences that remained bound to the target framework were collected, amplified, and used for the next round of bio-panning. After 4 rounds of bio-panning, the final elution was plated and ten plaques were randomly collected and sequenced to determine the binding peptide sequences. These sequences represent those with the strongest binding affinity and selectivity for the different framework targets because they persisted after several rounds of binding and elution. Since each of the tested metal-organic frameworks has a different structure and presumably different surface chemistry, they should select for different peptide sequences. Indeed, consensus sequences were discovered for ZIF-8, Fe-BTC, and MIL-53(Al)-FA indicating that these

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frameworks can effectively distinguish between peptide sequences in the starting library. We selected a handful of consensus sequences for further characterization based on their predicted solubility (Figure 2), while additional consensus sequences are listed in Table S1. The consensus peptide sequence for ZIF-8 was AHPHSDKLVPPR (Z1) (Figure 2). Sequence analysis of the ZIF-8 binding peptide Z1 revealed a relatively high percentage of proline residues (2-3 of 12). Given the structurally disruptive nature of prolines in polypeptide chains, this frequency was significantly higher than expected for the random 12-mer peptide phage library (0.7 proline per 12-mer sequence or 6%).62 Notably, peptide sequences with strong binding affinity to ZnO were also shown to contain a high frequency of prolines (Table S1).63 For Fe-BTC, we identified TLGLRPVPVATT (F1) as one consensus sequence (Figure 2). Of note, we observed that the “TISPS” motif of Fe2O3 (hematite)-binding peptides64 was conserved amongst sequences that bind to Fe-BTC (Figure S4). In contrast to the iron oxide binding peptides, the sequences of Fe-BTC binding peptides demonstrated a higher frequency (42%) of non-polar and hydrophobic amino residues, relative to hematite-binding sequences (28%). Finally, we identified TPTNQGGQARGM (M1) as a consensus sequence for binding to MIL53(Al)-FA. Specific sequences for binding to Al2O3 have not been reported so we were unable to make specific comparisons to metal oxide-binding sequences as we were with Z1 and F1. Together, these results demonstrate that phage display can be used to converge upon distinct framework-binding peptides, which share some compositional and sequential similarities with their oxide-binding counterparts. However, there were also key differences between the framework- and metal oxide-binding peptides, which establishes that previously identified metal oxide-binding peptides are not necessarily applicable to metal-organic frameworks. We next measured the dissociation constant between our consensus sequences and the corresponding target framework. On-target sequences (i.e. those discovered through phage display) should exhibit stronger binding to the target framework relative to random or off-target sequences. Varying concentrations of peptide were incubated with each framework and the

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amount of residual soluble peptide was quantified via fluorescence using Fluoraldehyde (ophthalaldehyde) (Figure S5-7). Adsorption isotherms were fitted using Langmuir adsorption theory to estimate the dissociation constant (KD). The majority of non-covalent interactions between biological macromolecules, including peptides, and inorganic materials have dissociation constants between 10-5-10-7 M. Indeed, measured dissociation constants between the peptides above and the examined metal-organic frameworks were in this range (Figure 3). The dissociation constant of AHPHSDKLVPPR (Z1) binding to ZIF-8 was measured at 19 ± 10 μM. Similarly, the KD of TLGLRPVPVATT (F1) binding to Fe-BTC was estimated to be 23 ± 9 μM. Sequence F1 also showed strong binding to MIL-100, a more crystalline structural analog of Fe-BTC (Figure S9). Finally, we measured on-target binding of TPTNQGGQARGM (M1) to MIL53(Al)-FA with a KD of 12 ± 5 μM. These values are consistent with previous reports describing sequence-dependent peptide binding to metal oxides. We next investigated off-target binding of the identified peptide sequences to confirm their specificity to the desired metal-organic framework. The dissociation constant of Z1 and Fe-BTC was measured at 790 ± 150 μM (Figure 3), which was a near 40-fold increase relative to the ontarget interaction of Z1 and ZIF-8. Likewise, the KD of Z1 binding to MIL-53(Al)-FA was 1014 ± 637 μM. The relatively large error for fitting these adsorption data could be a result of peptide insolubility at higher concentrations or deviations from ideal Langmuir theory due to peptidepeptide interactions. The KD of F1 and ZIF-8 was 223 ± 29 μM, nearly a 10-fold difference compared to the on-target interaction, while the KD of F1 to MIL-53(Al)-FA was 37 ± 12 μM. Finally, we measured the KD of M1 binding to ZIF-8 and Fe-BTC as 168 ± 34 μM and 31 ± 22 μM, respectively. For comparison, we also measured the binding strength of Bovine serum albumin (BSA) to ZIF-8 and Fe-BTC and found that BSA exhibited strong binding to both frameworks but could not differentiate between them (Figure S8). Overall, these results confirm that the peptide sequences identified via phage display exhibit strong and specific binding to the metal-organic framework targets.

