INORGANIC CHEMISTRY FRONTIERS This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online RESEARCH ARTICLE View Journal | View Issue Facile, fast and green synthesis of a highly porous calcium-syringate bioMOF with intriguing triple Open Access Article. Published on 02 March 2023. Downloaded on 3/28/2023 11:30:58 AM. Cite this: Inorg. Chem. Front., 2023, 10, 2165 bioactivity† Albert Rosado, *a Oriol Vallcorba, b Blanca Vázquez-Lasa,‡c,d Luís García-Fernández, c,d Rosa Ana Ramírez-Jiménez,c,d María Rosa Aguilar, c,d Ana M. López-Periago, a Concepción Domingo *a and José A. Ayllón *e A facile, fast and green strategy based on ethanol is utilized to prepare a new bioMOF, namely, CaSyr-1, with particular characteristics of full biocompatibility given by using just calcium and syringic acid, the latter being a phenolic natural product found in fruits and vegetables, permanent porosity with an out- standing surface area >1000 m2 g−1, and a micropore diameter of 1.4 nm close to mesopore values. Collectively, these data establish CaSyr-1 as one of the most porous bioMOFs reported to date, with high Received 10th December 2022, molecular adsorption capacity. The CaSyr-1 adsorptive behavior is revised here through the reversible Accepted 1st March 2023 adsorption of CO2 and the encapsulation of bioactive ingredients in the structure. Remarkably, CaSyr-1 DOI: 10.1039/d2qi02639b enables the development of triple therapeutic entities, involving bioactive Ca2+, syringic acid and an rsc.li/frontiers-inorganic impregnated drug. 1. Introduction and naturally occurring ligands have already been reported.6 Nevertheless, the integration of exclusively biocompatible Metal organic frameworks (MOFs) are fascinating crystalline units in the framework of a MOF is not a straightforward task, materials with remarkably high porosity and versatile chem- since most biomolecules possess low symmetry that prevents istry.1 Biological MOFs, known as bioMOFs, are composed of the formation of porous and stable networks, often requiring biocompatible metals and organic biomolecules as linkers, the use of (toxic) auxiliary ligands.7 Hence, the utilization of and are suitable for applications as diverse as gas adsorption2 bioMOFs in the biomedical area has been limited by the and medicine.3 The research on bioMOFs for biomedical difficulties found in preparing fully biocompatible com- applications, with particular interest in the development of pounds, considering not only the nature of the building units, drug delivery systems, is currently a hot topic in biomaterials but also the size of the particles as indicators of overall cyto- science.4 For this purpose, bioMOFs can be used either as-syn- toxicity.8 Regarding the latter, bioMOFs must be developed as thesized or after encapsulation of specific active pharma- nanoparticles, with a well-defined shape and narrow particle- ceutical products.5 Some interesting bioMOFs, constituted by size distribution, which are modulated by optimizing the non-toxic endogenous cations, e.g. Ca2+, Zn2+, Mg2+ or Fe2+/3+, experimental conditions during synthesis.9 An important point to consider in the development of bioMOFs is the chosen synthetic route. A typical reaction path a designed to develop MOFs relies on the use of high boiling Institut de Ciència de Materials de Barcelona (ICMAB), Consejo Superior de Investigaciones Científicas (CSIC), Campus UAB s/n, 08193 Bellaterra, Spain. point basic solvents, as those derived from formamide, under E-mail: arosado@icmab.es, conchi@icmab.es solvothermal conditions.10 This method is widely used because b ALBA Synchrotron Light Source, 08290 Cerdanyoladel Vallés, Spain it provides crystals of high quality suitable for structural elucida- c Instituto de Ciencia y Tecnología de Polímeros (ICTP), Consejo Superior de tion. However, the overall process generally involves harsh reac- Investigaciones Científicas (CSIC), C/Juan de la Cierva, 3, 28006 Madrid, Spain d tion conditions, long reaction/activation periods and large Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BNN), Av. Mon-forte de Lemos, 3-5, 28029 Madrid, Spain amounts of hazardous solvents that tend to get trapped in the e Departament de Química, Universitat Autònoma de Barcelona (UAB), Campus UAB internal cavities of the MOF, parameters that hinder not only s/n, 08193 Bellaterra, Spain. E-mail: JoseAntonio.Ayllon@uab.es their biomedical application, but also their scale-up pro- † Electronic supplementary information (ESI) available: Crystal structure descrip- duction.11 Currently, more sustainable methods are under tion, additional figures (S1–S12) and tables (S1–S4). CCDC 2214086. For ESI and research, such as those based on the use of non-toxic solvents, crystallographic data in CIF or other electronic format see DOI: https://doi.org/ 10.1039/d2qi02639b e.g., water or ethanol, and applying easy scalable mechanochem- ‡ This author is deceased. ical or spray-drying technologies.12 This journal is © the Partner Organisations 2023 Inorg. Chem. Front., 2023, 10, 2165–2173 | 2165 View Article Online Research Article Inorganic Chemistry Frontiers To advance the molecular design and synthetic aspects of bioMOFs, this work presents a facile, fast and green strategy for the preparation of a novel porous 3D framework, named here as CaSyr-1, composed of a calcium cation (Ca2+) as the This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. metal node and a syringate dianion (Syr2−) as the organic linker (Fig. 1), with unique textural properties and intriguing sorption and biomedical applications. The incorporation of Ca2+ into MOFs has recently gained significant attention, with more than 150 crystal structures already reported.13 This interest is attributed to multiple Open Access Article. Published on 02 March 2023. Downloaded on 3/28/2023 11:30:58 AM. health benefits,14 together with the mostly unexplored unique properties that this cation can provide, which are different from the well-known features of the universally employed tran- sition metals. Syringic acid (H2Syr) is a phenolic compound, often found in fruits and vegetables, with anti-oxidant, anti- inflammatory, anti-cancer and anti-hypertensive therapeutic properties.15 Contrary to Ca2+, the utilization of Syr2− in coordination chemistry has been scarce and absent in porous Fig. 2 (a) PXRD pattern of CaSyr-1 species compared with the simu- compounds.16 lated, (b) SEM and (c) TEM with the particle size histogram of the nano- powder, and (d) an optical microscope image of large crystals. 2. Results and discussion particle-size distribution was extremely narrow (100–200 nm), 2.1. Synthesis which indicates that CaSyr-1 exhibits adequate dimensional Porous CaSyr-1 nanopowder was synthesized in this work with properties for biosystems designed for flowing in blood a large space–time yield following an eco-friendly route in the vessels.18 The synthetic protocol was optimized to reduce the green solvent ethanol (EtOH).17 Remarkably, the material cost and time of the process, but conserving the desired could be prepared in only a few min (i.e., 10 min) by simply dimensional, morphological and textural properties of the end mixing quantitative molar amounts of reactants, calcium product. acetylacetonate (Ca(acac)2) and H2Syr, in a reduced volume of the solvent (1 mmol of each reactant in 1 or 10 mL of EtOH, 2.2. Crystal structure corresponding to reactants : EtOH with molar ratios of 1 : 8 and 1 : 80, respectively) at room temperature. Powder X-ray In order to elucidate the crystalline structure of CaSyr-1, crys- diffraction (PXRD) indicates that the obtained product was in tals of suitable quality (Fig. 2d) were prepared in dimethyl- both cases the explored phase CaSyr-1 (Fig. 2a and S1† for formamide (DMF) at 393 K and characterized by synchrotron 1 : 80 and 1 : 8 molar ratios, respectively). However, narrow par- XRD. The resolved crystalline structure has the formula ticle-size distributions, most appropriate for biomedical uses, [Ca2(Syr)2(H2O)2]n⊂(solvent), which was confirmed by elemen- were obtained in the system with an increase in the volume of tal analysis (Table S1†). A simulated PXRD pattern from the EtOH (Fig. 2b, c and S2, S3†), which allows a better control single crystal data matched those of both bulk large crystals over supersaturation and subsequent nucleation and crystal precipitated in DMF and the nanopowder obtained in EtOH growth. CaSyr-1 was thus precipitated as isometric porous (Fig. 2a). The CaSyr-1 framework consists of interconnected nanoparticles with a mean diameter of 64 ± 11 nm (Fig. 2b dimeric units containing two crystallographically independent and c). According to dynamic light scattering (DLS) measure- Ca2+ ions, two independent Syr2− linkers and two ancillary ments, the mean hydrodynamic diameter in suspension was H2O ligands (Fig. 3a). A detailed description of the crystalline ca. 150 nm when suspended in EtOH (Fig. S4†). Moreover, the structure can be found in the ESI.