Dual-Stimulus-Triggered Programmable Drug Release and

Jun 7, 2018 - ... have been discussed and evidenced, which could be quantitatively estimated via the rate constant related to the topological structur...
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Dual-Stimulus-Triggered Programmable Drug Release and Luminescent Ratiometric pH Sensing from Chemically Stable Biocompatible Zinc Metal-Organic Framework Kai Xing, Ruiqing Fan, Fengyou Wang, Huan Nie, Xi Du, Shuang Gai, Ping Wang, and Yulin Yang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b06270 • Publication Date (Web): 07 Jun 2018 Downloaded from http://pubs.acs.org on June 7, 2018

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Dual-Stimulus-Triggered Programmable Drug Release and Luminescent Ratiometric pH Sensing from Chemically Stable Biocompatible Zinc Metal−Organic Framework Kai Xing,† Ruiqing Fan,*† Fengyou Wang,‡ Huan Nie,‡ Xi Du,† Shuang Gai,† Ping Wang,† and Yulin Yang*†

KEYWORDS: drug delivery; programming kinetics; dual-stimulus responsive release; metal-organic frameworks; ratiometric luminescence



MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion

and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang 150001, P. R. China ‡

School of Life Science and Technology, Harbin Institute of Technology, Harbin,

Heilongjiang 150001, P. R. China Corresponding Author: * Ruiqing Fan and Yulin Yang E-mail: [email protected] and [email protected]

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ABSTRACT Metal−organic frameworks (MOFs), as drug delivery carriers, with high loading capacity and controllable release behavior can provide a more efficacious therapy in cancer treatments. In our work, a novel biocompatible zinc metal-organic frameworks Zn-cpon-1 with (3,6)-connected rtl 3D topological network was designed and synthesized through the template supporting induced approach by the ClO4- anion. The optically and chemically stable Zn-cpon-1 could be verified as a pH-responsive dual-emission platform and excellent drug delivery carrier with higher 5-Fluorouracil (5-FU) (44.75 wt %) loading behavior than 6-Mercaptopurine (6-MP) (4.79 wt %) ascribed to the influence of size and shape matching. The multiple interactions between Zn-cpon-1 and 5-FU drug molecules have been discussed and evidenced, which could be quantitatively estimated via the rate constant related to the topological structure. Specially, the gust release behavior of 5-FU@Zn-cpon-1 microcrystal was described and programmed via the Weibull distribution model and could be dual-triggered by the temperature and pH stimulus. This study illustrates that the Zn-cpon-1 without any post-modification performs a favorable potential of being used as biomedical drug delivery alternative carriers in effective drug payload, flexible release administration and superior dual-stimuli responsiveness.

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 INTRODUCTION As one of the most serious threat to the human health, cancer has caused millions of deaths annually. Owing to the limitations including undesirable side effects, poor pharmacokinetics and biodistribution of traditional direct drugs administration,1 extensive efforts have been devoted to applying various controlled release drug carrier systems during the last few decades, such as quantum dots, inorganic mesoporous silica, dendrimers, organic micelles and metal nanoparticles.2-6 Nevertheless, the drawbacks of low loading capacities, undesirable toxicity and unacceptable degradability prevent the further application of them.7 In this regard, developing a drug delivery system with both high drug capacity and controllable release ability still remains to be challenging. Zinc metal−organic frameworks (Zn-MOFs) have already been severed as a successful drug delivery platform as a result of the exceptional high surface area, intrinsic biocompatibility and low toxicity, tunable porosity to various host drug molecules and controllable host–guest interactions.8-12 Since the MOFs as drug vehicles applied to drug delivery was first reported by Ferey's group,13 the MOF based carrier systems are well established and developed continuously.14 Majority of them are guided by the post-modification, however, this procedure is complicated and might bring some negative effect to drug delivery, for instance, the reduction of drug loading capacity resulted by the inadequate utilization of porosity due to the grafted substance, the unnecessary leak of drugs caused during the tedious procedures and the unfavorable cost increase for practical applications. The administration of drug release profiles, particularly maintaining the quantity of drug molecules at remediable level for the longer time, is of great significance for improving the efficiency and security in drug delivery systems. The process has close relationship with the interactions between drug and carrier.15, 16 Specific to the MOF-based carrier materials, the type of host architecture is quantitatively correlated with the release of drug molecules. So if we can quantify such an interaction, the release curves of given drug molecule could be predicted.17 To 3

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control the drug release programming, the stimuli-responsive process based on the carrier−drug interaction is another key factor, which has aroused extensive attentions and be proved the most efficiency and effective way to control drug release process.18 Among them, many of diverse stimulation has be achieved upon outside activation, such as pH, magnetic field, ions, temperature, light and pressure. However, the complexity of the human body environment limits abilities to precisely deliver drugs in the body using single stimulus-responsive MOF drug carriers. To overcome this, multiple stimuli-responsive MOFs can be used as a better alternative to improve delivering capacities and chemotherapeutic efficiencies.19 In this contribution, we herein report a bio-friendly zinc metal organic frameworks

