Magnetic MetalâOrganic Framework Composite by Fast and Facile

Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Magnetic Metal−Organic Framework Composite by Fast and Facile Mechanochemical Process M. Bellusci,*,† P. Guglielmi,†,‡ A. Masi,† F. Padella,† G. Singh,§ N. Yaacoub,∥ D. Peddis,⊥ and D. Secci‡ †

Department of Materials and Processes, ENEA, CR Casaccia, 00123 Rome, Italy Department of Chemistry and Pharmaceutical Technologies, Sapienza University, 00185 Rome, Italy § Department of Materials Science and Engineering, Norwegian University of Science and Technology, Trondhiem-7491, Norway ∥ LUNAM, Université du Maine, Institut des Molécules et Matériaux du Mans CNRS UMR-6283, F-72085 Le Mans, France ⊥ Institute of Structure of Matter, National Research Council (CNR), 00015 Monterotondo Scalo, Rome, Italy ‡

S Supporting Information *

ABSTRACT: Magnetic porous metal−organic framework nanocomposite was obtained by an easy, efficient, and environmentally friendly fabrication method. The material consists in magnetic spinel iron oxide nanoparticles incorporated in an iron(III) carboxylate framework. The magnetic composite was fabricated by a multistep mechanochemical approach. In the first step, iron oxide nanoparticles were obtained via ball milling inducing mechanochemical reaction between iron chlorides and NaOH using NaCl as dispersing agent. Magnetic nanoparticles (MNs) were functionalized by neat grinding with benzene-1,3,5-tricarboxylic acid (1, 3, 5 BTC) and were then subjected to liquid assisted milling using hydrated FeCl3, water, and ethanol to obtain a magnetic framework composite (MFC) consisting of iron oxide nanoparticles encapsulated in a MOF matrix. We report, for the first time, the applicability of the grinding method to obtain a magnetic composite of metal−organic frameworks. The synthesized material exhibits magnetic characteristics and high porosity, and it has been tested as carrier for targeted drug delivery studying loading and release of a model drug (doxorubicin). Developed systems can associate therapeutics and diagnostics properties with possible relevant impact for theranostic and personalized patient treatment. Furthermore, the material properties make them excellent candidates for several other applications such as catalysis, sensing, and selective sequestration processes.

1. INTRODUCTION Metal−organic frameworks (MOFs) are porous crystalline solids made by the assembly of inorganic ions or clusters and organic ligands.1 This class of materials possesses an exceptional surface area (up thousands of m2/g) due to the highly porous structure derived by the crystalline ordering of the components. By selecting appropriate inorganic joints and ligands, the size, the spatial cavity arrangement, and the chemical environment of the resulting void space can be precisely controlled.1,2 The resulting morphology allows MOFs to interact with atoms, ions, and molecules at both particle surface and material bulk. The possibility to use these materials in many fields (i.e., absorption and separation of gaseous molecules,3 catalysis,4 sensing,5 optics,6 electrochemistry,7 pollutant sequestration,8 drug delivery,9,10 contrast agents,9,10 bioreactors11) makes them extremely interesting in scientific and technological fields. The ability to prepare tunable cavities with tailorable chemistry opens numerous opportunities to develop materials possessing definite properties. Focusing the attention on magnetic properties, for example, novel molecular magnetic alloy materials have been synthesized by Zeng et al., combining © XXXX American Chemical Society

chiral dicarboxylates and mixed-metal ions into a crystalline MOF material building.12 MOFs having innovative characteristics can also be obtained by introducing nanomaterials in their framework.13−15 Magnetic nanoparticles (MNs) combined with MOFs lead to magnetic framework composites (MFCs) that result in stimuli responsiveness and could be utilized “on demand” for targeted drug delivery, selective separation, catalysis, and sensing.16−19 For example, Tan et al. reported the fabrication of HKust-1/ Fe3O4 composite, by a dry gel conversion strategy, for the purification of hydrocarbon fuels,18 and Li et al. synthesized a novel magnetically recyclable MOF catalyst for Friedel−Crafts alkylation.19 In relation to biomedical applications, MFCs are very promising for engineering and development of biomedical theranostic systems due to their exclusive properties, including (a) exceptionally high surface area and porosity, which permit the loading of large amounts of active molecules with respect to existing materials, that show poor drug loading limited to the Received: October 19, 2017