† Briefly, regarding the calcium sphere, it is worth highlighting the double clamp-like coordination mode of Syr2− that is responsible for the connec- tion between Ca1 and Ca2 (through two μ2-oxo bridges, O2 and O5) and, thus, for the formation of the dimer. This coordi- nation mode is powered by the adjacent methoxy-phenolate- methoxy groups present in the ligand. Although isolated methoxy groups are extremely weak ligands, when positioned next to a coordinating group, such as phenolate, they tend to form this robust clamp-like coordination.19 With respect to syr- ingate, the role of the dicarboxylate groups is also noteworthy Fig. 1 Occurrence and bioactivity of CaSyr-1 building blocks. in the extension of the structure (Fig. 3b), since they serve as 2166 | Inorg. Chem. Front., 2023, 10, 2165–2173 This journal is © the Partner Organisations 2023 View Article Online Inorganic Chemistry Frontiers Research Article area of 1080 m2 g−1 (Langmuir 1205 m2 g−1) was derived from the isotherm, which is exceptional in comparison with other reported bioMOFs that are considered totally biocompatible (Table 1), as CaSyr-1, not including either toxic auxiliary This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. ligands in the framework and/or impregnated or coordinated harmful solvents in the pores. The measured surface area value for CaSyr-1 is just comparable with that reported for the γ-cyclodextrin macrocyclic CD-MOF-1. Regardless, CaSyr-1 exhibits a notably larger pore aperture diameter (1.4 nm) in comparison with CD-MOF-1 (0.42 and 0.78 nm), which would Open Access Article. Published on 02 March 2023. Downloaded on 3/28/2023 11:30:58 AM. extend for the former, the scope of possible bioactive ingredi- ents to be encapsulated.6a,c,22 Fig. 3 Structure of CaSyr-1: (a) dimeric unit, (b) connections through The lighter weight of Ca2+ with respect to transition metals dicarboxylate bridges, (c) pore structure, (d) void arrangement, and (e) offers gravimetric advantages for gas loading, which together 3D framework. with the large affinity of Ca2+ for CO2, makes Ca-based MOFs suitable materials for CO2 sorption. Uptakes in the order of 1–2 mmol g−1 (100 kPa and 273–298 K) are reported,13 which bridges of two different dimeric units and promote the for- could only be increased by synthetizing mixed-metal MOFs.23 mation of the 3D porous framework (Fig. 3c–e). The resulting Remarkably, the monometallic CaSyr-1 bioMOF described in network displays two types of prisms, triangular and hexagonal this work, with a CO2 sorption of 3.7, 2.4 and 1.8 mmol g−1 at (ratio 2 : 1), with a disposition in the space that resembles the 100 kPa and 273, 298 and 313 K (Fig. 4b), respectively, outper- Kagome lattice, frequently found in natural minerals, but also form the values previously described for Ca-based MOFs in many MOFs.20 (Table S2†). Actually, the found value of CO2 sorption for Void volume measurement using Mercury software ( probe CaSyr-1 is closer to that of basic adenine bioMOFs, specifically radius 1.2 Å) indicates that the porosity arises only from the designed for this application,24 and the industrially used acti- hexagonal section, in the form of unidimensional channels vated carbon or zeolite 13X (ca. 4 mmol g−1).25 From the data with a diameter of 1.4 nm. Note that CaSyr-1 has the largest extracted at different adsorption temperatures, the CO2 pore diameter value described for microporous bioMOFs, enthalpy of adsorption (Qst) could be estimated, giving rise to close to that of mesoporous bioMOFs.21 Additionally, a highly a value of ca. 18 J mmol−1 (Fig. S7†) in the range of physisorp- porous architecture of open pores is obtained, with 36 v% void tion. The PXRD spectra of CaSyr-1 after these analyses indicate space. that CO2 was desorbed without any structural modification of the adsorbent. For environmental and process cost reasons, in 2.3. Porosity and thermal stability the application of CO2 capture, the use of inexpensive renew- able biolinkers for MOF design, such as that in CaSyr-1, is pre- CaSyr-1 porosity was experimentally confirmed by N2 physi- ferred vs. those derived from non-renewable petrochemical sorption at 77 K, giving an isotherm of type I (Fig. 4a). The feedstocks.2 high adsorption values at a very low relative pressures indicate For adsorption-related applications, thermal stability plays microporosity (micropore volume of 0.32 cm3 g−1), which is in an important role in ensuring