[Zn(cpon)]n

(Zn-cpon-1),

constructed

by

semi-rigid

5-(4'-carboxyphenoxy)nicotinic acid (H2cpon) under the guidance of the anion template strategy featuring the chair-shaped one-dimensional channel along the c-axis simplified as (3,6)-connected rtl network topologically (Scheme 1). Zn-cpon-1 with good photo- and chemical stability can produce clear dual-emission signals through a charge transition between the ligand and metal ions, leading to ratiometric pH luminescence properties. Furthermore, Zn-cpon-1 without any tedious post-synthetic modifications, have been confirmed as an excellent drug delivery system, which shows

the

prior

encapsulating

behavior

to

5-Fluorouracil

(5-FU)

than

6-Mercaptopurine (6-MP) with 44.75 wt % and 4.79 wt %, within which the size and shape matching of model molecules bears huge impact to the distinct. The presence of Zn-O clusters, large conjugation and free ether moiety of ligand bring the multiple potential host-gust interaction between Zn-cpon-1 and 5-FU, which have been testified and quantitatively derived by the rate constant originating from the correlation with the topological structure. Accordingly, the release kinetic of 5-FU@Zn-cpon-1 was systematically investigated and suitably described by Weibull distribution model based on the four common dynamic releasing models after taking guest-guest interactions and structural effects into account. Under the dynamic guidance, the temperature and pH dual-triggered drug release process of microcrystal 5-FU@Zn-cpon-1 was also evaluated to break the limitation of the complexity of the 4

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human body environment. We envision that Zn-cpon-1 will make a contribution to deep disclose the potential of MOFs in drug delivery system for disease therapy.

Scheme 1. (a) The secondary building units of topological net in Zn-cpon and Zn-cpon-1. (b) The topological simplification of Zn-cpon and Zn-cpon-1.

 RESULTS AND DISCUSSION Structure Description of Zn-cpon and of Zn-cpon-1 The single crystal structure of Zn-cpon determined by X-ray diffraction illustrates a wavelike 2D metal organic layers crystallizing in monoclinic space group P21/c. As shown in (Figure S1a), per asymmetric unit consists of one crystallographically independent Zn(II) ion with tetrahedral geometry, one cpon2   ligand with monodentate (µ3- :  :  ) coordination mode and one coordinated

water molecule. Based on carboxylate group, the cpon2- bridges two neighbor Zn tetrahedrons to form one-dimensional wavelike chain structures along the b axis (Figure 1a). Further connected by nitrogen atom form the pyridine rings, two-dimensional layers are expanded in ab plane (Figure 1b). As shown in Figure 1c, the whole structure of Zn-cpon could be simplified as a (3,3)-connected fes-type network with Schläfli symbol of {4·82} topologically. Between the two layers, the 5

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strong hydrogen interactions through the carboxylate group and water molecule (the distance of O–HO is 1.969 Å) are observed and the three-dimensional supramolecular framework without any solvent accessible volume is constructed (Figure S2).

Figure 1. (a) The 1D wave-like chain of Zn-cpon. (b) The 2D layer structure in ab plane. (c) The topology simplification fes network of Zn-cpon.

Considering the structural character of dense framework with closed window of Zn-cpon and the inherent flexibility of H2cpon, the potential framework extension could be realized topologically and dimensionally. The zinc perchlorate in which ClO4- anion may lead the template effect was chose as metal origin and introduced to the self-assemble system. As consequence, single-crystals of Zn-cpon-1 suitable for single-crystal X-ray diffraction analysis were gained. The structure analysis illustrates that Zn-cpon-1 crystallizes same space group with Zn-cpon with one Zn(II) ion and one chelating mode cpon2- ligand in per asymmetric unit (Figure S3a). Without the coordinated water molecule, however, each Zn2+ is five-coordinated in quadrangular pyramid geometry (Figure S3b), which is further combined by carboxyl groups of four different ligands to generate a typical [Zn2(COO)4N2] pillar paddle-wheel secondary building unit (SBU). Only based on the carboxylate groups, the two-dimensional flat grid layers are expanded in ab plane (Figure 2a), containing two symmetry related left- and right-handed 21 helical chains along the a and b axes, 6

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respectively. Assembly together in SBU-by-SBU mode via three connected cpon2ligands, the three-dimensional framework of Zn-cpon-1 was well-constructed (Figure 2b). From the topological viewpoint, the underlying network of the MOF adopts a (3,6)-connected topology with a RCSR symbol of rtl. As shown in Figure 2c, the Zn-cpon-1 exhibits chair-shaped one-dimensional helical channels along the c-axis of about 17 × 20 Å2 with free ether oxygen site located in the wall of the channel, which increases the possibility of encapsulating or interacting with gust molecules. The guest accessible volume of the 3D framework accounted for 18.4% (229.4 Å3) of the unit-cell volume (1246.5 Å3), calculated using the PLATON program.20 It is reasonable to assume that the channel with oxygen free characteristic in Zn-cpon-1 can be regarded as a dependable deliver for small drug molecules and the porous peculiarity of it could probably be propitious to selectively accommodate small organic molecules applied in biological systems.

