Small Ti-based MOFs prepared with the introduction of tetraethyl

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Biological and Medical Applications of Materials and Interfaces

Small Ti-based MOFs prepared with the introduction of tetraethyl orthosilicate and their potential for use in drug delivery Yong Xie, Xujie Liu, Xinxin Ma, Yuefeng Duan, Youwei Yao, and Qiang Cai ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b01175 • Publication Date (Web): 04 Apr 2018 Downloaded from http://pubs.acs.org on April 4, 2018

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ACS Applied Materials & Interfaces

Small Ti-based MOFs prepared with the introduction of tetraethyl orthosilicate and their potential for use in drug delivery Yong Xie1,2, Xujie Liu1,3*, Xinxin Ma4, Yuefeng Duan1, Youwei Yao1, Qiang Cai1,2*

1. Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, P. R. China, [email protected]; [email protected]

2.

State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China.

3. Shenzhen Lando Biomaterials Co., Ltd., Shenzhen 518057, P.R. China

4. Southern China Branch, Sinopec Commercial Holding Company Limited, Guangzhou 510630, China.

KEYWORDS:

Ti-based

MOFs,

size

decrease,

controlled

biocompatibility

ACS Paragon Plus Environment

release,

drug

carrier,

ACS Applied Materials & Interfaces 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

ABSTRACT

Metal-organic frameworks (MOFs) have attracted much attention in the areas of biomedicine and medicine owing to their versatile porous structure. However, the oversize and high cellular toxicity of some metal-based MOF particles have hindered their development. Therefore, a series of small Ti-based MOFs are prepared with the introduction of tetraethyl orthosilicate (TEOS) into the reaction system. Compared with the Ti-based MOFs prepared by traditional methods, the size of the Ti-based MOFs prepared with this method is decreased by 42.78%. Meanwhile, the good biocompatibility of the prepared Ti-based MOF particles toward the L929 cell lines is proven using CCK-8 assays. Furthermore, the controlled release property of the Ti-based MOFs is evaluated by using Ibuprofen (IBU) as a model drug. The amount of drug loaded in the samples is shown to be approximately 10%, and approximately 95% of the IBU is released from the MOFs after exposure to PBS for 24 h. We conclude that the size-decreased Ti-based MOFs prepared with the introduction of TEOS into the reaction systems are potential drug carriers in terms of their good biocompatibility and effective performance in the controlled release of a drug.


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1. Introduction

Porous metal-organic frameworks (MOFs), composed of metal ions and organic ligands, have attracted much attention owing to their potential applications in separation, catalysis technology, sensing and gas storage.

1-7

Among the special features of MOFs, the versatile

porous structure and high porosity provide unprecedented opportunities for their wide use in the areas of biomedicine.

8-11

Much effort has been made to introduce MOFs into the design

and application of drug delivery systems as drug carriers.

12-14

For example, MIL-100 and

MIL-101(Cr) were first used to load IBU and were proven to be effective for a controlled release.

15

Furthermore, Zn-based MOFs loaded with doxorubicin (DOX) were shown to be

efficient drug delivery vehicles in cancer therapy with a pH-responsive release. 16 Apart from the highly ordered porosities and well-defined structures, the host-guest interactions between porous MOFs and therapeutic agents also contribute to the wide use of MOFs as drug carriers. 17

Generally, considering that the drug carrier needs to be introduced into the human body, MOFs should be toxicologically compatible in terms of bio-applications. Currently, a few of the transition metal ions have been nominated for the construction of MOFs in view of their acceptable toxicity for bio-applications. The oral lethal dose 50 (LD50) is an important parameter for the potential evaluation of MOFs as drug carriers,

18-22

which have been

determined to be 30 g kg–1 for Fe, 350 µg kg–1 for Zn, 4.1 g kg–1 for Zr, 1.5 g kg–1 for Mn, 8.1 g kg–1 for Mg, and 25 mg kg–1 for Cu. In 2008, MIL-53 (Fe) was used to adsorb IBU by injecting the solids in an IBU-containing hexane solution with a loading capacity of 20 wt%.



23

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Then, Cu-based MOFs and UiO-66 were also reported as nanocarriers.

24-25

However,

considering that carriers are usually the major components with weights that are far greater than the drugs, which results in a relatively lower drug loading capacity of the MOFs, the amount of MOFs required in vivo is considerable. Therefore, it is better for the nominated MOFs to contain metal ions with a high LD50 value.

As far as we are concerned, Ti-based MOFs seem to be a perfect choice for use as a drug carrier among all of the existing MOFs. The LD50 of the Ti ion is 25 g kg–1, which is better than any other metal ions except for Fe in terms of biocompatibility. Furthermore, the Ti-based MOFs exhibit a significant porosity. The specific surface area of the Ti-based MOFs, MIL-125, is up to 1200 m2. Additionally, the tetragonal cavities (6.1 Å) and octahedral cavities (12.5 Å) provide structural superiority for the encapsulation of drugs.

26-27

Furthermore, the Ti-based MOFs modified by an amino group exhibits a good chemical stability in water. 28 Moreover, the Ti-based MOFs are usually considered as a semiconductor and an effective catalyst because of its visible photocatalytic activity,

29-31

so the potential

property of an illumination response for Ti-based MOFs provides more opportunities for it to be used as a smart drug carrier. Although there are many merits of Ti-based MOFs, some efforts should still be made to prove their performance as drug carriers. First, it is necessary to confirm the biocompatibility of Ti-based MOFs. Moreover, the size of the porous Ti-based MOFs should be optimized in consideration of the cellular uptake. Actually, oral administration is a common drug delivery method because it can provide continuous exposure of the diseased region to the drugs over a long time. Unfortunately, some orally administered drugs have little chance to get into the blood system owing to their poor


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solubility, stability and permeability, and would be eliminated by the first metabolic process with cytochrome P450 and by the efflux pump of P-glycoproteins (P-gp).