the integrity of MOFs during accordance with the size of the cavities observed in the interaction with an adsorbate and in the regeneration process resolved crystalline structure. N2 uptake at high relative press- of the material for further reuse.26 Here, the thermal stability ures, accompanied by hysteresis, is assigned to interparticle of CaSyr-1 was evaluated through thermogravimetric analysis mesoporous voids. A high value of an apparent BET surface (TGA) under N2 flow (Fig. S8†). The weight decay at ca. 330 and 420 K is ascribed to the loss of EtOH and water molecules, respectively, both trapped in the cavities of the bioMOF during synthesis and manipulation, resulting in a total weight loss of about 20 wt%. The weight decrease does not involve any struc- tural change in the framework of CaSyr-1, which was con- firmed by a variable-temperature PXRD (VTPXRD) analysis, measured continuously from 298 to 500 K. Actually, no signifi- cant differences among the patterns recorded at the different temperatures were noticed (Fig. S9†). Hence, the removal of the solvent from the voids does not compromise the stability of the porous framework. The TGA suggests that CaSyr-1 is Fig. 4 Adsorption behavior: (a) N2 isotherms at 77 K for pristine CaSyr-1 thermally stable up to ca. 600 K, the temperature at which the and impregnated CaSyr-1(ibu), and (b) CO2 isotherm at 273, 298 and pyrolysis of the bioligand induces the degradation of the 313 K of CaSyr-1. network. This notable thermal stability is usual in Ca-based This journal is © the Partner Organisations 2023 Inorg. Chem. Front., 2023, 10, 2165–2173 | 2167 View Article Online Research Article Inorganic Chemistry Frontiers Table 1 Representative porous biocompatible bioMOFs constructed from bioligands and their reported textural properties Apparent BET Micropore Pore aperture BioMOF Bioligand surface area (m2 g−1) volume (cm3 g−1) diameter (nm) Ref. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. CaSyr-1 Syringate 1080 0.32 1.4 This work CD-MOF-1 γ-Cyclodextrin 1220 0.47 0.42/0.78 6a sc-CCMOF-1 Curcumine 350 0.10 N/A 6c [Cu2(μ3-ade)2(μ2-OOCCH3)2]·H2O Adenine/acetate 505 0.17 N/A 22a {[Zn(FDC)]·H2O}n 2,5-Furandicarboxylate 780 N/A 0.63 22b MOF-1201 L-Lactate 430 0.18 0.78 22c Open Access Article. Published on 02 March 2023. Downloaded on 3/28/2023 11:30:58 AM. MOFs containing O-donor linkers due to the ionic character of ibuprofen in CaSyr-1 using non-toxic supercritical CO2 the formed Ca–O bonds.13 (scCO2). In the impregnated sample, designated as CaSyr-1 (ibu), ibuprofen was assumed to reside solely in the pores of 2.4. Biocompatibility and drug release the bioMOF, since no sign of drug recrystallization outside the The focus on applications for the newly designed CaSyr-1 nanoparticles was noticed in the SEM images (Fig. S12†) or in bioMOF is primarily directed to biomedicine. Although CaSyr- the PXRD pattern (Fig. S13†). For CaSyr-1(ibu), the adsorption 1 constituents are known to be non-toxic, it is of major impor- branch of the N2 isotherm displayed a complete drop in gas tance to examine the bioMOF biocompatibility, since para- adsorption at low relative pressures (Fig. 4a), which indicates meters such as constituents’ interactions, particle size or that the micropores were already filled with the drug. The per- trapped solvent residue could influence the overall cytotoxicity, centage of ibuprofen in CaSyr-1(ibu) was estimated by 1H evaluated in this work through the half maximal inhibitory nuclear magnetic resonance (1H-NMR) after sample treatment concentration (IC50). The IC50 for the bioMOF was calculated with hydrofluoric acid. The 1H-NMR spectrum shows a to be 9.6 mg cm−3, close to the 7.8 mg cm−3 found for pristine 3 : 1 molar ratio of syringate : ibuprofen, which equates to a ca. H2Syr (Fig. S10 and S11†) and far from the values considered 21 wt% ibuprofen loading (Fig. S14–S16†), similar to other cytotoxic,27 which situates CaSyr-1 as a biocompatible platform reported values.30 By modifying the experimental conditions ready for biomedical use. in the scCO2 approach, the ibuprofen loading can be con- The pristine bioMOF could be used to physiologically trolled in the range ca. 10–25 wt%. release Ca2+, essential for a healthy skeleton, and Syr2−, with a The multicomponent release of CaSyr-1(ibu) was studied strong inhibition activity for COX-2 – recognized as the main here by suspending the impregnated bioMOF in a solution of anti-inflammatory target.28 To