Figure 2. (a) The grid layer structure in Zn-cpon-1. (b) The 3D framework of Zn-cpon-1. (c) The binodal edge-transitive networks, natural tiling and 3D (3,6)-connected rtl topology of Zn-cpon-1.

In powder X-ray diffraction (PXRD) patterns, the match in key peak positions between simulation and the as-synthesis of Zn-cpon and Zn-cpon-1 testified the phase purity. Under the combination of single-crystal diffractions, element analysis 7

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(EA) and thermogravimetric analysis (TGA), the final chemical formulation is confirmed. The TGA curve of Zn-cpon shows that the removal of one H2O molecule results weight loss of 5.31% (cal. 5.29%) (Figure S6). After 395 °C, the framework starts to collapse. The weight loss of Zn-cpon-1 can keep instant till 375 °C. Subsequently, the collapse of whole framework happens. The resulting residues of these two MOFs both are zinc oxide. Luminescence properties First, due to character of large conjugation π-system of the semi-rigid H2cpon ligand, the emission spectra of H2cpon, Zn-cpon and Zn-cpon-1 were investigated in solid state and aqueous suspensions at 298 K. As indicated in Figure S7, H2cpon shows the yellow-green luminescence under UV irradiation. Zn-cpon exhibits abroad emission band at 544 nm, which could be ascribed to the intraligand π*→π transition.21-24 The emission of Zn-cpon-1 is indicated in Figure S7. It could be observed that Zn-cpon-1 exhibits an emission at 532 nm that is assigned to the ligand-based emission and coupled with a very weak luminescence emission peak at 443 nm attributed to the charge transition between the ligand and the metal ions excited by 365 nm UV light. And the Commission Internacionale d’Eclairage (CIE) coordinates is (0.34, 0.47). Comparing with Zn-cpon-1, the relative lower luminescence intensity of Zn-cpon is mainly attributed to the dense structural 2D packing mode in space and more flexible twist of ligand. The closed π-π stacking and intramolecular rotations of ligand would increase the ratio of nonradiative pathway for the excitons to decay.25-28 In addition, the excellent luminescence emission of Zn-cpon-1 could be kept steady in intensity and good day-to-day stability. After two weeks storage in air condition and deionized water, the luminescence intensity of Zn-cpon-1 has no distinct change (Figure S8). The high photostability of Zn-cpon-1 brings the beneficial platform for its further application.

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Figure 3. (a) pH-dependent luminescence of Zn-cpon-1 in NaCl buffer solution with pH ranging from 2.0 to 6.5. (b) The ratiometric response curve showing the variation of I532/I443 with pH. (c) pH-dependent luminescence of Zn-cpon-1 in NaCl buffer solution with pH ranging from 8.0 to 11.5. (d) The ratiometric response curve showing the variation of I532/I443 with pH. The insects of (b) and (d) are the potential luminescence recognition process between Zn-cpon-1 and pH.

Concerning the materials with dual-emission, luminescence response behavior might show better sensitivity to the outside environment, which may have influence on the charge transition pathway.29 Hence, the standard luminescence pH titrations were performed in NaCl buffer solution (0.02 M) with a probe concentration of 0.55 mM. With the pH values decreasing from 6.5 to 2.0, the emission intensity at 532 nm gradually increased and the emission peak at 443 nm almost disappeared with an isoemission point at 465 nm (Figure 3a) excited by 365 nm. When the pH of the solution reached 2.0, the relative ratio of the emissions at 532 nm and 443 nm became 2.56. From the relationship between pH and the emission ratio (Figure 3b), an apparent pKa of 2.70 was predicted for Zn-cpon-1 according to the Henderson– Hasselbalch-type mass action equation (Figure S9a).30, 31 In the pH range of 6.5 to 8, the emission intensity of Zn-cpon-1 kept nearly constant. Upon the pH increases from 8 to 11.5, the intensity of emission at 443 nm decreased with the emission intensity enhance of the peak at 532 nm, which remained steady till pH 11 (Figure 3c). 9

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According to the response curve of the intensity ratio towards pH (Figure 3d), the emission ratio I532/I443 increases by 5.6-fold, and a pKa of 8.86 was calculated based on the function of relative ratiometric intensities in Zn-cpon-1. The existence of two emissive bands with changeable intensity relatively in a parted manner is premise to realize the self-calibrate system ensuring the accuracy ratio signals. The interaction of hydrogen bonds between ether bond moiety of Zn-cpon-1 and protons/hydroxide may be responsible to the changes of luminescence intensity, during which the energy transfer from ligand to metal center were mainly disturbed.32-35 Simultaneously, the chemical resistance was examined by soaking the as-synthesized samples of Zn-cpon-1 in pH 2-11.5 aqueous solution at room temperature for 24 h. The PXRD patterns of these samples remained almost intact under relative harsh conditions, indicating the integrity of the framework without the phase transition or collapse (Figure S10). The oxygen atoms of the ether bond in the ligand located the walls of the channels regarded as efficient hydrogen-bonding acceptors make huge contribution to the high acid-/base- stabilities of Zn-cpon-1, preventing the attack of H+/OH- in outside environment, further restrict the dissociation of coordination bond around connection sites. In addition, the recyclability of the pH sensor was also investigated. The used Zn-cpon-1 in NaCl buffer solution was adjusted to neutral, generating the recovered sensor materials. As shown in Figure S11, the regenerated Zn-cpon-1 almost returned to the initial relative emission ratio of I532/I443, suggesting Zn-cpon-1 can be repeatedly used for monitoring of pH in water system. The interesting pH response in luminescence and the acid/base resistance will not only can be as a stimulating sensing signal to the environment but also expand the field of this material in the boarder pH aqueous condition. Drug loading of Zn-cpon-1 Due to the high chemical stability in various pH conditions and the photostability in luminescence emission of Zn-cpon-1 configuring appropriate porosity and window size, the model drug molecules loading experiments were carried in methanol and phosphate-buffered saline solution (PBS) and the potential capability for drug delivery was verified by UV-vis spectra. On consequence of the accessible void 10

