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A Large Capacity Cationic Metal-Organic Framework Nanocarrier for Physiological pH Responsive Drug Delivery Yanyu Yang, Quan Hu, Qi Zhang, Ke Jiang, Wenxin Lin, Yu Yang, Yuanjing Cui, and Guodong Qian Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.6b00374 • Publication Date (Web): 14 Jul 2016 Downloaded from http://pubs.acs.org on July 16, 2016

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Molecular Pharmaceutics

A Large Capacity Cationic Metal-Organic Framework Nanocarrier for Physiological pH Responsive Drug Delivery Yanyu Yang,† Quan Hu,‡ Qi Zhang,† Ke Jiang,† Wenxin Lin,† Yu Yang*,† Yuanjing Cui† and Guodong Qian*† †

State Key Laboratory of Silicon Material, Cyrus Tang Center for Sensor Material and Applications,

School of Materials Science and Engineering, Zhejiang University, Hangzhou 310027, PR China ‡

Department of Pharmacology, School of Medicine, Hangzhou Normal University, Hangzhou 310036,

PR China

ACS Paragon Plus Environment 1


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ABSTRACT. A nanoscale cationic porous drug carrier ZJU-101 (ZJU = Zhejiang University), synthesized by the solvothermal method to get the crystal size of ~300 nm, was used to load diclofenac sodium, an anionic drug. This positively charged host materials showed a large loading capacity of diclofenac sodium (~0.546 g/g) through ion exchange and penetration procedures. The drug delivery in the inflamed tissues (pH = 5.4) exhibited a more effective release in comparison with that in the normal tissues (pH = 7.4), demonstrating a physiological pH responsive drug release. This discriminating drug release process was controlled by anion exchange between anions in phosphate buttered saline (PBS) and coordinated/free diclofenac anions. KEYWORDS. Nanoscale carrier, cationic MOF, drug loading capacity, physiological pH responsive release


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INTRODUCTION Diclofenac sodium (DS), one of the most useful non-steroidal anti-inflammatory drugs, is widely used to treat post-surgery infection to ease pain and improve health.1-4 However, the sharp fluctuation of drug concentration in blood may cause adverse effects such as hypersensitivity reactions, peptic ulceration and depression of renal functions.5 Therefore, the drug delivery systems (DDS) which use various carriers to load drugs and control their release have received much attentions.6-9 To ensure the efficient therapy, the drug carriers have many basic requirements. First, the carriers are required to entrap drugs with high payloads.10 Second, to facilitate the release of drugs by intravenous administration, the carriers are hoped to be in nanoscale.11 Third, good water and heat stabilities are expected for the carriers to ensure the drug release be well controlled. Furthermore, the carriers are required to be low or non-toxic and can be degraded in the human bodies.12 Towards these concerns, tremendous efforts on carriers have been made in recent years.10, 13 In the past several years, different kinds of metal organic frameworks (MOFs) have been used as drug carriers for control and postpone drug release.8, 13-15 Very recently, the ionic MOFs have introduced a new pathway for drug loading. An et al. have successfully adopted anionic bio-MOF-1 as the procainamide carrier, leading to a loading capacity up to 0.22 g/g after 15 days.16 Sun et al. have reported an anionic MOF Zn-TATAT, which was provided by the decomposition of the DMF solvent in channels. However, only a neutral anticancer 5-FU was loaded with a loading capacity of 0.5 g/g.17 Hu has also successfully prepared a positively charged framework MOF-74-Fe(III) by post-oxidation and loaded ibuprofen anions with a loading capacity of 0.19 g/g.12 However, the size of MOF-74-Fe(III) is about 2 µm, which is not applicable for the intravenous administration, just suitable for oral medication.8, 12, 18 It is well known that the drug taken by oral administration is relatively difficult to be absorbed by human bodies, and stays in the intestines for a quite long time, which damages the drug effect partly. On the other hand, the drug taken by intravenous administration is easily circulated to the