32-33

Therefore,

nanoparticles used as drug carriers provide an alternative solution for the oral delivery of drugs across the gastrointestinal barrier owing to their extremely small size. Taking into account their adhesion to and interaction with biological cells, the size of the nanoparticles should be seriously controlled. Therefore, an effective method for the size control of the Ti-based MOFs is required. Furthermore, the property of the controlled release for Ti-based MOFs should also be studied comprehensively.

Taking the problems mentioned above into account, we first prepared Ti-based MOF particles with different sizes with the introduction of tetraethyl orthosilicate (TEOS) into the crystal growth system. Then the cell toxicity of the prepared nanoparticles was evaluated by using the L929 cell line as a cell model. Moreover, the drug loading capacity of the prepared Ti-based MOFs was measured by using IBU as a model drug. The release profiles of IBU from the Ti-based MOFs were also analyzed.



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2. Experimental Section

2.1 Materials

2-Aminoterephthalic acid (98%), titanium butoxide (C16H36O4Ti, AR), tetraethyl orthosilicate (C8H20O4Si, 98%), N,N-dimethylformamide (DMF, 99%), methanol (AR), n-hexane (99%) and IBU (98%) were purchased from Macklin Corp. (Shanghai, China) and were used without further purification, and the L929 cell line was purchased from Shanghai Zhong Qiao Xin Zhou Biotechnology Co., Ltd., China.

2.2 Preparation of Ti-based MOFs with different sizes

A modified reported recipe was used for the preparation of the Ti-based MOFs powder.

29

2-Aminoterephthalic acid (1 g) was added into a beaker containing a DMF (15 mL) and methanol (2 mL) mixed liquid while stirring was provided for 30 minutes. Then the mixed solution of tetraethyl orthosilicate (TEOS) and titanium butoxide (TPOT) with different volume ratios, that is, 0 for sample S1 (2 mL of TPOT), 1/3 for sample S2, 2/3 for sample S3, 1 for sample S4, 1.5 for sample S5 and 3 for sample S6, was added into the mixed liquid and stirred for 30 minutes. Then the mixed solution was transferred to a Teflon-lined stainless steel auto-clave (50 mL). The reaction was carried out in an explosion-protected oven at 150 °C for 48 h. The DMF and methanol were used as the detergent to remove the residual reactants for two times once the heated reaction was finished, then the light-yellow powder was obtained after being kept for 1 day in an 80 °C air dry oven.

2.3 Characterization of MOFs


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X-ray diffraction (XRD) analysis was conducted using a Rigaku D/max 2500/PC diffractometer with CuKa radiation (λ = 1.5418 Å) in a scanning range of 5–30° at a rate of 1° min-1. Field emission scanning electron microscopy (FE-SEM, HITACH S4800) at 5 kV was employed to characterize the morphology of the powders. Fourier transform infrared spectroscopy (FTIR) was obtained from an FTIR spectrometer (Thermo Scientific Nicolet iS 50) in the range of 400–4000 cm-1. Thermogravimetric analysis (TGA) was conducted on a NETZSCH STA449F3 thermal analyzer from room temperature to 800 °C at a heating rate of 15 °C min-1 in N2 atmosphere. N2-physisorption experiments were carried out at 77 K in a specific surface area analyzer (BelSorp Max). The samples were degassed at 423 K under vacuum for 16 hours before the measurements. The particle size was determined in a laser particle size analyzer (Mastersizer 2000Hydro2000MU).

2.4 In vitro cytotoxicity

The immortalized cell line of L929 mouse fibroblast cells were seeded in a 48-well plate at a density of 15,000 cells per well. The samples S1, S3 and S5 were elected as experimental objects, and 3 concentrations, that is 50 µg/mL, 100 µg/mL and 150 µg/mL, were set. After seeding of cells for 2 days, the CCK-8 assay was performed for the cell proliferation assay. Briefly, CCK-8 (Dojindo, Japan) with a 10 %vol. of the medium was added into the each well. After incubation at 37 °C for 2 hours, the absorbance (O.D) of the solution was measured by a microplate reader at 450 nm. The experiments were carried out in quadruplicate.

2.5 IBU loading

IBU (300 mg) was resolved into an n-hexane solution (10 mL) in a sealed and light-tight



glass bottle, then the prepared Ti-based MOFs (100 mg) were added with stirring. After adsorption for 4 days, the Ti-based MOFs loaded with IBU were filtered and washed two times with water.

2.6 Drug release

Drug-loaded Ti-based MOFs (30 mg) were placed in a dialysis bag (10000-MW cut-off) and dipped into a dissolution medium (10 mL, phosphate buffered saline, PBS, pH 7.4) at 37 °C. The dissolution medium (2 mL) was replaced by fresh PBS at predetermined time intervals for determination of the drug concentration. UV-vis spectrometry was employed to analyze the IBU concentration.

2.7 Stability of MOFs

Field emission scanning electron microscopy was employed to observe the morphological change of the Ti-based MOFs. The Ti-based MOFs powder (0.1 g) was suspended in PBS (2 mL) at 37 °C for 48 h, and then filtration and washing operations were employed for the preparation of the specimen.

2.8 Statistical analysis

Experimental results were expressed as mean±standard deviation (S.D.). The statistical significances of differences in the means were determined by one-way analysis of variance (ANOVA) followed by post hoc comparisons with the least significant difference (LSD) method using SPSS 19.0 software. A value of p

Small Ti-based MOFs prepared with the introduction of tetraethyl

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