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volume of the Zn-cpon-1, the short biological lifetime and anticancer therapy effect, 5-Fluorouracil (5-FU, 3×6 Å) and 6-Mercaptopurine (6-MP, 6×10 Å) which have been extensively utilized for sustainable and controllable drug delivery were employed as model drug molecules.36, 37 As shown in Figure 4, the UV-vis curves of the 5-FU and 6-MP show the decrease in intensities comparing with the beginning owing to the encapsulation of drugs within Zn-cpon-1 pores at the time periods. The structural integrity of Zn-cpon-1 and the crystallinity of drug molecules were validated by PXRD (Figure S12). The encapsulation of 5-FU and 6-MP could also be supported via the IR spectra analysis of resulting solids compared with the host materials. After 5-FU loading, some additional absorption bands around 1234 cm−1 and 800–540 cm−1 region are appeared in contrast to Zn-cpon-1, attributed to the C−N vibration and the C−F deformations of 5-FU drug molecule (Figure 4a,b).38 Concerning the 6-MP loading, the characteristic band located in 2677 cm−1 ascribed to the thiol vibration of 6-MP also appears in [email protected] Additionally, the obvious decrease of absorbance band of drug molecules may show the potential interaction between the drugs molecules and framework of Zn-cpon-1. In order to realize the drugs loading as complete as possible, the optimal loaded conditions were investigated. The maximum loading capacities of 5-FU and 6-MP molecules were both realized by immersing Zn-cpon-1 in 5-FU and 6-MP molecules containing methanol solutions for 5 days in weight ratio value of 3:1 (Table S5 and S6). The contents of drugs included in the Zn-cpon-1 were estimated via calibration curves of UV-vis spectra. As shown in Figure S22a, Zn-cpon-1 displayed an inferior loading to the 6-MP compared with 5-FU, and the uptake amounts were separately evaluated to be 0.81 g of 5-FU g-1 and 0.05 g of 6-MP g-1 of Zn-cpon-1, which could also be supported by TGA and the results illustrated 44.75 wt % 5-FU and 4.76 wt % 6-MP loading, corresponding to 2 molecules of 5-FU and 0.11 molecules of 6-MP per formula unit of Zn-cpon-1 in average, respectively (Figure S15). The drug-loading capacities of the Zn-cpon-1 are comparable with other reported MOF materials (Table S7).39 In view of the above results, it is reasonable to propose that the drug loading ability of Zn-cpon-1 has direct relationship with the size and geometry of drug molecule. The more suitable 11

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size match between 5-FU with the Zn-cpon-1 than 6-MP, together with the suitable pore volume of Zn-cpon-1 is very likely to contribute to the higher drug loading capacity. (b) Transmittance /%

Transmittance /%

(a)

5-FU@Zn-cpon-1 Zn-cpon-1 5-FU

4000

3500

3000

2500

2000

1500

1000

500

6-MP@Zn-cpon-1 Zn-cpon-1 6-MP

4000

3500 3000

Wavenumbers /cm-1

2500 2000

1500 1000

500

Wavenumbers /cm-1

(c)

(d) 1.0

Absorbance

1.2

Absorbance

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

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0.9 0.6 0.3

0.6 0.4 0.2 0.0

0.0 200

0.8

250

300

350

400

200

250

Wavelength/nm

300

350

400

450

Wavelength/nm

Figure 4. (a) IR spectra of 5-FU, Zn-cpon-1 and 5-FU@Zn-cpon-1. (b) IR spectra of 6-MP, Zn-cpon-1 and 6-MP@ Zn-cpon-1. The UV-vis absorption spectra of 5-FU (c) and 6-MP (d) in methanol solutions (the black and red lines represent the original and drug loaded states).