advance the therapeutic pro- PBS (buffer pH = 7.4) in D2O at 310 K for 1 day. During this perties of CaSyr-1, this bioMOF can be loaded with a wide period, several aliquots were collected at different times and range of drugs, taking advantage of its high porosity and large measured by NMR (Fig. S17–S20†). Interestingly, in all the pore diameter, to develop a triply bioactive CaSyr-1(drug) cases (from 10 min to 1 day), the signals assigned to both ibu- system, i.e., activity found in Ca2+, Syr2− and the impregnated profen and H2Syr were visible, and the corresponding inte- drug (Fig. 5). gration peaks ratio remained nearly constant (ca. 2.5–2.8 : 1, Therapeutic regimens based on the use of multicomponent syringate : ibuprofen), with values consistent with the initial drugs are an effective alternative to the one-target single mole- molar ratio in the solid form (3 : 1). This indicates not only a cular entities, since multiple targets can be involved in the fast delivery of the cargo, but also of CaSyr-1 building blocks, treatment of a particular disease.29 Herein, this possibility was induced by the degradation of the framework under physio- experimentally tested, demonstrating the easy impregnation of logical conditions. For small hydrophobic drugs, such as ibu- profen, physiologically unstable MOFs have already been con- templated as potential delivery vehicles to increase their bio- availability.31 This favourable burst phenomenon is promoted by the release of the drug confined in the bioMOF in the mole- cular form, making it dissolve much more easily than crystal- line drugs. The IC50 of the impregnated sample was found to be 5 mg cm−3, almost half of the CaSyr-1 IC50 (Fig. S10†). The overall cytotoxicity increases due to the inherent mild toxicity of ibu- profen, with a calculated IC50 of 1.9 mg cm−3 (Fig. S11†). Ibuprofen, even as one of the most prescribed nonsteroidal anti-inflammatory drugs, must be administered with caution due to its negative secondary effects related to dosage.32 In the Fig. 5 Schematic representation of drug encapsulation in CaSyr-1 and designed CaSyr-1(ibu), the merging of the COX-2 anti-inflam- subsequent triply bioactive release. matory activity of syringic acid and that of ibuprofen is 2168 | Inorg. Chem. Front., 2023, 10, 2165–2173 This journal is © the Partner Organisations 2023 View Article Online Inorganic Chemistry Frontiers Research Article expected to result in a positive decrease in the required dosage The contents of both vials were then mixed, attaining a molar of ibuprofen. Moreover, the use of ibuprofen is associated with ratio of reactants : EtOH of 1 : 80, and left to rest for 10 min at increased blood pressure and must be excluded from patients room temperature. The obtained crude product was washed diagnosed with hypertension, ca. 30% of the worldwide adult three times with 10 mL of EtOH by vortex-centrifugation and This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. population.33 Quite the reverse, CaSyr-1 could help in decreas- finally dried under vacuum (yield = 87 wt%). ing blood pressure, since both calcium and syringic acid have CaSyr-1 large crystal synthesis. For the synthesis of CaSyr-1 demonstrated anti-hypertensive effects.34 Hence, the popu- large crystals, suitable for structure elucidation through syn- lation targeted with the administration of ibuprofen could be chrotron radiation, 0.5 mmol of CaCl2 and 0.5 mmol of H2Syr increased by embedding hypertensive ibuprofen into the were initially dissolved in 15 and 10 mL of DMF, respectively. CaSyr-1 anti-hypertensive bioMOF. Each vial was sonicated for 5 min. Both solutions were then Open Access Article. Published on 02 March 2023. Downloaded on 3/28/2023 11:30:58 AM. mixed in a 50 mL Pyrex glass vial, tightly closed, and intro- duced into an oven at 393 K for 7 days. After this period, the 3. Conclusions recovered product was washed twice with 25 mL of DMF, fil- tered and dried under vacuum. The crystals were preserved in Homogeneously sized nanoparticles of CaSyr-1 can be easily Fomblin® Y oil for further structural elucidation. prepared from renewable biocompatible components in a sus- CaSyr-1 impregnation, CaSyr-1(ibu). Prior to the impreg- tainable strategy with a large space–time yield. These proces- nation process, CaSyr-1 nanopowder was activated under sing aspects, along with the displayed exceptionally high vacuum up to 15 Pa in an oven at 373 K for 6 h, in order to surface areas and pore