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Figure 3. Measured dissociation constants for binding between peptide sequence and metal-organic framework. Error bars represent error from Langmuir fitting. We next examined the effect of peptide-binding on framework physical properties to confirm that peptide-binding does not disrupt framework structure or morphology. Each framework was incubated at saturated concentration of peptide under ambient conditions then characterized using PXRD and TEM. According to these measurements, the morphology of ZIF-8, Fe-BTC, and MIL-53(Al)-FA after peptide conjugate binding was identical to each as-synthesized framework (Figure S10-11). This shows that the structural integrity of each framework remains intact following peptide modification. Next, nitrogen adsorption isotherms were measured at 77 K and uptake was compared to control frameworks. No significant decrease in accessible surface area between peptide-functionalized (F1-Fe-BTC: 1155 m2 g-1; Z1-ZIF-8: 1775 m2 g-1; M1-MIL-53(Al)-FA: 794 m2 g-1) and control frameworks (Fe-BTC: 1200 m2 g-1; ZIF-8: 1631 m2 g-1; MIL-53(Al)-FA: 948 m2 g-1) was observed, indicating that peptides did not interfere with gas adsorption in the frameworks (Figure S12-14). We also measured changes in surface charge following peptide binding, since this is a critical parameter governing interactions with biological

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systems. Changes in framework surface chemistry were monitored using dynamic light scattering (DLS) measurements before and after binding of framework-binding peptides (Figure S15). After binding of F1, the Fe-BTC-peptide complex showed a significant decrease in ζ potential, dropping from 33.8 mV to +8.7 mV. Such dramatic decline in ζ potential may be attributed to a strong interaction between F1 and the surface of Fe-BTC. A similar trend was also observed in the Z1-ZIF-8 complex with a measured  potential of +23.1 mV compared to +34.4 mV for unmodified ZIF-8. Nanomaterial surface charge frequently limits their in vivo utility since adsorption of serum proteins to charged particles can lead to rapid immune clearance by the body.65 Thus, the decreased ζ potential of peptide-functionalized frameworks could be exploited to minimize their clearance as negatively or near neutral charged nanomaterials exhibit attenuated adsorption of proteins.65 Robust stability in the physiological environment is a key requirement for using the identified peptides as noncovalent surface modifiers in drug delivery.66 Peptide binding may also augment the water or media stability of the frameworks, potentially improving their stability in other applications where they may come into contact with water or water vapor. Therefore, we measured the resistance of our peptides to surface detachment under a variety of different washing and perturbation conditions they are likely to encounter in various applications. The quantity of detached peptide was measured via fluorescence spectroscopy and we found that less than 10% of bound peptide detached from the ZIF-8 particles after 4X washing in neutral PBS (pH 7.4). Similarly, more than 85% of Z1 remained on the surface of ZIF-8 after 4X washing in acidic PBS (pH 6.0) (Figure S16). We also confirmed the amount of peptide remaining on the framework using thermal gravimetric analysis (TGA). After three rounds of washing peptide-functionalized Z1-ZIF-8 in pH 7.4 PB buffer, the amount of peptide remaining on the surface of ZIF-8 was measured to be 3.0 wt% using TGA, which was comparable to the initial value obtained from the spectroscopic measurement (2.5 wt%, Figure S16-17).

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Figure 4. (a) FITC-labelled Z1 peptide preparation. (b)-(e) CLSM image of ZIF-8 after FITC-labelled Z1 peptide attachment and inset the fluorescence profile of the highlighted MOF particle (b: green channel, c: bright field, d: merged). The peptides are too large to fit in the pores of ZIF-8, Fe-BTC, or MIL-53(Al)-FA and should be localized to the surface of the frameworks. Thus, we used confocal laser scanning microscopy (CLSM) to directly visualize and confirm the location of peptides on the framework surfaces (Figure 4). Peptides (Z1) were conjugated in situ with 5(6)-carboxyfluorescein succinimidyl ester (NHS-Fluorescein), dialyzed against borate buffer (pH = 8.5) and further purified by size exclusion chromatography (SEC) (Figure S19). Purified fluorescently tagged peptides were then incubated with ZIF-8, which was subsequently imaged using CLSM. Representative images (Fig. 4b-e) showed that the FITC-peptide conjugates were concentrated around the exterior of the ZIF-8 particles as evidenced by the observed green halo and bimodal fluorescence intensity profile. We also confirmed that the observed fluorescence profile was not do to fluorescein quenching in the pores by encapsulating the dye during ZIF-8 synthesis (Figure S20). These results are consistent with a strong interaction between the framework

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surface and the peptide conjugates and combined with the gas adsorption results, demonstrate the localization of the peptide conjugates to the outer surface of the metal-organic frameworks.