Theoretically, the complexation stoichiometry between 5-FU and Zn-cpon-1 could also be preferably confirmed via the Job’s curve of 19F NMR spectra owing to the fact that the change of the 5-FU molecular character signal values in

19

F NMR

spectra is more obvious than that in 1H NMR spectra. As shown in Figure 5a and Table S8, the chemical shift of F atom moved to the upfield as the relative proportion of 5-FU decreased. On the basis of to the Job’s plot (Figure 5b), when the fraction of the 5-FU was 0.333, the maximum value was reached, suggesting the binding stoichiometric ratio was 1:2, consisting with the stoichiometry obtained from TGA studies viz. (5-FU)2@Zn-cpon-1. Accordingly, the Hill coefficient (n) and association constant (Ka) could be obtained by using the Hill equation based on the

19

F NMR

results.40 As the consequence of derivation from the Hill equation curve in a series of 12

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drug loaded Zn-cpon-1 systems (Figure S17), the Hill coefficient value and apparent binding constant were 5.35 and 7.56×102 M-1 respectively. Based on the results, 5-FU molecules were bound with Zn-cpon-1 in a strongly positive cooperative method, illustrating that the affinity to another drug molecule will increase once one 5-FU molecule have already combined on the framework. (a)

(b) 0.25 χ5-Fu = 0.004 χ5-Fu = 0.084

0.20

1:2

χ5-Fu = 0.124 χ5-Fu = 0.168

0.15

χ5-FU∆δ δ

χ5-Fu = 0.208 χ5-Fu = 0.332 χ5-Fu = 0.460 χ5-Fu = 0.584

0.10 0.05

χ5-Fu = 0.708 χ5-Fu = 0.832 χ5-Fu = 1.000

-172.2

-172.4

-172.6

0.00

-172.8

-173.0

0.0

δ5−FU / ppm

(c)

O 1s F 1s

0.4

0.6

0.8

1.0

χ5-FU Zn 2p 2p1/2

Intensity/ a.u.

Zn 2p

0.2

(d)

Zn-cpon-1 5-FU@Zn-cpon-1

Intensity/ a.u.

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

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C 1s

2p3/2

Ι.

ΙΙ.

N 1s 1200

1000

800

600

400

200

0

1050 1045 1040 1035 1030 1025 1020 1015

Binding energy / eV Binding energy / eV Figure 5. (a) Chemical shift variation of 5-FU in 19F NMR of 5-FU@Zn-cpon-1 loading system along with distinct proportions of 5-FU (χ5-FU). (b) The Job’s curve of Zn-cpon-1 and 5-FU displaying the maximum at 0.333. (c) The XPS spectra survey for Zn-cpon-1 and 5-FU@Zn-cpon-1. (d) The XPS spectra of Zn 2p for Zn-cpon-1 (Ι.) and 5-FU@Zn-cpon-1 (ΙΙ.).

The comparable high drug loading capacity of Zn-cpon-1 was perhaps imputed to the accessible pore volume and the interactions between 5-FU and Zn-cpon-1. A remarkable luminescence quenching of 5-FU for the Zn-cpon-1 dispersion confirmed the strong interaction between 5-FU and Zn-cpon-1 (Figure S18). In general, possible interactions comprise coordination binding, π–π packing between the 5-FU and electron-rich frameworks of Zn-cpon-1, hydrogen bond forming with ether bond moiety of the ligand and electrostatic interaction.41 Amongst these interactions mentioned herein, relative stronger coordination binding consisting of the deprotonated imino group of 5-FU molecules and multitudinous Zn ions within 13

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Zn-cpon-1 architecture was a largely dominant factor during uptake process, verified via UV-vis spectrophotometry (Figure S19) and X-ray photoelectron spectroscopy (XPS) (Figure 5c). Comparing with the UV-vis spectrum of 5-FU, after 5-FU loading into Zn-cpon-1, the red shift of that implied the formation of 5-FU-Zn connection within the Zn-cpon-1 framework, proved via the similarity with modification of 5-FU by adding Zn2+ as well. The XPS analysis illustrated the binding energy of Zn 2p shifted from 1044.38 and 1021.12 eV for Zn-cpon-1 to 1043.88 and 1020.68 eV for 5-FU@Zn-cpon-1 (Figure 5d). The binding energy of Zn 2p shifting to lower levels after 5-FU payload might stem from electron transfer upon 5-FU binds to the potential Zn site.42 The similar coordination formations between 5-FU and metal centers (Zr and Fe) have already been reported.43, 44 Because of the formation of more stable coordination binding, the Zn-cpon-1 indicated a notable and effective 5-FU loading. Generally speaking, the drug delivers with better loading capability of 5-FU drug molecule usually in micro- or nanometer size.45 Hence, to further improve efficiency of drug loading, the polyvinylpyrrolidone (PVP) served as the template agent was induced to scale down drug delivery materials into the smaller. The PXRD reflection of the obtained Zn-cpon-1 microcrystals was in agreement with the simulation, illustrating the high crystallinity of Zn-cpon-1 microcrystals (Figure S20). Moreover, the morphology of the microcrystals was characterized by SEM. The microsheet, with a size average of 2–3 µm as revealed in Figure 6a and b. The encapsulation of 5-FU does not significantly change the morphology of Zn-cpon-1 after drug loading, and still basically retained regular rhombus sheets with better dispersal (Figure 6c, d). Meanwhile, the uniformly distribution of Zn and F elements in 5-FU@Zn-cpon-1 was further proved by scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy element mapping (Figure S21), which was essential and basic criterion for drug loading systems. Moreover, the loading amount of 5-FU was estimated to be 47.13±0.2 wt% by same method, illustrating the strategy of scaling down drug-carrying materials to micrometer size is effective and benefit to the drug delivery process. 14

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Figure 6. The SEM images of the Zn-cpon-1 microcrystals (a, b). 5-FU@Zn-cpon-1 (c, d).