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DOI: 10.1021/acs.inorgchem.7b02697 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

Figure 1. Synthesis scheme

2. EXPERIMENTAL SECTION

external nanocarrier surface and burst release; (b) versatile chemistry and pore size, to interact with different drugs; (c) intrinsic biodegradability; (d) responsivity to magnetic stimuli to carry active agents directly to target organs or specific locations in the body, limiting spreading of drug and decreasing side effects of therapy; (e) responsivity to external stimuli to control drug or therapeutic effect release (i.e., heat release for hyperthermal therapy); and (f) possible engineering as contrast agents for multimodal imaging in diagnostics.16 Studies on MFCs are recent, and only a few works are reported on their applicability in the biomedical field.16,20−22 The synthesis methods generally utilized are multisteps involving the use of several solvents, and the toxicity and capability of obtained materials for biomedical applications should be studied. Therefore, the research of innovative MFCsbased theranostic agents via simple and sustainable synthesis methods is an interesting challenge. Herein, we report a novel mechanochemical synthesis of a magnetic composite consisting of iron oxide nanoparticles enclosed in a Fe(III)-trimesate metal−organic framework, and we prove its drug loading and in vitro release properties by using a model molecule, doxorubicin hydrochloride, an anthracycline anticancer drug exhibiting a broad spectrum of reactivity and excellent antineoplastic activity against a multitude of human cancer diseases. The results reveal that the reported synthesis method is an easy, economical, and environmentally sustainable approach to fabricate magnetic, porous materials for drug delivery and in perspective for numerous other applications. To the best of our knowledge, this is the first example of the fabrication of MFCs by a mechanochemical approach. The composite components were chosen based on their biocompatibility and their properties that have to be functional to the final application. In fact, the Fe(III)-trimesate metal− organic framework is reported as nontoxic and degradable. Iron oxide nanoparticles are easy and cheap to produce, are biocompatible, and have contrast effects in magnetic resonance (MR) imaging. Moreover, various formulations of iron oxide nanoparticles have already been approved by the FDA for their clinical use as magnetic resonance contrast agents. In our case, iron oxide nanoparticles were synthesized by an unconventional mechanochemical process consisting of milling of precursor salts in the presence of a dispersing agent.23−26 By using neat grinding (NT), obtained nanoparticles were decorated with MOF ligand (trimesic acid), grafting the organic linker on the iron oxide particles surface to increase compatibility toward MOF and promote the growth of the MOF around the magnetic carrier. After 10 min of milling with trimesic acid, in the vial iron(III) chloride and a mixture of water/ethanol were introduced to perform liquid assisted grinding (LAG) for composite development. A scheme of the magnetic composite synthesis is reported in Figure 1.

