Controlled Transdermal Release of Antioxidant Ferulate by a Porous Sc(III) MOF.

The Sc(III) MOF-type MFM-300(Sc) is demonstrated in this study to be stable under physiological conditions (PBS), biocompatible (to human skin cells), and an efficient drug carrier for the long-term controlled release (through human skin) of antioxidant ferulate. MFM-300(Sc) also preserves the antioxidant pharmacological effects of ferulate while enhancing the bio-preservation of dermal skin fibroblasts, during the delivery process. These discoveries pave the way toward the extended use of Sc(III)-based MOFs as drug delivery systems (DDSs). Crown

Introduction

Metal-organic frameworks (MOFs) are one of the most recent classes of porous materials integrating a unique chemical and topological richness with an almost infinite combination of metal ions and multidentate organic linkers (Furukawa et al., 2013, Jiang et al., 2016, Kitagawa et al., 2004). This family of porous solids first seen as a curiosity in the field of materials science, has been envisaged for further applications, including but not limited to, gas storage (Makal et al., 2012, Murray et al., 2009, Suh et al., 2012), catalysis (Li et al., 2012, Sumida et al., 2012, Wu et al., 2012), sensors (Chen et al., 2010a, Cui et al., 2012, Kreno et al., 2012, Tchalala et al., 2019), electrical conductivity (Sheberla et al., 2014, Sheberla et al., 2017), and drug delivery (Chen and Wu, 2018, Horcajada et al., 2012, Simon-Yarza et al., 2018). Some of these hybrid materials combine outstanding adsorption/separation performances of highly challenging molecules with green synthesis and easy scale-up that make them highly attractive to address a large panel of social concerns (Chen and Wu, 2018, Horcajada et al., 2012, Simon-Yarza et al., 2018). In particular, MOFs show great potential for the design of modern drug delivery technologies (Chen and Wu, 2018, Horcajada et al., 2012, Jie and Ying-Wei, 2020, Simon-Yarza et al., 2018, Tibbetts and Kostakis, 2020). Unlike conventional drug carriers envisaged so far, e.g., micelles, liposomes, dendrimers, and mesoporous silica nanoparticles (Gillies and Fréchet, 2005, Porter et al., 2007, Senapati et al., 2018, Zhang and Ma, 2013, Zhang et al., 2012), MOFs offer a unique opportunity to modulate the incorporated drug payload and release kinetics by a fine engineering of their pore dimension (size/shape) and a fine-tuning of the nature/strength of the adsorption sites decorating their internal pore walls as well as of the functionalization of their external surfaces (Liang et al., 2019). The high degree of variability targets an efficient encapsulation of a broad range of highly challenging active pharmaceutical ingredients (APIs) in order to enhance their bioavailability and “shelf life” (Chen et al., 2018, Giménez-Marqués et al., 2016, Horcajada et al., 2010, Liu et al., 2019, Luo et al., 2019, Teplensky et al., 2017, Wang et al., 2018, Xiao-Gang et al., 2019, Ya-Pan et al., 2019, Ying et al., 2019). Cargo drug loading in MOFs can be accomplished either by an encapsulation during the synthesis (Doonan et al., 2017, Liang et al., 2015, Liang et al., 2019), or by a post-synthetic infiltration in the porosity of already-formed architectures (Chen et al., 2018, Horcajada et al., 2010, Teplensky et al., 2017, Wang et al., 2018). This later strategy has been widely explored in the development of controlled drug delivery systems (DDSs) of diverse natures for a large number of therapeutic agents. However, when contemplating any nano-carrier materials for biomedical applications several criteria are desired: (1) achieving an optimal drug loading efficiency (Horcajada et al., 2012), (2) allowing the protection of the drug to avoid any degradation under physiological media, (3) ensuring a gradual release of the drug once administrated to circumvent a “burst release effect” (Bellido et al., 2014, Li et al., 2017, Ruyra et al., 2015, Velásquez-Hernández et al., 2019), and (4) not having toxic effects on the body. In this context, a number of porous MOFs, built up from bio-compatible metal ions, i.e., Ca(II), Mg(II), Zn(II), Zr(IV), Ti(III), and Fe(III), has been discovered (Chen and Wu, 2018, Chen et al., 2018, Doonan et al., 2017, Horcajada et al., 2010, Horcajada et al., 2012, Liang et al., 2015, Liang et al., 2019, Simon-Yarza et al., 2018, Teplensky et al., 2017, Wang et al., 2018). However, only a small fraction of them encompass the adequate features to fulfill all requirements mentioned above (Chen and Wu, 2018, Horcajada et al., 2012, Simon-Yarza et al., 2018). Typically, most of these MOFs suffer from a fast degradation in presence of phosphates, essential components in body fluids, hampering their applications for controlled drug delivery (Bellido et al., 2014, Li et al., 2017, Ruyra et al., 2015, Velásquez-Hernández et al., 2019). The collapse of the framework is induced by a highly favorable complexation of the phosphate species to most of the metal centers tested so far, e.g., Zr(IV), Fe(III), and Zn(II) (Bellido et al., 2014, Li et al., 2017, Ruyra et al., 2015, Velásquez-Hernández et al., 2019).