Drug release kinetics and host−guest interaction analysis To validate the sustained release property and gain more detailed understand to the kinetic process, the 5-FU molecule releasing experiment was conducted in simulated body fluid at 37 °C. 5-FU and 5-FU@Zn-cpon-1 was dispersed in PBS solution, and dialyzed against distilled water. The content of 5-FU in the samples taken out was monitored by UV-vis spectrophotometry. Here, pure 5-FU was dialyzed as a control experiment for comparison, which showed fast cumulative release and the releasing amount reached 96.4% within 7 h (Figure S22b). In contrast, 5-FU released from 5-FU@Zn-cpon-1 could be released within 96 h (Figure 7). The whole drug release process can be divided into three stages. During the first 12 h, approximately 22.25% of the loaded 5-FU was released burst, followed by 21.28% of 5-FU release in the next 60 h. The third step showed a very slow release speed up to 192 h, contributing to approximately 50% of drug release. Theoretically, the framework with same chemical composition of ligand and topology should have a certain relevancy to 15

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the release of probe molecules. To gain the better insight to the 5-FU release behavior of 5-FU@Zn-cpon-1 and search for the best model to fit the experimental release profiles, four common models was firstly chose to describe drug release process including the zero order model, first order model, Higuchi model and Korsemeyer-Peppas model. The detailed results using different models for simulation were compared as shown in Figure 7. Concerning to the four simulation models, neither of them could provide reasonable regression coefficient for the release profile of 5-FU drug molecule when comparing the fitted curved with the experimental data. However, the fitting degree of the first order model is higher than the others (Table S9 and Figure S23). Based on the first-order rate equation, the guest-guest interactions and structural confinement effects should be taken into account. Hence we take guest-guest interactions as well as structural confinements as a parameter, n, and plug it into the first-order release equation in the ideal substrate. Since the guest-guest interactions and structural effects varies with time, and give rise to shape changes in the release curve in experiments, after the introduction of n the release equation should be no more first-order. Therefore, the Weibull distribution releasing dynamics model in the cumulative form was built (Equation 1).46 y = 1-e( )



(Equation 1)

where y is the released proportion of the loaded 5-FU molecule when releasing time is t, k and n are the release rate constant and guest−guest interaction parameter respectively. Then the Weibull model was applied to fit the experimental releasing curve of 5-FU molecule in Zn-cpon-1 system. It was apparent that the fitted line conducting by this new model was well-matched with the experiment (Figure 8b) (R2 = 0.994). The standout fitted performance of the Weibull model comparing with the others in releasing process of 5-FU molecules indicated that the Weibull model was more suitable to describe the releasing profile and correlate with the interactions of 5-FU molecules releasing from Zn-cpon-1 system.

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(a)

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60

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5-FU released / %

5-FU released / %

(b)

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Korsemeyer-Peppas model

0

8

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Time / d

Figure 7. The release curves of 5-FU@Zn-cpon-1 in the Zero order (a), first order (b), Higuchi (c) and Korsemeyer-Peppas model (d) (red dash line: simulated curves, blue circles: release curves)

Obviously, there are close and multiple interactions between the 5-FU molecule and the host architecture which may be response for the three stages embodying in the release profile. Due to the inherent structural characters of large conjugation, Zn-O paddle-wheel clusters and free ether oxygen site located at the wall of the host, the binding or abundant host-gust interaction (such as N−H···O, N−H···π and the π–π interactions) existing in the loading process will be separately destroyed step by step. Therefore, the initial burst release was ascribed to the release of 5-FU located and away from the outer channels with the intermolecular interactions among the drug molecules and the weak interaction between 5-FU and ligand along the channels broken. Then, the forces dominated via the N−H···π hydrogen bonds, π–π stacking and binding interaction between the 5-FU molecules and aromatic architectural wall of Zn-cpon-1 are response for the following slow release of 5-FU from inner channels and the windows of the cavities. Notably, the routine release process of 5-FU@Zn-cpon-1 is not ample and incomplete, which might be further improved by 17

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the outside environmental simulation.

Figure 8. (a) Schematic illustration of release process of 5-FU from Zn-cpon-1 through three energy states. (b) The Weibull distribution model simulation of 5-FU release curve and the energy states of different interactions between framework and 5-FU molecules.