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whole body and absorbed by the specific tissues.19 However, in such an application occasion, drug carriers in nanoscale are required. We reported here a cationic nanocarrier MOF ZJU-101, which has a large loading capacity towards anionic drug diclofenac sodium. The nanoscale character of the ZJU-101 enables the drug to be taken by intravenous administration. We demonstrate that ZJU-101 with encapsulated DS (denoted as DS@ZJU-101) is a physiological pH responsive DDS for post-surgery therapy. DS release from DS@ZJU-101 is faster in inflamed tissues (pH = 5.4) than under physiological conditions (pH = 7.4). The cytotoxicity and the cellular uptake of ZJU-101 are further demonstrated by in vitro cell assays in rat pheochromocytoma cells (PC12).

RESULTS AND DISCUSSION The cationic porous nanocarrier ZJU-101 is constructed by combining zirconium with 2,2’-bipyridine-5,5’-dicarboxylate (BPYDC).20 As the BPYDC ligands locate at the junctions of the microporous cages, the N atoms of the ligand can be easily modified, introducing a small methyl onto the pyridyl groups.21 There are two types of cage in ZJU-101, the octahedral cages with a diameter of 1.6 nm and the tetrahedral cages with a diameter of 1.2 nm, which are both larger than the size of diclofenac sodium (0.95*0.55 nm2).22 Thus, the anionic drugs are absorbed by the pyridyl N+-CH3 on the pore surface which ensures the high drug payloads. This procedure is demonstrated in figure 1a. Before modification, the neutrally MOF-867 has no loading capacity of diclofenac sodium even under stirring for seven days (Supporting Information Figure S1), which probably is attributed to the repulsion between the electronic cloud out of the pyridine ring and diclofenac anion.20 After modification, 56.6 % of N in BYPDC has been converted into N+-CH3 by stirring with methyl trifluoromethanesulphonate for 24 hours. The alkylation reaction is monitored by 1H NMR spectra (Supporting Information Figure S2). The zeta potential of ZJU-101 has also been tested in ethanol (Supporting Information Figure S3). Result from Figure S3 shows the positive zeta potential of ZJU-101 (ζ=43.8 mV), because of the ACS Paragon Plus Environment 4

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N+-CH3 groups on the pores. The encapsulation of DS is accomplished with a rate up to 0.546 g/g which is the highest loading capacity in comparison with those of other typical ionic MOFs used in biomedicine (Table 1). The high loading capacity can be explainable by the high affinity of anionic drug with cationic ZJU-101 (Figure 1c). After modification, no obvious change has been found from powder X-ray diffraction patterns (PXRD) (Supporting Information Figure S4). In order to get smaller nanoscale crystals, the synthesis procedure is improved by reducing the amount of the ligand and metal ion to one-tenth without reducing solvent compared with that reported by Zhang et al.21 The Scanning electron microscopy (SEM) images (Figure 1b) showed the polled octahedral structure of ZJU-101, and the porous crystal in an average of ~300 nm, which can be administrated by intravenous injection and easily absorbed by human bodies. Diclofenac sodium can form diclofenac anions in the solution which make it easily get into the porous cationic MOF by ion exchange. The diclofenac sodium loading procedure is carried out in the ethanol solution at room temperature with continuous stirring. The zeta potential of ZJU-101 in the ethanol solution of diclofenac sodium is also tested. When ZJU-101 is immersed into drug solution, the ζ has a sharp decrease from 43.8 mV to 20 mV, indicating the strong coulombic interaction between diclofenac anions and cationic frameworks (Supporting Information Figure S3). The samples are also monitored at different period of time by 1H NMR spectra to analyze the loading capacity (Supporting Information Figure S5). In the first four days, the ratio of drug/MOF increases steadily (Supporting Information Figure S6). After that, the loading capacity keeps almost unchanged at around 0.546 g diclofenac for 1 g dried ZJU-101. The loading process is revealed in Figure S6. The PXRD pattern of DS@ZJU-101 is also as same as that of the ZJU-101 (Supporting Information Figure S4). The potential of DS@ZJU-101 as a pH-responsive delivery system is studied. Figure 2 shows the cumulative release profiles of DS@ZJU-101 with o.546 g/g of DS loading. The test is carried out in PBS solution of various pH values at 37 oC. All curves indicate that there is no premature release in the drug delivery systems, which is identical with the expectation for using MOF as the drug carrier. A smooth release is also shown in the first a few hours which is a significant character in the MOF-based ACS Paragon Plus Environment 5