In this context, Sc(III)-MOFs have never been investigated for drug delivery applications to date. This is likely mostly a result of the controversy on the bio-compatible nature of this metal. On the one hand, Sc(III) was demonstrated to be reactive toward proteins owing to its ability to replace Ca(II) in many biochemical events causing negative effects in enzyme systems and cell metabolism (Ford-Hutchinson and Perkins, 1971, Sánchez-González et al., 2013). On the other hand, Sc(III) is successfully used as a radioactive isotope in medical applications (Horovitz, 2012, Szkliniarz et al., 2016), and a low concentration of Sc(III) was proven to positively enhance specific antibiotic overproduction and have beneficial antibacterial effect (Kawai et al., 2007). Therefore, this critically urges for a comprehensive study on Sc(III) MOFs for potential drug delivery applications to address these open questions.

The present work reports the applicability of MFM-300(Sc), also denoted NOTT-400 (Ibarra et al., 2011), as drug carrier for transdermal administration of ferulic acid (FA). FA is a natural superior antioxidant since its phenolic nucleus and unsaturated side chain allow the formation of resonance-stabilized phenoxy radical acting as free radical scavenger (Antolovich et al., 2004, Chen et al., 2010b, Zduńska et al., 2018). FA also exhibits anti-diabetic, anti-cardiovascular, and anti-inflammatory properties (Antolovich et al., 2004, Chen et al., 2010b, Zduńska et al., 2018). Interestingly, this molecule has a protective role for the main skin structures such as collagen, fibroblasts, keratinocytes, and elastin (Zih-yi et al., 2019). Consequently, this therapeutic agent has been widely used in skin care formulations as photoprotective agent and delayer of skin photoaging processes and in the treatment of rosacea (Antolovich et al., 2004, Chen et al., 2010b, Zduńska et al., 2018). Owing to the importance of FA as active ingredient in a variety of cosmetic products, transdermal delivery is the most common administration route (Zih-yi et al., 2019). However, on premature exposure to sunlight FA undergoes oxidation reactions leading to the formation of quinones, dimers, and aldehydes (Antolovich et al., 2004). The photodegradation of FA not only limits its shelf-life but also reduces its effectiveness before it permeates the stratum corneum (SC) (Antolovich et al., 2004), which is the most superficial layer of the epidermis, and acts as skin barrier (Kalpana et al., 2010, Pegoraro et al., 2012). In order to circumvent these limitations, herein, we propose to encapsulate FA in the pores of MFM-300(Sc) with the main idea to prevent the photodegradation process of FA and to allow its continuous and sustained release over time that does not require frequent dosing.