2.1. Iron Oxide Nanoparticles (MNs). Magnetic iron oxide nanoparticles (MNs) were synthesized by an unconventional mechanochemical process similarly as previously reported.26 In a typical procedure, about 5 g of a stoichiometric mixture of reactants (FeCl3·6H2O, FeCl2·4H2O, and NaOH by Sigma-Aldrich) was loaded in a Teflon-coated stainless steel vial, with 45 mL capacity, containing five ZrO2 balls (10 mm diameter). A surplus of sodium chloride (100 wt %) was added to the stoichiometric mixture as phase control agent to limit crystalline growth phenomena. The final powder-to-ball weight ratio was 1:5. The vial atmosphere was saturated by argon, and the closed vial was sealed in an aluminum−polymer composite sheet. The synthesis was carried out by high-energy ball milling using a Spex 8000 apparatus. The materials mixture was collected after 60 min milling time, and the powder was washed with water, dried at 70 °C under vacuum, and characterized. 2.2. Iron(III) 1,3,5-Benzenetricarboxylate (Fe-BTC). A novel procedure to synthesize nonfluorinated Fe-(BTC) MOF was developed and successively applied to MFC material synthesis. Fe(BTC) was synthesized by liquid assisted grinding (LAG)27−29 of about 2.5 g of FeCl3·6H2O and 1,3,5-benzenetricarboxylic acid mixture in a molar ratio of 3:2 using a 1:1 volume ratio of a water/ethanol mixture with η = 0.81 μL/mg. The grinding was performed for 1 h in a Spex 8000 apparatus using a coated stainless-steel jar with 5 mm ZrO2 balls and a powder-to-ball weight ratio of 1:5. The vial was sealed in an argon atmosphere. The sample was collected and purified by Soxhlet extraction carried out in ethanol for 24 h. The washed sample was dried at room temperature in air. 2.3. Iron(III) 1,3,5-Benzenetricarboxylate Magnetic Composite (MN@Fe-BTC). For the magnetic composite synthesis, iron oxide nanoparticles were initially decorated with 1,3,5-benzenetricarboxylic acid by neat grinding. At the outset, 0.5 g of MNs were ground with 0.43 g of H3BTC for 10 min. Then FeCl3·6H2O and 2 mL of water/ etanol mixture (1:1 volume ratio) were added and the grinding was continued for 1 h. Milling operations and purification steps were performed using the same conditions reported for Fe-BTC synthesis. 2.4. Materials Characterization and Data Treatments. A Seifert PAD VI diffractometer was used to collect X-ray diffraction patterns. The apparatus was equipped with Mo Kα radiation and a LiF monochromator on the diffracted beam. Data were collected in the 4− 50° 2θ range, with a 0.02° step width. After phase purity check by comparison with cards in the JCPDS reference card database, crystallographic and microstructural parameters were obtained by applying the Rietveld refinement30,31 on collected XRD patterns. All elaborations were performed by using MAUD-Materials Analysis using diffraction software by Lutterotti.32 Mil-100(Fe) (OCD 7102029)33 and γ-Fe2O3 (OCD: 9006316)34 were used as reference structural models. Refining lattice parameters, crystallite size and microstrain, and evaluating the numerical goodness of the fits with a weighted-profile parameter, Rwp, gave the values reported in Table S1. Experimental and calculated patterns are reported in Figure S1. IR spectroscopic analysis was performed with a MIRACLE 10 single reflection attenuated total reflectance (ATR) instrument. CHNS elemental analysis was performed with an Elementar Vario Macro Cube apparatus. B


Article

Inorganic Chemistry Thermal analysis of the obtained materials was performed by using a TGA/DTA analyzer (PerkinElmer Pyris Diamond), heating the sample at 10 °C/min in an inert atmosphere (Ar) or in air. Nitrogen adsorption isotherms were obtained at 77 K using an Autosorb iQ instrument. The samples to be analyzed were preheated overnight under vacuum at 150 °C.35 Density functional theory (DFT)35,36 was used to obtain the pore size distributions using Quantachrome NovaW software and appling a NLDFT−zeolite N2@ 77 K kernel considering a cylindrical pore model. Scanning transmission electron microscopy (STEM) was performed using a high-resolution microscope Hitachi S5500 operating at 30 kV. The 57Fe Mössbauer absorption spectra were obtained at room temperature in standard transmission geometry, using a source of 57Co in rhodium with activity 370MBq. The samples consist of a thin layer of about 40 mg of the powdered compound located in a sample holder. The isomer shift (IS) values were referred to those of α-Fe at 300 K. The hyperfine structure was modeled by a least-squares fitting procedure involving Zeeman sextets composed of Lorentzian lines. DC magnetization measurements were performed using a Quantum Design SQUID magnetometer equipped with a superconducting coil (Hmax = ±5 T). To avoid any movement of the nanoparticles during the measurements, powders were immobilized in epoxy resin. The field dependence of remanent magnetization was measured using the IRM (isothermal remanent magnetization) and DCD (direct current demagnetization) protocols. The DCD curve was measured by saturating the sample and then measuring the remanence MDCD(H) after applying reverse fields Hrev up to Hmax (5 T). The IRM curve was obtained starting from a totally demagnetized state by applying a positive magnetic field, which was then removed, and the remanence MIRM(H) was measured; the process was repeated increasing the field up to Hmax. 2.5. In Vitro Degradation Tests. The degradation of Fe-BTC and MN@Fe-BTC was studied by adding 50 mg of solid, placed in a dialysis membrane, in 10 mL of phosphate buffer solution (PBS, pH 7.4) or in water. These suspensions were stirred at 37 °C for different times. At each time point, the buffer solution was recovered and replaced with the same volume of fresh PBS. Released organic linker, trimesic acid, was quantified by UV−vis spectroscopy (284 nm). The experiment was done in triplicate. 2.6. Loading and Release of Doxorubicin Hydrochloride (Dox). Typically, about 450 mg of solids was activated by outgassing at 150 °C for 18 h and suspended in 10 mL of a water Dox solution (10 mg/mL). The activation removes solvent molecules from pores, making them free for drug adsorption. The suspension was kept at room temperature under stirring for 24 h in order to ensure that equilibrium was reached. Then, solid was separated by centrifugation and was washed twice with water. Drug solution was obtained after the 24 h treatment and after washing solutions were tested using UV− visible spectroscopy to evaluate the amount of loaded drug. The amount of Dox was indirectly calculated by monitoring the decrease of the drug UV−vis bands from water solutions. Using the Lambert− Beer law, the concentration was calculated from the absorbance peak at λ = 480 nm. Moreover, the quantity of adsorbed drug was confirmed by elemental analysis. The drug release kinetics was studied by keeping about 50 mg of loaded solid, earlier freeze-dried, in phosphate buffer (PBS, pH 7.4) at 37 °C. At defined times, aliquots of the solution were collected and analyzed by UV−vis spectroscopy. The experiment was done in triplicate.