sizes, make this material a promising remove the solvent from the pores. The impregnation of CaSyr- candidate for adsorption. Two main application areas have 1 with ibu was run in scCO2. In a typical experiment, a 100 mL been envisaged: the reversible adsorption of CO2 and the high-pressure vessel was loaded with a short beaker containing encapsulation of bioactive ingredients in the structure. It must 185 mg of ibu (0.90 mmol) and a stir bar. A table grid, support- be emphasized that CaSyr-1 enables the development of triply ing a rolled filter paper enclosing 150 mg (0.60 mmol, consid- bioactive entities with promising activity as a multicomponent ering the empirical formulae) of activated CaSyr-1, was placed drug system. on the beaker inside the reactor. Once closed, liquid CO2 was flushed into the vessel at 6.0 MPa and heated at 313 K. The pressure was increased to 15 MPa by compressing CO2 with a 4. Experimental section Teledyne Isco 260D syringe pump and the stirring was adjusted to 500 rpm. These working conditions were main- 4.1. Materials tained for a period of 20 h. After this time, the reactor was iso- The employed reactants for the CaSyr-1 preparation were syrin- thermally depressurized and then cooled down to room temp- gic acid (H2Syr 98%, abcr) and either calcium acetylacetonate erature. Finally, the impregnated product was recovered. (Ca(acac)2 98%, abcr) or calcium chloride (CaCl2 > 95%, Merck). The used solvents were absolute ethanol (EtOH, 4.3. Characterization techniques Scharlab) and dimethylformamide (DMF, abcr). For drug Single crystal X-ray diffraction. Single-crystal X-ray diffraction impregnation, the active compound was (S)-(+)-ibuprofen (ibu (SCXRD) experiments for the structural elucidation of the 99%, Sigma-Aldrich) dissolved in supercritical CO2 (scCO2), CaSyr-1 compound were performed in the XALOC beamline at which was provided as compressed CO2, 99.95 wt%, by the ALBA synchrotron.35 Data were collected at 100 K with a Carburos Metálicos S.A. 0.72931 Å wavelength using a Dectris Pilatus 6M detector placed at 120 mm from the sample. ϕ scans were performed 4.2. Synthetic procedure from 0 to 360° in steps of 0.5° with a collection time of 0.15° CaSyr-1 nanopowder synthesis. The synthesis of CaSyr-1 per step. The scan was repeated at three different κ angles (0, nanopowder was carried out in EtOH, starting from equimolar 45 and 90°) and merged afterwards to increase the complete- ratios of the reagents, optimizing the volume of the solvent as ness and redundancy when possible. Data were indexed, inte- the main parameter as follows. grated and scaled using the XDS software.36 The crystal struc- 1 mL of EtOH. 1.0 mmol of Ca(acac)2 and 1.0 mmol of ture was solved by intrinsic phasing and refined with SHELXL H2Syr were introduced into a vial containing 1 mL of EtOH. (version 2014/7)37 using Olex2 as the graphical interface.38 The attained molar ratio of reactants : EtOH was 1 : 8. The Powder X-ray diffraction. Powder X-ray diffraction patterns slurry was sonicated for 1 min and left to rest for 10 min at (PXRD) were recorded at room temperature in a Siemens room temperature. The obtained crude product was washed D5000 diffractometer with Cu Kα incident radiation. The three times with 10 mL of EtOH by vortex-centrifugation and selected 2θ range for data acquisition was 5–30° in steps of dried under vacuum (yield = 82 wt%). 0.02° s−1. For the sample prepared in DMF involving large crys- 10 mL of EtOH (the optimized protocol). 1.0 mmol of Ca tals, the product was ground by hand in an agate pestle prior (acac)2 and 1.0 mmol of H2Syr were separately introduced into to PXRD characterization. two vials containing 5 mL of EtOH each and sonicated for Variable-temperature PXRD. The variable-temperature PXRD 1 min, resulting in a suspension and a solution, respectively. (VTPXRD) measurements were performed at the BL16-NOTOS This journal is © the Partner Organisations 2023 Inorg. Chem. Front., 2023, 10, 2165–2173 | 2169 View Article Online Research Article Inorganic Chemistry Frontiers beamline of the ALBA synchrotron, from 298 up to 500 K. Data in water) were added. The mixture was heated at 333 K over- were collected at 20 keV (0.62074 Å wavelength) in the trans- night to evaporate the solvent and excess HF, resulting in a mission mode using a Mythen-II detector (6 modules at crude product that contained CaF2, protonated H2Syr and ibu- 535 mm from the sample). The powdered sample was placed profen. DMSO-d6 