To find the theoretical guidance and feasible method, the dynamic energy analysis of the best fitted Weibull model was conducted. Initially, the physical meaning of the fitted parameters in Weibull model should be attributed according to the connection with physical chemistry principles. The rate parameter k, has the same dimension with first-order rate constant, so the assumption that the meaning of k is the rate constant of the release process with a constant guest-guest interaction. Therefore, the strength of interaction is derived from the rate parameter by adopting the Arrhenius equation (Equation 2). 

k = A 

(Equation 2)

Where Ea is the activation energy, namely, the energy gap between the transition and reactant states. As shown in Figure 8a, if the release process of the 5-FU molecules could be regarded as a whole chemical process, the “reactant state (ⅰ)” represents a 18

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condition that 5-FU drugs have loaded on the framework of MOF, the “transition state (ⅰ)” and “resultant state (ⅰ)” are the 5-FU stood inside the MOF pores but no interaction with the wall and free outside the framework, respectively. Therefore, the “activation energy” exactly reflects the interaction energy between the guest and the architecture.47 Obviously, there is a close relationship between rate constant k with activation energy and temperature. Hence, from the dynamic perspective, one of the feasible and clinic available methods is incremental temperature. The other the key aspects related to improve release performance and therapy effect at a certain stage in a controllable rate is concentrated on decreasing the activation energy and increase the number of activated molecule via possible outside simulation inducing the interaction weaken or destroyed. Temperature and pH dual-responsive for drug delivery According to the kinetics results, at the high temperature environment resulting from thermal therapy, the reactant rate of gust drug molecule and host framework will increase, which is benefit to the release process.48 As shown in Figure 9a, the sustained drug delivery profiles were obtained from 5-FU@Zn-cpon-1 in PBS (pH 7.4) at 25, 37, 45, and 60 °C. Interestingly, there is a significantly heat-activated drug delivery phenomenon. The premature releases at 25 and 37 °C were similar, whereas the 5-FU release was apparently accelerated with the a little premature release of drug-encapsulated MOFs when the temperature ascended to 45 °C. Especially at 60 °C, approximately 68.3% of drug payload from 5-FU@Zn-cpon-1 was released for the 70 h, and the releasing rate has improved contrasting with that at normal body temperature, implying that the increasing temperature would have positive effect to the delivery of model drugs as a result of broken host–guest interactions. The higher the temperature is, the quicker the loading release. This indicates the potential application of Zn-cpon-1 as temperature-responsive drug vehicle.

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pH Time / d Figure 9. (a) 5-FU released from Zn-cpon-1 in PBS operated by different thermal activation. (b) The comparison of release rate in different temperatures. (c) 5-FU released from Zn-cpon-1 in PBS operated by pH changes. (d) The comparison of release rate in different pH conditions.

Besides the temperature-responsiveness, from the identity characteristic of the drug carrier itself perspective, the 5-FU-loaded Zn-cpon-1 is more sensitive in an acidic environment, in which the potential hydrogen bond between the ether oxygen acceptor and the drug molecules would debilitate and even broken, as consequence, more 5-FU molecules could escape from the restriction of former mentioned interactions with the wall of the framework and accelerate the release of the binding drug molecules. In order to bring insight into the influence of pH variation and dynamics on controllable releasing and reveal the pH-dependent character of the framework of Zn-cpon-1, the delivery processes of 5-FU encapsulated in Zn-cpon-1 were measured under the various pH conditions at 25 °C. As indicated in Figure 9c, upon the pH value of solution dropped to 6.5, the proportion of released 5-FU molecules has a slight increase. With the pH in a further downtrend, the releasing speed of drugs was also related with the pH of surrounding environment. Upon the pH value reached 4, 36% of drug molecules were released within half day, while the pH 20

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value was 2, the release quantity of drug molecules were approximate 49% at this time interval. Moreover, the releasing contents would accelerate with temperature up to 37 and 45 °C via vertical comparison to that in these pH conditions (Figure S24). Generally, it is well-known that the pH value around the cancer cell is lower than that in body fluid and healthy cell (alkalescence), the response drug loading-releasing systems could prevent the dispensable drug loss when the drug loaded materials circulated in body and ensure the efficiency of anticancer drugs in cancer cells.49, 50 In addition, the release speed of drug molecules in the surrounding of the cancer cells would be faster than the sites around the healthy cell, consequently, it is convinced to suppose the delivery of the anticancer drug through this system might weaken its disadvantageous side-effects. Therefore, the change of pH value in environment plays synergically role on the 5-FU delivery with temperature as another trigger, which can be utilized as a better alternative to improve loading capacities and chemotherapeutic efficiency, address the limitation induced by the complexity of the human body environment. Based on the above-described results, Zn-cpon-1 has a great potential as drug delivery system with thermal stimuli-triggered release. Furthermore, the cytotoxicity and biocompatibility have already verified the significance of Zn-cpon-1 as for the more rigorous standard. In order to evaluate the cytotoxicity of Zn-cpon-1 and 5-FU@Zn-cpon-1, an MTT assay was employed through incubating with HepG2 (human hepatoblastoma) cells and HASMC (human airway smooth muscle cells).51 As depicted in Figure S25, the cell viability of HepG2 and HASMC was both above 90% at various concentrations, even if the concentration of Zn-cpon-1 was as high as 100 µg mL-1 indicating the negligible cytotoxicity of Zn-cpon-1. However, the viability of HASMC was obviously higher than HepG2 when incubated with same concentration of 5-FU@Zn-cpon-1. These results suggest the biological compatibility of Zn-cpon-1 being used as new drug carriers and the potential high treatment efficiency for selected drug molecules delivery because of the targeting and selective release towards tumor cells. 21