Figure 2. XRD pattern of iron oxide nanoparticles (MN), Fe-BTC, and magnetic composite MN@Fe-BTC.

maghemite, γ-Fe2O3 (PDF card 39-1346), although the presence of the magnetite, Fe3O4, may not be completely excluded. Magnetite nanoparticles with a relatively smaller size are unstable and are oxidized very easily to maghemite. Magnetite and maghemite have the same spinel crystal structure and similar cell parameters; therefore, it is difficult to distinguish between them using X-ray diffraction methods. Rietveld refinement gives a mean crystallite diameter of about 7 nm, with negligible values of microstrain, and lattice parameters a = b = c = 8.358 (Å), which lies between the lattice constants of magnetite (8.396 Å) and maghemite (8.351 Å). To study the magnetic structure of the sample, 57Fe Mössbauer spectra have been recorded at 300 and 77 K (Figure S2 in the Supporting Information). The spectrum recorded at 300 K (Figure S2a) exhibits broadened lines, suggesting the presence of superparamagnetic phenomena. In fact, noninteraction or weakly interacting magnetic nanoparticles show Mössbauer spectra consisting of a superposition between sextets, due to particles with relaxation time long compared with the time experimental window (τs Moss.= 5 × 10−9) and doublet with shorter relaxation times. The relative area of the doublet increases with increasing temperature. In addition, in spinel ferrite, Fe3+ ions have slightly different Mössbauer parameters according to their occurrence either in tetrahedral or in octahedral coordination. However, both at 300 and at 77 K, it is impossible to give a real estimation of the proportions of iron cations located in different interstitial sites because of the lack of resolution. At 77 K (Figure S2b), the Mössbauer hyperfine structures split into asymmetrical sextets resulting from octahedral and tetrahedral Fe sites. The mean isomer shift at 77 K (0.44(±0.01)) confirms the absence of Fe2+ and then that nanoparticles are constituted by maghemite. Using a liquid assisted mechanochemical approach, a crystalline nonfluorinated iron(III) 1,3,5 benzene-tricarboxylate, denoted Fe-BTC, was obtained, as confirmed by PXRD diffraction (Figure 2). In comparison with the standard material,37 the XRD profile shows broadening and overlapping of peak profiles, most likely ascribable to a small crystallite size. The cell parameter resulting from Rietveld analysis is 72.67 (Å), revealing a slightly contracted cell with respect to the reference material 73.34 (Å), as reported for similarly synthesized materials,27 with crystallite size of approximately 26 nm and a slight microstrain (0.4%). The diffraction profile of MN@Fe-BTC shows the peaks characteristic of iron oxide nanoparticles and Fe-BTC. No impurity peaks were detected, indicating successful synthesis of magnetic composite. As obtained from Rietveld quantitative