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drug delivery systems. At inflamed tissues (pH = 5.4), DS is released at a more rapid rate, which can be ascribed to the higher ion concentration at lower pH in comparison with that at neutral pH. The ion exchange between anions in PBS of pH = 5.4 and coordinated/free diclofenac occurs more frequently, which discharges the coulombic interaction between the positive charged host porous materials and negative charged drug.23 It is estimated that half of the drug amount has been released from DS@ZJU-101 for around 15, 42, 65 hours at PBS of pH = 5.4, 6.5 and 7.4, respectively (Figure 2). This release time is much longer than the half-life period of the pure drug for no more than 2 hours.1 As the pH value in areas of inflamed tissues is known to be lower than those in blood and normal tissues (pH = 7.4), a pH responsive drug delivery system can reduce undesired drug release and improve the effective release of the diclofenac in inflamed tissues. Because drug is expected to release faster at the inflamed sites than the surrounding normal tissues maintaining a physiological pH of 7.4, pH-sensitive DS@ZJU-101 is expected to be a particular promising candidates for anti-inflammatory drug delivery. The cytotoxicity of ZJU-101 is tested in PC12 using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay and confocal microscopy. The MTT assay is carried out by incubating PC12 with ZJU-101 at doses ranging from 20 to 200 µg/mL, for 24 hours. The MTT assay reflects the cell viability from the amount of the formazan which is exchanged from MTT by the succinodehydrogenase in viable cell’s mitochondria.24 The amount of the formazan turned by MTT is related to the amount of mitochondrial metabolism in live cells. Figure 3 indicates that the cell viability decreases slightly with the increase of the ZJU-101 concentration, while the cell viability is still around 80% until the concentration of ZJU-101/DS@ZJU-101 reaches 200 µg/mL. The cytotoxicity of ZJU-101 is also tested by the confocal microscopy, which is more visualized than MTT tests. The nature of PC12 makes it always adhere to the culture plate, and therefore PC12 can be easily observed under microscopy after dyeing by 4’,6’-diamidino-2-phenylindole (DAPI, blue, a nuclei dye).25 Furthermore, PC12 cells are neuron cells with enriched long cone of neuritis, which can be easily observed by microscopy to judge the living state of the cells. Figure 4 shows that there is no severe distinction between PC12 cells with and without the presence of ZJU-101. Many MOFs clusters ACS Paragon Plus Environment 6