was added to dissolve the organic com- This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. inside an ad hoc capillary reaction cell (fused silica capillary ponents, and the subsequent suspension was filtered before with 0.7 and 0.85 nm inner and outer diameters, respectively) transferring it to the 1H-NMR tube in order to remove the pre- with a capillary connected online to both a gas-handling and a cipitated calcium salt. The analysis was carried out in a Bruker vacuum line. An Oxford Cryostream 700 instrument was used Avance NEO 300 MHz. Both, ibuprofen and syringic acid to control the temperature of the sample. exhibited well-defined 6H signals in the 1H-NMR spectrum, Microscopy. CaSyr-1 large crystals were optically analyzed corresponding to two methyls and two methoxides at δ = 0.86 Open Access Article. Published on 02 March 2023. Downloaded on 3/28/2023 11:30:58 AM. with an Olympus IX53 inverted microscope connected to a and 3.80 ppm, respectively (Fig. S14 and S15†). Hence, in XC30 camera. The crystal morphology of the nanopowder was CaSyr-1(ibu), the molar ratio of ibu with respect to H2Syr can observed by scanning electron microscopy (SEM) in a Quanta be estimated by comparing the integration of the signal at FEI 200 FEG-ESEM microscope. For better resolution, the 0.86 ppm with the integration of the signal at 3.80 ppm sample was coated with Au/Pd. The histograms of the particle- (Fig. S16†). size distribution were obtained by measuring >200 discrete particlesin images taken with a transmission electron micro- 4.4. Bioactive release and biocompatibility assays scope (TEM; JEOL 1210) using the ImageJ program. Bioactive release. The release of the organic bioactive com- Dynamic light scattering. The particle-size distribution in ponents present in CaSyr-1(ibu) was tracked by 1H-NMR, utiliz- suspension was estimated by the dynamic light scattering ing the same spectrometer as in the previous section. For that, (DLS) method, using a Zetasizer Nano ZS Malvern Inst. Prior 25 mg of CaSyr-1(ibu), corresponding to the IC50, was sus- to the measurement, CaSyr-1 was suspended in EtOH and pended in 5 mL of PBS in D2O (buffer pH = 7.4) under stirring sonicated for 1 h. at 200 rpm for 1 day at 310 K. The system was maintained Gas adsorption. The porosity of the samples was determined under inert conditions to avoid the exchange of D2O with H2O by analysing the N2 adsorption–desorption isotherms recorded from the air. During this period, four aliquots were collected at 77 K using ASAP 2020 Micromeritics Inc. equipment. The at different times, i.e., 10 min, 1, 3 and 24 h, and centrifuged apparent specific surface area was calculated by applying the to remove the precipitate and characterized by 1H-NMR. The BET (Brunauer–Emmett–Teller) equation or the Langmuir molar ratio of the syringate with respect to ibuprofen was esti- model. The micropore volume was determined by the t-plot mated as in the previous section. method. The CO2 sorption capacity was assessed by analysing Cell culture. Biocompatibility was tested on a human osteo- the isotherms at 273, 298 and 313 K up to 0.1 MPa. In both sarcoma cell line (MG63, ATCC CRL1427). MG63 cells were cul- cases, the samples were first degassed at 373 K under high tured on the MEM NEAA medium (Sigma Aldrich), sup- vacuum (10 Pa) for 20 h. The CO2 enthalpy of adsorption (Qst) plemented with 10 wt% of fetal bovine serum (FBS, Sigma), was determined through the graphical representation of the 1 wt% penicillin/streptomycin (Invitrogen) and 2 wt% pressure logarithm (ln p) for a given adsorbed amount (n) as a L-glutamine (Invitrogen). Cells were cultured at 310 K and 5 v% function of the reciprocal temperature (1/T ). The Qst at a CO2 in a humidified chamber until confluence before the specific adsorbate loading was then estimated using the assays. Cells were used from 4 to 8 passages in all the Clausius–Clapeyron equation (eqn (1)): experiments. Toxicity tests. For pristine syringic acid and ibuprofen com- Qst ðnÞ ¼ R lnðp2 =p1 ÞðT 1 T 2 =ðT 2  T 1 ÞÞ ð1Þ pounds, MG63 cells were cultured on a 96 well-plate at 100 000 cells per cm3 and incubated at 310 K and 5 v% CO2. After 24 h, Elemental analysis. The chemical composition of CaSyr-1 the medium was replaced by seriated dilutions of syringic acid nanopowder, regarding carbon and hydrogen, was estimated in culture medium and ibuprofen in 1 v% DMSO added to the by elemental analysis (EA). Data were recorded in a Flash culture medium. The