3. RESULTS AND DISCUSSION 3.1. Chemical, Morphological, and Structural Characterization. The synthesis procedure described in section 2 is schematically reported in Figure 1. Powder X-ray diffraction (PXRD) patterns of the MNs, FeBTC, and MN@Fe-BTC samples are shown in Figure 2. The MN PXRD pattern indicates the nanometric size of the crystallites as evidenced by the wide peaks in the diffractogram. The pattern fits very well with the cubic symmetry of C


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Inorganic Chemistry

Figure 3. Transmission scanning electron micrographs of (a) iron oxide nanoparticles, (b) the Fe-BTC metal−organic framework, and (c) the MN@Fe-BTC composite.

Figure 4. (a) IR spectra of iron oxide magnetic nanoparticles (MN), 1,3,5-benzenetricarboxylic acid (BTC), the metal−organic framework (FeBTC), and the magnetic composite (Mn@Fe-BTC). (b) Thermogravimetric analysis of iron oxide nanoparticles. (Inset) Fe-BTC magnetic composite and derivative curve.

1618−1570 cm−1 (asymmetric stretching vibrations of −COO−1), in the range 1440−1366 cm−1 (symmetric stretching vibrations of − COO−), and at 755 cm−1 (ringout-of-plane vibrations of the 1,3,5-substituted benzene of the linker molecules). These results demonstrate that the coordination reaction was successful, with minimal residues of the unreacted linker. The presence of iron oxides in the composite materials is not easily detectable by IR measurement because of overlap with other peaks. In the case of iron oxide nanoparticles (inset in Figure 4b), thermogravimetric analysis evidences a weight loss (∼3.5 wt %) to ∼180 °C ascribable to removal of water adsorbed on the particles surface and another (∼2.5 wt %) occurring between 200 and 500 °C that can be attributed to hydroxyl groups. Fe-BTC MOF shows the first weight loss (∼28.2%) at ∼210 °C related to the release of the pore water, a second one between 210 and 310 °C (∼5.8%) due to water molecules interacting with the iron trimers, and a final one (∼38.8%) in the range 310−620 °C associated with framework degradation. The results obtained for the latter two weight losses are almost in agreement with the expected theoretical values (5.5 and 34.3 wt %, respectively); the presence of residual trimesic acid is confirmed. The thermal profile of the MN@Fe-BTC sample is similar to the Fe-BTC one. The weight loss of MN@Fe-BTC in the range 400−500 °C appears earlier than the one of Fe-BTC, indicating that iron oxide nanoparticles have a catalytic action on MOF degradation, affecting the thermal stability of materials. Anyway, the use of the synthesized material is expected at lower temperatures.

phase analysis, the crystalline fraction of the material is composed by 58 wt % of Fe-BTC (17 nm mean crystallites size) and 42 wt % of iron oxide nanoparticles (14 nm mean crystallite size) that Mössbauer investigation indicates as maghemite. To better understand the microstructure of the synthesized materials and confirm that the powder is a composite rather than a mixture of separated inorganic materials and MOF, the samples were characterized using STEM. The STEM images (Figure 3) of the nanocomposite reveal that the sample mainly consists of irregular nanoparticles with a size range of 25−150 nm, showing an embedded structure with magnetic nanoparticles having a diameter of about 10 nm interspersed in the Fe-BTC matrix. FTIR, TGA, and elemental analyses were used to determine the formation and the composition of synthesized samples. Figure 4a shows the IR spectrum of the MN@Fe-BTC nanocomposite. Transmittance data for iron oxide nanoparticles (γ-Fe2O3), BTC, and Fe-BTC are also reported for comparison. The γ-Fe2O3 spectrum shows materials hydratation, and M−OH and M−OH2 stretching (700−1100 cm−1) are detectable. The band 1340−1650 cm−1 is featured for H− O−H bending and is due to water molecules adsorbed on the material surface. The broad band in the range 2500−3650 cm−1 corresponds to symmetric and asymmetric stretching of the O− H bond. In the IR spectrum of MN@Fe-BTC, the characteristic bands of the nonionized carboxyl groups of BTC νOH (3082 cm−1) and νC = O (1720 cm−1) disappear or become very weak (peak at 1720 cm−1), and new bands become visible in the range D