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are observed and segregated in the cytosol by the endocytosis, as shown in Figure 4. In some cells, MOFs are enriched in the growth cone of neurites. Immunological staining of cell nuclei (blue) shows the good survive state of the PC12 cells. At the opposite ends of the nuclei, the microtubular cytoskeleton is spreading and expanding, demonstrating the low toxic or the nontoxic for neuron survival nor does it impair neurite outgrowth. CONCLUSION In summary, the cationic nanoscale metal-organic framework ZJU-101, is used to load the anionic diclofenac. The large drug loading capacity, physiological pH responsive drug release and low cytotoxicity make it a promising drug carrier. The drug release in PBS of pH = 5.4 is more rapid than that in PBS of pH =7.4. This can be ascribed to the interaction difference between the drug anions and carriers. Thus, the cationic carriers loading the anionic drug ensure the effective drug release in the certain tissues. EXPERIMENTAL SECTIONS General Procedure. 2,2’-bipyridine-5,5’-dicarboxylate (BYPDC) and other chemicals were obtained from commercial corporations and used as received without further purification. Powder X-ray diffraction (PXRD) patterns were carried out on a PANalytical X’Pert Pro powder X-ray diffractometer in the 2θ=5-50 degree at room temperature. 1H NMR spectra were texted on a Burker Advance DMX 500 spectrometer using tetramethylsilane (TMS) as an internal standard. Drug delivery analyses were carried out on an Agilent 1200 chromatographic system by high performance liquid chromatography (HPLC). The machine is employed Zorbax Eclipse XDBC18 reverse-phase column (5 m, 4.6 mm* 250 mm), supplied by Waters. The cell proliferation after incubating with ZJU-101 was visualized by Olympus FV-1000 confocal laser scanning microscope and IX-71 inverted microscope. ZJU-101. The cationic drug carrier ZJU-101 was synthesized from MOF-867 after post-modification. To form the cationic framework, the methyl groups were added to the pyridyl sites of MOF-867. The 2,2’-bipyridine-5,5’-dicarboxylate (BPYDC; 12.2 mg, 0.05 mmol), ZrCl4 (11.7 mg, 0.05 mmol), DMF ACS Paragon Plus Environment 7


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(18 mL) and glacial acetic acid (2 mL, 35 mmol)were putted in 50 mL Teflon-lined steel autoclave. The reaction mixture was stirred for a few minutes and then kept in 120 oC for 24 hours, after that, naturally cooled to room temperature. The resulting white powder was isolated by centrifugation. Before dried in a vacuum oven, the powder was washed with DMF and methanol repeatedly. The MOF-867 (700 mg) was placed in a 25 mL vial with 15 mL CHCl3, and trifluoromethanesulphonate (4.44 mL) was added dropwise while stirring at room temperature. The solution was stirred for 24 hours at room temperature. The solvent was removed through centrifugal separation and filtration, and resulting solid was washed with CHCl3 for several times. Then the powder was dried under vacuum oven before loading drugs. The temperature was maintained at 60 oC and the vacuum degree at 0.08 MPa for 6 hours. DS@ZJU-101. The crystal powder (33.3 mg) was putted into the solution of diclofenac sodium (100 mg) in ethanol (10 mL) and stirred at room temperature for 5 days. The resulting solid was filtered and washed with ethanol for 3 times to remove the redundant drugs in the solvents and then dried in the vacuum oven to yield diclofenac-containing ZJU-101. Cell culture, imaging and ZJU-101 cytotoxicity. Rat pheochromocytoma cells, PC12, were grown in Dulbecco’s Modified Eagle’s Medium (DMEM, Neuronbc) supplemented with 10% fetal calf serum (FCS) and 1% penicillin/streptomycin (P/S, Boster) for 3 days in a humidified incubator (37 oC, 5% CO2). The ZJU-101 cytotoxicity was evaluated through employing an MTT assay in 96 wells plate. The cells (about 104 cells/mL, 200µL) were incubated in the humidified incubator for 24 hours with MOFs in different concentrations (20, 50, 100, 150 and 200 µg/mL). After that, 50 µL MTT solutions were added to each wells and incubated for another 4 hours with the tin foil covered. Then, the supernatant liquor was removed and 150µL dimethyl sulfoxide was added to each wells. 30 minutes later, the absorbance of each sample at 490 nm were measured using microplate reader. The cell viability was calculated by the ratio of absorbance of sample well to that of the cell control. The same concentration of the samples were sextuplicated, then calculated the average. For imaging experiments, PC12 cells were seeded in 24-well plate in 760µL DMEM with 10% FCS and 1% P/S and incubated for 24 h (37 oC, 5% CO2). 40 µL of 1 mg/mL ZJU-101 in DMEM with 10% ACS Paragon Plus Environment 8

