Constructing Redox-Responsive Metal-Organic Framework

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Functional Nanostructured Materials (including low-D carbon)

Constructing Redox-Responsive Metal-Organic Framework Nanocarriers for Anticancer Drug Delivery Bingqian Lei, Mengfan Wang, Zelei Jiang, Wei Qi, Rongxin Su, and Zhimin He ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b19693 • Publication Date (Web): 25 Apr 2018 Downloaded from http://pubs.acs.org on April 25, 2018

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ACS Applied Materials & Interfaces

Constructing Redox-Responsive Metal-Organic Framework Nanocarriers for Anticancer Drug Delivery Bingqian Lei a, Mengfan Wang *ac, Zelei Jiang a, Wei Qi *abc, Rongxin Su abc, Zhimin He a a.

School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering,

Tianjin University, Tianjin 300350, P. R. China. b. The Co-Innovation Centre of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, P. R. China. c.

Tianjin Key Laboratory of Membrane Science and Desalination Technology, Tianjin 300350, P. R.

China.

ABSTRACT Metal-organic frameworks (MOFs), which are a unique class of hybrid porous materials built from metal ions and organic ligands, have attracted significant interest in recent years as a promising platform for controlled drug delivery. Current approaches for creating MOFs-based responsive drug carriers involve encapsulation of stimuli-responsive compositions into MOFs or post-synthetic surface modification with sensitive molecules. In this study, we developed a novel intrinsic redox-responsive MOFs carrier, MOF-M(DTBA) (M= Fe, Al or Zr) by using iron, aluminum or zirconium as metal nodes and 4,4’-dithiobisbenzoic acid (4,4’-DTBA) as the organic ligand. The disulfide bond in 4,4’-DTBA is cleavable by glutathione (GSH), which is often overexpressed in tumor cells. It was found that MOF-Zr(DTBA) synthesized at 40 °C displayed appropriate size and properties as a drug carrier. By incorporating curcumin (CCM) into MOF-Zr(DTBA), CCM@MOF-Zr(DTBA) nanoparticles were obtained that displayed faster releasing behavior in vitro and enhanced cell death compared to free CCM. The in vivo anticancer experiments indicate that CCM@ MOF-Zr(DTBA) exhibit much higher antitumor efficacy than free CCM. This strategy for constructing responsive MOFs-based nanocarriers might open new possibilities for the application of MOFs in drug delivery, molecular imaging or theranostics. KEYWORDS: metal-organic frameworks (MOFs), curcumin, drug delivery, redox-responsive, nanocarrier

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INTRODUCTION Cancer is one of the most life-threatening diseases.1-2 Currently, chemotherapy is still the dominant treatment method for most cancers.3 However, the intrinsic limitations of chemotherapy, such as poor specificity to tumor cells, undesirable side effects and low stability, always lead to unsatisfactory therapeutic effects and discomfort in cancer patients.4 To solve these problems, nanoscale drug delivery systems (NDDS) that use various carriers to encapsulate drugs have attracted more and more attention because the enhanced permeability and retention (EPR) effect, which tends to accumulate nanodrugs in tumor tissue much more than they do in normal tissues.5 In recent years, stimuli-responsive NDDS have been designed as smart carriers to enhance the therapeutic efficacy by rapidly releasing chemotherapy agents at the tumor site and retarding the drug leaking into healthy physiological environment.6 The abnormal microenvironment at tumor sites, such as low pH,7 high glutathione (GSH) concentration,8 or up-regulated matrix metalloproteinases,9 can be utilized to trigger drug release from NDDS towards cancer cells. Metal-organic frameworks (MOFs) are a class of hybrid porous materials built via the assembly of metal ions as nodes and organic ligands as bridges.10 A growing number of studies have been focused on the use of MOFs in catalysis,11-12 gas storage,13 enzyme immobilization,14-16 fluorescent detection,17 and drug delivery.18-20 As a newly developed material, MOFs-based NDDS for cancer therapy exhibit various advantages.21-22 First, the size of MOFs can be controlled within the nanoscale, which facilitates the uptake of drugs. Second, toxicity can be tactfully averted by choosing biocompatible metals and organic ligands. Third, MOFs possess high drug loading capabilities due to their ultra-high porosity and can be easily biodegraded after drug release. MOFs can also be designed as smart carriers through encapsulating stimuli-responsive compositions into the MOFs or performing post-synthetic surface modification with sensitive molecules.23-25 As a matter of fact, it is more facile to construct intrinsic smart MOFs based on the stimuli-responsiveness of organic ligands or on the coordination between the ligand and the metal, but very few such MOFs have been reported so far.26-29 Zou et al. reported the one-pot synthesis of anticancer drugs loaded into ZIF-8 nanocarriers based on the pH-sensitivity of ZIF-8 toward the acidic microenvironment at tumor sites.26 Yang et al. reported that ZJU-101 can release drugs based on the pH-responsive interaction between the positively charged MOFs-based carrier and the negatively charged drug.28 In this study, a novel GSH-sensitive organic ligand, 4,4’-dithiobisbenzoic acid (4,4’-DTBA), was designed to develop an intrinsic redox-responsive MOFs-based carrier. The disulfide bond in 4,4’-DTBA is cleavable by GSH, which is often overexpressed in tumor cells. Iron, aluminum and zirconium have acceptable toxicity which exist in the human body at appreciable amounts.30-32 Therefore, MOF-Fe(DTBA) MOF-Al(DTBA) and MOF-Zr(DTBA), built with the respective metals and 4,4’-DTBA, were investigated for responsive drug delivery. Curcumin (CCM) is a natural polyphenol anticancer drug which is safe and well-tolerated, even at high doses33. However, its low water solubility and rapid degradation in the physiological environment leads to poor cellular uptake and bioavailability of the 2 ACS Paragon Plus Environment