cells were incubated at 310 K and 5 v% Smart™ elemental analyzer. The results were compared with CO2 for 24 h. MG63 cells in culture medium and 1 v% DMSO the theoretical values calculated from the crystallographic for- in culture medium were used as the control systems. After mulae contained in the generated CIF from single crystal struc- 24 h, the medium was replaced by the culture medium tural data (without considering the solvent in the pores). without phenol red (Sigma Aldrich). Thermogravimetric analysis. The thermal stability of CaSyr-1 For CaSyr-1 and CaSyr-1(ibu), 200 μL of MG63 cells was cul- was evaluated by thermogravimetric analysis (TGA) under N2 tured on transwell insets (collagen coated, cut-off = 0.4 μm, flow using a SDT 650-TA instrument. diameter = 6.5 mm, Costar) at 100 000 cells per cm3. The 1 H-nuclear magnetic resonance. Proton nuclear magnetic insets were incubated in a 48-well plate with 400 μL of culture resonance (1H-NMR) was employed to quantify the content of medium and at 310 K and 5 v% CO2. After 24 h, the medium ibuprofen in the impregnated sample CaSyr-1(ibu). In order to of the inset was replaced by fresh medium, and the medium of release all the ibu and H2Syr from CaSyr-1(ibu), 20 mg of the the well plate was replaced by seriated dilutions of CaSyr-1 and sample was suspended in methanol, and 4 drops of HF (40 v% CaSyr-1(ibu) in culture medium (starting at 25 mg cm−3). After 2170 | Inorg. Chem. 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Muhadzib and Nasruddin, Biological reader (Biotek Synergy HT spectrophotometer) with laser exci- metal–organic frameworks (Bio-MOFs) for CO2 capture, tation at 590 nm and measuring the emitted fluorescence at Ind. Eng. Chem. Res., 2021, 60, 37–51. 530 nm. The cell viability (%) was calculated using the follow- 3 A. C. McKinlay, R. E. Morris, P. Horcajada, G. Férey, ing equation (eqn (2)): R. Gref, P. Couvreur and C. Serre, BioMOFs: metal–organic Open Access Article. Published on 02 March 2023. Downloaded on 3/28/2023 11:30:58 AM. frameworks for biological and medical applications, Angew. Cell viability ð%Þ ¼ 100  ðODS  ODBÞ=ðODC  ODBÞ ð2Þ Chem., Int. Ed., 2010, 49, 6260–6266. where ODS, ODB, and ODC represent the emitted fluorescence 4 (a) I. Abánades Lázaro and R. S. Forgan, Application of zir- at 530 nm for the sample (S), blank (B, culture medium conium MOFs in drug delivery and biomedicine, Coord. without cells), and control (C), respectively. The experiments Chem. Rev., 2019, 380, 230–259; (b) W. Cai, J. Wang, C. Chu, were conducted in triplicate for each sample, and the data W. Chen, C. Wu and G. Liu, Metal–organic framework- obtained were expressed as mean values ± SD. based stimuli-responsive systems for drug delivery, Adv. Sci., 2019, 6, 1801526; (c) A. Bieniek, A. P. Terzyk, M. Wiśniewski, K. Roszek, P. Kowalczyk, L. Sarkisov, S. Keskin and K. Kaneko, MOF materials as therapeutic Conflicts of interest agents, drug carriers, imaging agents and biosensors in There are no conflicts to declare. cancer biomedicine: Recent advances and perspectives, Prog. Mater. Sci., 2021, 117, 100743. 5 S. Rojas, T. Devic and P. Horcajada, Metal organic frame- Acknowledgements works based on bioactive components, J. Mater. Chem. B, 2017, 5, 2560–2573. This work was supported by the Spanish Ministry of Science 6 (a) R. A. Smaldone, R. S. Forgan, H. Furukawa, and Innovation MICINN through the Severo Ochoa Program J. J. Gassensmith, A. M. Z. Slawin, O. M. Yaghi and for Centers of Excellence (CEX2019–000917-S), by the Spanish J. F. Stoddart, Metal–organic frameworks from edible National Plan of Research with projects PID2020-115631GB-I00 natural products, Angew. Chem., Int. Ed., 2010, 49, 8630– and PID2020-114086RB-100 and by CIBER (Spain) – Consorcio 8634; (b) H. Su, F. Sun, J. Jia, H. He, A. Wang and G. Zhu, A Centro de Investigación Biomédica en Red (Ref. CB06/01/ highly porous medical metal–organic framework con- 0013), Instituto de Salud Carlos III, MICINN. This research structed from bioactive curcumin, Chem. Commun., 2015, work was performed in the framework of the Nanomedicine 51, 5774–5777; (c) N. Portolés-Gil, A. Lanza, N. Aliaga- CSIC HUB (Ref. 202180E048). ALBA synchrotron is acknowl- Alcalde, J. A. Ayllón, M. Gemmi, E. Mugnaioli, A. M. López- edged for the provision of beam time. A. R. acknowledges the Periago and C. Domingo, Crystalline curcumin BioMOF financial support of FPI 2019 grant. 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