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FCS and 1% P/S was added to each well, and the final concentration of ZJU-101 was 20 µg/mL. The 24-well plate was incubated in the incubator for 24 hours. After incubation, the cells were washed twice with 400µL of Phosphate Buttered Saline (PBS). After that, the PBS containing 4% paraformaldehyde was putted into the plate and kept for 15 minutes, and then washed with 400µL PBS for twice. The cells were incubated with DAPI for five minutes, and then still washed with PBS for twice. After the whole operations, the morphologies of all cells were observed using a confocal laser scanning microscope. Drug Release. The release assays of diclofenac-containing ZJU-101 were carried out by soaking the samples (100 mg) in the PBS solution (50 mL) of pH = 5.4, which is the pH under pathological conditions including inflamed tissues, and pH = 7.4, which is the pH in the normal cells. The drug delivery under the PBS solution of pH = 6.5 was also compared. All release assays were carried out on an electric-heated thermostatic water bath to keep the temperature a steady 37 oC. Reaction mixture was extracted with a syringe after a certain period of time and centrifuged to yield diclofenac-containing solution. Then the concentration of diclofenac was analyzed by HPLC. The mobile phase was composed of 20% phosphoric acid and 40% distilled water in methanol. The injection volume was 25 µL, the flow rate is 1.0 mL/min, and the effluent was monitored at 276 nm.



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FIGURES

Figure 1. (a) Schematic presentation of the post-modification and drug loading processes. (b) SEM images of the ZJU-101. (c) The coulombic attraction between the ligand of the cationic framework and anionic drug.

Figure 2. The cumulative release profiles of DS@ZJU-101 in the PBS of different pH.


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Figure 3. Cell viability data of ZJU-101 and DS@ZJU-101 at different concentration obtained from MTT assay by PC12 cells. Error bars represent the standard deviation of each point.

Figure 4. (a) and (b) are the confocal microscopy images of pure PC12 cells incubated with complete DMEM(Dulbecco’s Modified Eagle’s Medium) for 24h. (c) and (d) are the confocal microscopy images of mixed PC12 cells incubated with ZJU-101 of 20µg/mL for 24h and the nuclei (blue) are fluorescently stained by DAPI in (b) and (d).



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Table 1. Drug loading capacity of different ionic MOF, as well as the BET surface/pore size.

MOFs

Framework character

ZJU-101 MOF-74-Fe(III)12 Bio-MOF-116 Zn-TATAT17

Cationic Cationic Anionic Anionic

BET surface or pore size 561 m2/g 11 Å 1700 m2/g 20 Å

Drug loading capacity 0.55 g/g 0.19 g/g 0.22 g/g 0.5 g/g


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AUTHOR INFORMATION Corresponding Author *Phone: +86-571-87952229. Email: [email protected] (G.Qian). Author Contributions The manuscript has been discussed and commented by all authors. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We gratefully acknowledge the funding support for this work by the National Natural Science Foundation of China (Nos. 51272231, 51372221, 51472067, 51472217 and 51432001), Zhejiang Provincial Natural Science Foundation of China (Nos. LR13E020001 and LZ15E020001), and Fundamental Research Funds for the Central Universities (No. 2016FZA4007). SUPPORTING INFORMATION AVAILABLE The supporting information is available free of charge via the Internet at http://pubs.acs.org. ABBREVICATIONS USED PBS, phosphate buttered saline; DS, Diclofenac sodium; DDS, the drug delivery systems; PC12, rat pheochromocytoma

cells;

MOFs,

metal

organic

frameworks;

BPYDC,

2,2’-bipyridine-5,5’-dicarboxylate; PXRD, powder X-ray diffraction patterns; SEM, scanning electron microscopy; MTT, 4’,6’-diamidino-2-phenylindole; DAPI, 4’,6-diamidino-2-phenylindole REFERENCES (1). Al-Kahtani, A. A.; Sherigara, B. S. Controlled release of diclofenac sodium through acrylamide grafted hydroxyethyl cellulose and sodium alginate. Carbohydr Polym 2014, 104, 151-7.



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