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compound.34 By incorporating CCM into MOF-M(DTBA) (where M refers to Fe, Al or Zr), the obtained CCM@MOF-M(DTBA) can be easily taken up by tumor cells through EPR effect and cellular endocytosis. Once the loaded carrier system has entered the cancer cells, the disulfide bonds in the MOFs are cleaved by GSH, which triggers the crash of the MOFs and the release of free CCM. Through this method, the low solubility and poor stability of CCM are conquered, and the tumor cells can be rapidly killed under high intracellular concentrations of free drug (Scheme 1). To our knowledge, this is the first time that ligands containing disulfide bonds have been used to create a redox-responsive MOFs-based carrier for cancer therapy.

Scheme 1. Schematic illustration of (A) the preparation of CCM@MOF-M(DTBA), and (B) the redox-responsive degradation of CCM@MOF-M(DTBA) in tumor cells for cancer therapy.

RESULTS AND DISCUSSION MOF-M(DTBA) synthesis and drug loading In the case of Fe3O(BPDC)3, DUT-5 and UiO-67, MOFs were obtained via coordination between the metal ions and the aromatic carboxylates of 4,4'-biphenyldicarboxylic acid. To endow the MOFs with redox-responsive properties, the disulfide-bridging phenyl carboxylate (4,4’-DTBA) was used instead of 4,4'-biphenyldicarboxylic acid. FeCl3, Al(NO3)3 and ZrCl4 provided the metal ions for each type of MOF according to the previously published procedures for the synthesis of Fe3O(BPDC)3,35 DUT-5,36 and UiO-67.37 Table 1 summarizes the various morphologies, sizes, surface charges and drug loading capability (DLC) of the synthesized MOF-Fe(DTBA), MOF-Al(DTBA) and MOF-Zr(DTBA), which were obtained using different metal ions and synthesis temperatures (in general, referred to as 3 ACS Paragon Plus Environment


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MOF-tM(DTBA)). In addition, the responsive index (R.I.), which was defined as the ratio of CCM released from the MOFs in GSH solution relative to that in plain buffer, was used to estimate the responsive properties of the MOFs-based carriers. For the synthesis of MOF-Fe(DTBA), no obvious product was detected at 40 °C. When the synthesis temperature was increased to 60-120 °C, nanorod- or nanofiber-shaped MOF-Fe(DTBA) was obtained. However, the high aspect ratio of these structures is inappropriate for drug carriers. In addition, the R.I. value of all of the MOF-Fe(DTBA) were undeterminable due to their negligible DLC. MOF-Al(DTBA) showed superior responsive properties. The R.I. values for these frameworks were in the range of 1.65-2.67 and varied according to the synthesis temperature. However, all of the MOF-Al(DTBA) displayed the morphology of amorphous clusters with average sizes far beyond 200 nm. This implied the agglomeration of the MOFs in water, which was also verified by the low zeta potentials. As a result, the formation of large clusters leads to the poor dispersibility and the low external surface area, which also reduces the DLC and do harm to drug delivery. The particle size of MOF-Zr(DTBA) synthesized at 40 °C is less than 200 nm, which is suitable for drug delivery through cellular endocytosis. DLS analysis revealed that the average hydrodynamic diameter of MOF-40Zr(DTBA) was approximately 125 nm, whereas the particle sizes of MOF-Zr(DTBA) synthesized at 60-120 °C are all beyond the acceptable size range. Additionally, the DLC and R.I. values of MOF-40Zr(DTBA) are higher than those of the other MOFs, reflecting the superiority of MOF-40Zr(DTBA) as a drug carrier. Table 1. MOF-M(DTBA) synthesized at different temperatures Metal

MOF-

40Fe(DTBA)

Photo

TEM/SEM a

N.D.

Morphology

N.D.

Size (nm)

N.D.

DLC d

ζ potentials (mV)

(wt %)

N.D.