Figure 5. (a) Drug (Fluorescein) releasing profile in Phosphorus Buffer (PB, pH = 7.4 or 6.0) before and after Z1 binding (Error bars represent standard deviation from three separate runs). (b) PXRD pattern of FITC@ZIF-8 with and without Z1 modification after immersion in pH 6.0 PB buffer for three days. Finally, we studied the effect of framework-binding peptides on the pH-responsive release of image probes from dye encapsulated ZIF-8 particles as an approximation of drug delivery performance. Dye loaded ZIF-8 was prepared based on a modified literature procedure.58 We first incorporated fluorescein (FITC), which is commonly used as a fluorescent drug model, into ZIF-8 using in situ synthesis and encapsulation (FITC@ZIF-8). The maximal loading of FITC was measured as 1.0 wt %, with an 11% loading efficiency, both of which were comparable to those of existing metal-organic framework drug delivery systems.58 Release of the fluorescein cargo from FITC@ZIF-8 was monitored by the absorbance of the supernatant at 495 nm under

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various aqueous conditions (Figure 5a). After 12 hours, less than 5% of fluorescein release was detected after immersion in pH 7.4 buffer. In contrast, more than 50% of the encapsulated fluorescein was released within two hours of exposure to the acidic buffer (pH 6.0) using unmodified [email protected] As predicted, functionalization of FITC@ZIF-8 with Z1 peptide to form FITC@Z1-ZIF-8 resulted in the attenuation of fluorescein release in pH 6.0 PB buffer (Figure 5). Less than 10% fluorescein cargo release was observed from FITC@Z1-ZIF-8 after two hours’ immersion at pH 6.0 compared to the peptide-free control. Interestingly, the remaining dye concentration in FITC@Z1-ZIF-8 remained above 20% after 24 hours in acidic buffer and gradual release was observed over the next three days. We next confirmed that the release of fluorescein from ZIF-8 under acidic conditions was due to decomposition of the framework and hypothesized that Z1 binding slows dye release kinetics by improving ZIF-8 stability under acidic conditions. TEM analysis of ZIF-8 particles immersed in PB for one day revealed that the spheres in neutral PBS maintained their size and shape, whereas the particles in the pH 6.0 PB solutions dissociated (Figure S21). Similarly, PXRD analysis showed a rapid (less than 4 h) phase change for ZIF-8 in acidic buffer (Figure S22). In contrast, a PXRD pattern of the peptide-functionalized Z1-ZIF-8 displayed peaks characteristics of ZIF-8 after immersion in acidic buffer for three days (Figure 5b). These results suggest that framework-binding peptides improve the aqueous stability of metal-organic frameworks and can potentially be used to adjust release kinetics for frameworks that rely on structural decomposition to release their cargo. Furthermore, peptide-functionalized frameworks may protect sensitive cargo in early stage endocytosis (pH 6.0-6.5) and facilitate endosomal release via the “proton sponge” effect, similarly to some polymeric nano-particles.68 In contrast, un-modified frameworks are subject to clearance via the immune system and may cause premature endosomal rupture to limit overall therapeutic efficacy.69 CONCLUSION

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We demonstrated that phage display could be used to identify specific peptide sequences with strong binding affinity to water-stable metal-organic frameworks. Thermodynamic binding strength was sequence dependent, demonstrating that peptides could differentiate between different metal-organic frameworks. Framework-binding peptides did not negatively influence framework physical properties and they enhanced framework stability under physiologically relevant conditions. Finally, we demonstrated controlled release of cargo using peptide-binding, small-molecule-loaded ZIF-8 and showed that the kinetics of this process could be tuned using peptide

surface

functionalization.

Overall,

we

envision

that

peptide-based

surface

functionalization of metal-organic frameworks will serve as a general platform to optimize frameworks for targeted therapeutic and diagnostic reagent delivery, as well as a potential means to modify framework surfaces for use in non-biological applications, such as gas sorption, catalysis, and sensing.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs. PXRD patterns, fitting parameter,  potential, TGA, standard curves, CLSM and TEM images. (PDF) AUTHOR INFORMATION § Current address: Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, United States of America Corresponding Author *Email: [email protected]

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Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work was supported by the Welch Foundation (Grant No. F-1929 and F-1904) and partially supported by the National Science Foundation through the Center for Dynamics and Control of Materials: an NSF MRSEC under Cooperative Agreement DMR-1720595. We gratefully acknowledge the use of facilities within the core microscopy lab of the Institute for Cellular and Molecular Biology (ICMB), University of Texas at Austin. The authors would also like to acknowledge Gauri G. Bora and Vismaya Kondapalli for their help in metal-organic framework synthesis.

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Table of Contents (TOC) artwork:

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Sequence-Dependent Peptide Surface Functionalization of Metal

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