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Inorganic Chemistry

The field dependence of the magnetization recorded at 300 K (Figure 6a) indicates for both samples the presence of superparamagnetic nanoparticles (i.e., zero remanence and zero coercivity). Saturation magnetization of the MNs sample is around 55 A m2 kg−1, lower than that of bulk materials (Ms Bulk ≅ 80 A m2 kg1−), as already observed for magnetic nanoparticles of spinel iron oxides.40 As expected, a strong reduction of the saturation magnetization for the MCF sample (Ms ≅ 15 A m2 kg1−) is observed, due to the low quantity of magnetic materials in the nanocomposite. Anyway, it is important to underline that this value of magnetization is compatible with the application of the MCF for magnetic drug delivery.41 Also it is important to observe that the magnetization at 2T for the Fe -BTC sample is (M2T ≅ 0.2 A m2 kg1−) 60 times lower with respect to the M2T for the MCF sample. In other words, in the nanocomposite, the magnetic behavior at high field is dominated by magnetic nanoparticles with respect to the iron ions distributed in the metallorganic framework. In order to better understand the effect of MNs on the magnetic properties of the MN@Fe-BTC sample, an investigation of interparticle interactions has been done. In particular, DCD and IRM remanent magnetization was investigated at 5 K. For an assembly of noninteracting monodomain particles with magnetization reversal by coherent rotation and uniaxial anisotropy (both conditions are satisfied on our samples), the two remanence curves are related via the Wohlfarth relation:

The iron oxide nanoparticles content, estimated by elemental analysis and confirmed by TGA, results to be ∼25 wt %. Based on TGA results (Figure 4b), indicating for Fe-BTC a C and Fe content equal to 26% and 19%, respectively, in agreement with elemental and ICP-AES values, the composition of Fe-BTC corresponds to the formula Fe3O(OH)(H2O){C6H3(CO2)3}2·nH2O with n ≈ 14 despite an excess of carbon content (calculated: 24% C, Fe 19%). Similar results were reported in the literature.37−39 The discrepancy with the Rietveld refinement results is most likely ascribable to the different investigated properties: the XRD results reflect in fact the fraction of crystalline material, neglecting the amount of poorly crystalline or amorphous species, while the thermal decomposition observed in the TG is obviously related to the organic part. This value does not coincide with XRD results due to free water content present on samples. The Brunauer−Emmet−Teller (BET) surface areas (SBET) and the porosity of the metal−organic frameworks were measured by N2 adsorption experiments performed in liquid nitrogen. For MNs a SBET of 118 m2/g was measured, corresponding to an equivalent diameter size of approximately 10 nm and therefore in agreement with XRD results and STEM analysis. The nitrogen physisorption isotherms for Fe-BTC and MN@Fe-BTC activated at 150 °C (shown in Figure S3 in the Supporting Information) reveal isotherms of type 1b for both samples, characteristic of microporous solids. In both cases, secondary uptake steps are evident in the 0.05−0.15 P/Po range, ascribable to large micropores, as expected from the theoretical structure. The corresponding BET surface area was estimated to be 1100 and 760 m2/g for Fe-BTC and MN@FeBTC, respectively. Pore size distributions (Figure 5) were determined using density functional theory (DFT). In accordance with previous

MDCD(H ) = 1 − 2MIRM (H )

(1)

Equation 1 indicates that a deviation from the linearity in the so-called “Henkel plot” (i.e., MDCDvs MIRM) is usually directly linked with interparticle interactions. Kelly et al.42 rewrote the Wohlfarth relation to explicitly reveal deviations from a noninteracting case. ΔMDCD(H ) = MDCD − (1 − 2MIRM )