N.D.

N.D.

10.1±0.4

N.D.

N.D.

29.9±0.5

N.D.

N.D.

25.5±0.7

N.D.

N.D.

R.I. e

L=520~2353 60Fe(DTBA)

nanorod

80Fe(DTBA)

nanofiber

120Fe(DTBA)

nanofiber

W=80±9 b

Fe L=380~2377 W=58±10 b

L=499~2159 W=76±5 b

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amorphous 40Al(DTBA)

cluster


cluster

623±13 c

4.3±0.6

1.9

1.65±0.55

309±2 c

14.2±0.3

3.0

2.67±0.11

412±2 c

13.7±0.1

2.8

2.51±0.07

430±7 c

23.1±0.1

2.5

2.16±0.20

Al amorphous 80Al(DTBA)

cluster


cluster

40Zr(DTBA)

nanoparticle

125±1 c

33.0±1.4

11.8

2.01±0.11

60Zr(DTBA)

crystalline

482±4 c

32.8±0.3

6.5

1.32±0.10

80Zr(DTBA)

nanosphere

334±1 c

41.9±0.2

2.0

1.73±0.12

472±5 c

40.3±0.8

4.3

1.33±0.20

Zr

amorphous 120Zr(DTBA)

a

cluster

Scale bars = 200 nm. b Statistical analysis by TEM/SEM, L: length, W: width. c Measured by DLS.

d

DLC: drug loading capability of MOF-M(DTBA). e R.I., responsive index = (cumulative amount of CCM released from the MOFs over 5 h in 10 mM GSH solution)/ (cumulative amount of CCM released from the MOFs over 5 h in plain buffer). Figure S1 (see supporting information) shows the morphology of CCM@MOF-Zr(DTBA), which was similar to that of MOF-Zr(DTBA), implying that the incorporation of hydrophobic drugs did not affect the intrinsic morphology of the MOF-Zr(DTBA). In addition, after the loading of the drug, the average size of the CCM@MOF-Zr(DTBA) increased to 169.4 nm (Figure S2), which is still satisfactory for drug delivery. Figure 1A displays the PXRD patterns of 4,4’-DTBA, free CCM, MOF-Zr(DTBA), CCM@MOF-Zr(DTBA), and UiO-67 that was prepared according to Schaate et al37 (methods in supporting information). The results of PXRD analysis indicated that the dominating crystal structure of 5 ACS Paragon Plus Environment


MOF-Zr(DTBA) is similar to that of UiO-67, while the broadened diffraction peaks might come from the forming of amorphous MOF-Zr(DTBA) induced by flexibility of ligands.38-39 The diffraction peaks of MOF-Zr(DTBA) were maintained after drug loading without the presence of any CCM peaks, confirming the structural stability of MOF-Zr(DTBA). The incorporation of CCM was confirmed by the results of EDX, NMR and UV-Vis spectra (Figure S3, Figure S4 and Figure 1B). As shown in Figure 1B, CCM@MOF-Zr(DTBA) displayed a characteristic absorption band at 455 nm which was 30 nm redshifted compared to that of free CCM, but no obvious absorption band was observed for MOF-Zr(DTBA). This is in agreement with Xie’s result in which CCM was encapsulated into ZIF-8 nanoparticles.29 The photographs in the inset of Figure 1B indicate the color change of CCM from clear yellow to red after being encapsulated, and this bright red color was maintained after the CCM@MOF-Zr(DTBA) was vacuum dried (Figure S5). Based on the UV-Vis curves, the DLC and DLE of CCM@MOF-Zr(DTBA) can be calculated as 11.8% and 78.7%, which are similar values to those of a the previously reported intrinsic responsive MOFs-based carriers. 29

Figure 1. (A) PXRD analysis results. (B) UV-Vis absorption of MOF-Zr(DTBA), free CCM, and CCM@MOF-Zr(DTBA) in methanol solution, inset is the photographs of free CCM (a) and CCM@MOF-Zr(DTBA) (b). (C) Zeta potential of MOF-Zr(DTBA) and CCM@MOF-Zr(DTBA). (D) TGA curves of free CCM, MOF-Zr(DTBA) and CCM@MOF-Zr(DTBA). Both MOF-Zr(DTBA) and CCM@MOF-Zr(DTBA) were highly dispersed and stable in water according to the zeta potential analysis. As shown in Figure 1C, the zeta potential value of 6 ACS Paragon Plus Environment

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CCM@MOF-Zr(DTBA) is about +20.4 mV, which is lower than that of MOF-Zr(DTBA) (+33.0 mV). Sudipta et al. found that the electrons in the β-diketones of CCM efficiently interact with metal ions.40 Accordingly, the zeta potential of CCM@MOF-Zr(DTBA) decreased after the incorporation of CCM. The nanoscale size (

Constructing Redox-Responsive Metal-Organic Framework

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