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 CONCLUSION In conclusion, a biocompatible drug-loadable zinc MOF Zn-cpon-1 has been obtained successfully. Zn-cpon-1 without any post-modification presented a ratiometric pH-sensing dual-emission and excellent drug delivery behavior with better 5-FU loading capability than 6-MP. Size and shape match of model drug could be responsible for this distinction. The abundant binding interaction between Zn-cpon-1 and 5-FU was discussed in detailed and could quantitatively evaluated by the rate constant according to the correlation with the topological structure. Additionally, the release kinetics of 5-FU@Zn-cpon-1 in PBS fitted well with the Weibull distribution model and the controllable releasing could be triggered via the thermal and pH dual-stimulus to better applied the complicated bio-environment. Overall, the Zn-cpon-1 would be a promising candidate in antitumor therapy owing to the effective and controllable drug delivery and this work also brings the alternative strategy in development of drug carrier system and the prediction of release kinetic behavior on account of the understanding of host–guest interaction.

 EXPERIMENTAL SECTION Synthesis of Zn-cpon A solution of Zn(NO3)2·6H2O (60.0 mg, 0.20 mmol), H2cpon (26.0 mg, 0.1 mmol) in CH3CN (1.0 mL) and H2O (7.0 mL) was prepared. After adjusting the pH value to 3.0 by 1:10 (v/v) HNO3 solution, the above prepared solution was transferred in a 20.0 mL Teflon reactor to continuous heat at 120 °C for 5 d. After the reactor cooled to the room temperature, yellowish block crystals of Zn-cpon were obtained and washed by ethanol. The final products were dried in normal atmosphere (yield, 61 %, based on H2cpon). Element analysis (%) calcd. for C13H9NO6Zn (Mr: 340.58): C, 45.84; H, 2.66; N, 4.11. Found: C, 45.81; H, 2.70; N, 4.09. FT-IR (cm–1) for Zn-cpon (Figure S4a): 3504 (br, m), 3069 (w), 1641 (m), 1582 (m), 15441 (m), 1399 (s), 1385 (s), 1259 (m), 1113 (w), 968 (w), 853 (m), 715 (m), 640 (w), 515 (w), 496 (w), 461 (w). Synthesis of Zn-cpon-1 A mixture of Zn(ClO4)2·6H2O (37.2 mg, 0.10 mmol), H2cpon (26.0 mg, 0.1 mmol), H2O (8.0 mL) and 1:10 (v/v) HNO3 (0.5 mL) was stirred in a Teflon reactor 22

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(20.0 mL) for 30 min and then heated at 120 °C for 5 d. After the reactor cooled to the room temperature, yellowish block crystals of Zn-cpon-1 were obtained and washed with ethanol. The final products were dried in normal atmosphere (yield, 56 %, based on H2cpon). Element analysis (%) calcd. for C13H9NO6Zn (Mr: 322.59): C, 48.40; H, 2.81; N, 4.34. Found: C, 48.37; H, 2.85; N, 4.30. FT-IR (cm–1) for Zn-cpon-1 (Figure S4b): 3431 (br, m), 3064 (w), 1605 (m), 1592 (w), 1560 (w), 1384 (s), 1270 (s), 1107 (w), 953 (w), 748 (w), 635 (w), 549 (w), 491 (w), 474 (w). Preparation of microcrystal of Zn-cpon-1 Microcrystals of Zn-cpon-1 were prepared via facile one-pot hydrothermal method. In brief, a mixture of Zn(ClO4)2·6H2O (372 mg, 1 mmol), H2cpon (260 mg, 1 mmol), PVP (0.05 g) were added in DMF (5 mL) and water (30 mL) mixture solution with 1:10 (v/v) HNO3 (5 mL) and stirred for 30 min. Then the mixture was transferred to a Teflon reactor (50.0 mL) and heated at 120 °C for 8 h. After the reactor cooled to the room temperature, the yellow precipitates were obtained by centrifugation (8000 r/min for 30 min) and washed by DMF and ethanol for serval times to remove the unreacted remaining ligand. The filtrated products were dried in normal atmosphere at 373 K for 12 h.

 ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at Internet http://pubs.acs.org. Structural Information for Zn-cpon and Zn-cpon-1, IR spectra, TGA curves, PXRD patterns, and selected bond lengths and angles for Zn-cpon and Zn-cpon-1 (PDF) X-ray crystallographic files (CIF)

 AUTHOR INFORMATION Corresponding Authors *E−mail: [email protected] *E−mail: [email protected] Notes 23

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The authors declare no competing financial interest.

 ACKNOWLEDGEMENTS This

work

was

supported

by

National

Key

R&D

Program

of

China

(2017YFB1300104) and the National Natural Science Foundation of China (Grant 21371040 and 21571042).

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A bio-friendly and dual-emissive zinc metal-organic framework is designed and presents the high loading and dual-triggered programmable release ability to 5-Fluorouracil.

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