(2)

Equation 2 indicates that when ΔM is reported versus reversal magnetic field (i.e., the field applied before to measure remanent magnetization at zero field), a positive deviation indicates the predominance of exchange interactions, while a negative one can be attributed to the predominance of dipole− dipole interactions.43 The amplitude of the deviation (i.e. peak) can be considered as a semiquantitative indication of the strength of magnetic interactions, allowing comparison of two or more systems. ΔM plots for both samples (Figure 6b) clearly indicate the prevalence of dipolar interaction as always expected in spinel oxide nanoparticles.44,45 The ΔM peak is centered at 0.09T for the MN sample, and it decreases at 0.07 T in MN@FeBTC. Also, the amplitude of the peak is decreasing going from a MN (∼1.13) to MN@Fe-BTC (∼0.85). These results clearly show a decrease of dipolar interaction between magnetic nanoparticles when they are embedded in a metal−organic framework. Generally speaking, the dipolar energy between the nanoparticles can be described by the formula:

Figure 5. Pore size distribution calculated by the DFT method.

studies, the DFT pore distribution curve of the Fe-BTC MOF displays a multimodal pore distribution, with peaks centered at about 12, 20, and 25 Å.38,39 The magnetic composite shows instead a modification of the pore size profile, most likely as a consequence of the magnetic nanoparticles presence. 3.2. Magnetic Properties. As a preliminary measurement, the field dependence of Fe-BTC samples (shown in Figure S4 in the Supporting Information) has been recorded at 300 K. As expected, the behavior is due to the paramagnetic Fe3+ incorporated in the network. On the other hand, a more deep investigation of magnetic properties has been done on MNs and MN@Fe-BTC.

Ed ≈

μp 2 d3

(3)

where μp is the magnetic moment of the nanoparticles and d is the distance between them. With μ being equal in both samples, the reduction of interparticle interactions can be ascribed to the increase of interparticle distance. In other words, these results confirm that the proposed synthesis E


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Inorganic Chemistry

Figure 6. (a) Field dependence of magnetization recorded at 300 K for MNs (full symbols) and MCF (empty symbols) samples; (b) ΔM plots recorded at 5 K for MNs (full symbols) and MCF (empty symbols) samples.

of iron octahedra. The trimers are then linked by BTC forming hybrid supertetrahedra assembled into a MTN-type zeolitic architecture that forms two types of cages of free apertures of about 25 and 29 Å accessible through pentagonal and hexagonal windows of ca. 5.6 and 8.6 Å. Fe(III) trimers have accessible coordinatively unsatured metal sites (CUS) that are reported as able to coordinate the doxorubicin molecule.47 It was reported that doxorubicin interacts with the Fe(III) trimeric unit by coordination to CUS centers, eliminating coordinated water molecules. This hypothesis was confirmed by the thermal profile of the materials containing doxorubicin (Figure 8) that shows disappearance of the peak due to hydroxyl groups (range 200−500 °C).

method allows obtaining a metal−organic framework with magnetic nanoparticles well dispersed in the matrix. 3.3. Incorporation and Release of Doxorubicin into Fe-BTC and MN@Fe-BTC. The performance of pure Fe-BTC and magnetic composite in terms of degradability under physiological conditions and in water was evaluated. In PBS buffer at 37 °C both samples showed similar profile with more than 50% of degradation after 7 days, sign of a reasonable in vitro degradability (Figure 7). No significant degradation was observed in water (data not shown).

Figure 7. Release of BTC ligand from Fe-BTC and composite under simulated physiological conditions (PBS, 37 °C). Figure 8. Thermogravimetric analysis and derivative curve of samples loaded with doxorubicin.

Next, in order to explore the capacity of the pure metal− organic framework and magnetic composite as drug carriers, doxorubicin hydrochloride, an anticancer drug, was loaded on synthesized porous materials. Delivery of anticancer drugs received particular attention due to the existence of severe side effects related to therapies. Doxorubicin is the drug of first choice for the treatment of various cancers. However, side effects associated with its administration (i.e., cardiotoxicity and nephrotoxicity) require the development of innovative and engineered nanosystems able to accumulate the drug selectively at the target site. The amount of the drug loaded on synthesized materials was obtained by UV−vis spectroscopy and elemental analysis (N content) and was determinated to be 6.5 and 2.2 wt % for Fe-BTC and MN@Fe-BTC, respectively. These values are higher than those generally reported for existing carrier systems but lower than the MOF loading capacity obtained with smaller molecules.46,9 This can be justified by a reduced accessibility of the binding sites inside the framework pores due to the small size of the pore windows. It should be noted that the drug molecules (15.3 × 11.9 Å) are large with respect to the diameter of the pore opening. In fact the iron carboxylate framework is made of oxocentered trimers

After Dox adsorption, the volumes of pores for Fe-BTC and MN@Fe-BTC decrease inducing the supposition that doxorubicin binding occurs both in the accessible pores of the MOF framework and on the nanoparticles surface (Figure 9). The performance of doxorubicin release was then examined, and the results are shown in Figure 10. The drug release profile has been slow and sustained. It was found that after 16 days doxorubicin was partly released by Fe-BTC (69%) and MN@ Fe-BTC (21%), suggesting strong chemical interaction with materials. Several kinetic models, selected from the most important, were also used to analyze drug release from developed materials. The correlation coefficient value was used as the criterion to choose the model that best fits and describes drug release. The obtained values, reported in Table 1, showed a complex release mechanism from these materials, suggesting a combination of diffusion and erosion models. The n values obtained by using the Ritger−Peppas equation confirm an anomalous release resulting from mechanisms combination.48 F


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Inorganic Chemistry

The potential of the obtained materials as drug delivery vehicles was studied by evaluating loading and release of doxorubicin. The drug molecule is incorporated in the Fe-BTC and in the magnetic composite, forming stable coordination bonds, and it is released by a mechanism controlled by diffusion and material degradation. The exploited synthesis approach is applicable to the production of a broad range of compounds, characterized by the benefits of porous materials and magnetic functional characteristics, opening new opportunities to develop multifunctional MOF-based materials for applications in several fields, such as drug delivery, catalysis, or removal of organic contaminants.

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Figure 9. Pore size distribution of samples containing doxorubicin.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b02697. Rietveld refinement, field dependence of magnetization, 57 Fe Mö ssbauer spectra, N2 adsorption−desorption isotherms on Fe-BTC and magnetic composite. (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Figure 10. Doxorubicin delivery under simulated physiological conditions.

ORCID

Table 1. Correlation Coefficients from Drug Release Data Analysis

Notes

M. Bellusci: 0000-0003-2170-726X G. Singh: 0000-0001-9700-3344 The authors declare no competing financial interest.

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Applied mathematical model Zero-order

First-order

Higuchi

Material

2

r

2

r

2

r

r

2

n

Fe-BTC MN@Fe-BTC

0.895 0.933

0.953 0.949

0.962 0.991

0.936 0.966

0.470 0.499

ACKNOWLEDGMENTS The authors thank Sicor for the generous donation of doxorubicin HCl. The authors also thank Dr. Simone Carradori for helpful suggestions.

Ritger−Peppas

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REFERENCES

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In the case of MN@Fe-BTC, the release is slower and only 21% of the drug was released after 16 days, indicating an interaction between drug and iron oxide nanoparticles. Probably, doxorubicin conjugates with the magnetic nanoparticles and with their intermediates formed in the solution during release tests. We plan to further investigate this evidence in future work. According to previous studies,49 by incorporating iron oxide nanoparticles into the Fe-BTC framework structure, loading capacity as well as the release profile were significantly influenced. The results obtained are aligned with some of the evidence reported in the literature49 for similar systems (Bhattacharjee et al); however, specific loading capacity values and release profiles depend on material design, frameworks chemistry, and magnetic nanoparticles content.49,50

4. CONCLUSIONS Fe-BTC metal organic framework and iron oxide based magnetic composites were successfully synthesized by a simple and sustainable mechanochemical method. The developed synthesis method enables the production of significant amounts of these materials, because it can easily be scaled up and has strong potential for industrial applications. G


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