Results and Discussion

MFM-300(Sc) as Drug Carrier of FA (FER–)

MFM-300(Sc) of chemical formula [Sc2(BPTC) (OH)2], was synthesized and activated according to a previously reported procedure (Supplemental Information) (Ibarra et al., 2011). A series of characterization tools confirmed the phase purity of the material and the full activation of its porosity (see Supplemental Information). This MOF crystallizes in the chiral tetragonal space group I4122, with each [Sc2(μ-OH)] (Figure S1) binuclear center octahedrally coordinated to six O-donors, four from four different carboxylate groups of BPTC−4 ligand (BPTC−4, biphenyl-3,3′,5,5-tetracarboxylate) and two from two different μ-OH groups, leading to a 3D framework with a channel of about 8.1 Å (Figure S1) (Ibarra et al., 2011). To evaluate the capacity of MFM-300(Sc) as drug delivery carrier, ferulic acid was initially loaded as ferulate species (FER–) (vide infra) within the MOF by a simple impregnation process, i.e., aqueous solution of ferulic acid (FA) at pH = 9 (Supplemental Information). Since the pore opening of MFM-300(Sc) exceeds the dimension of the drug (10.0 × 7.1 × 1.8 Å3), FER– is expected to be confined in its channels. UV-vis absorption spectroscopy was employed to monitor the concentration of FER– during the impregnation process (Figure S2). The maximum FER– payload (16.1 wt%) was achieved after 5 days of incubation; we determined this percentage by quantifying free FER– in the supernatants when the MOF dispersion was centrifuged (Supplemental Information). The drug content was further corroborated by TGA analysis (Figure S5). Powder X-ray diffraction analysis of the drug-loaded matrix FER@MFM-300(Sc) (ferulate is adsorbed as FER– and Na+) shows that the impregnation process does not modify the crystalline structure of MFM-300(Sc) (Figure S3), whereas N2 adsorption measurements revealed a decrease of the Brunauer, Emmett and Teller (BET) area and pore volume with respect to the pristine solid (915 m2 g−1 and 0.39 cm3 g−1 versus 1,300 m2 g−1 and 0.56 cm3 g−1, respectively) (Figure S4). Grand Canonical Monte Carlo (GCMC) simulations (see Supplemental Information for details) further predicted a lower uptake of FER– confined in the pores (10.7 wt%) associated with a decrease of the theoretical N2-accessible surface area from the empty to the FER@MFM-300(Sc) materials (1,480 m2 g−1 versus 1,290 m2 g−1). This strongly suggests that part of the experimental payload is not associated with a confinement of FER– in the pores of the MOF.

The drug-release kinetics of FER@MFM-300(Sc) was further assessed by in vitro studies using a dialysis bag diffusion technique (Supplemental Information). Two distinct regimes can be distinguished in the drug-release profile (Figure 1). Initially, ca. 37.0% of FER– is released within the first 6 h; this fast initial release is associated with the well-known burst effect (Bellido et al., 2014, Li et al., 2017, Ruyra et al., 2015, Velásquez-Hernández et al., 2019), and we can exclude that it is related to the degradation of MFM-300(Sc), since we have evidenced that the structure maintains its integrity after the drug release experiments and under the simulated physiological conditions used for the cytotoxicity assays (Supplemental Information, Figure S3). Interestingly, this payload (6.4 wt%) corresponds roughly to the deviation between the total experimental uptake and the predicted value for FER– confined in the pores (5.4 wt%). This first regime is thus most probably assigned to the release of FER– initially adsorbed at the external surface of the MOF. In other words, this first FER– release does not come from the micropores of MFM-300(Sc). This most likely comes from the external surface of the MOF crystals. Conversely, in the second regime the release process is considerably slower, releasing ca. 53% of the loaded drug during further ca. 94 h, approximately 4 days. Release of 9.7 wt% (end of the experiment) is in good agreement with the 10.7 wt% predicted by our calculations, supporting that this corresponds to the delivery of FER– initially confined in the pores of the MOF material.

Figure 1

Controlled Release of FER in FER@MFM-300(Sc)

Comparison between the in vitro release profile of free FER– (red circles) and the FER– delivered from the MFM-300(Sc) thorough the dialysis bag technique (blue circles). Five independent in vitro experiments were performed to generate the error bars (statistics). Lines are shown to guide the eyes. A schematic representation of the release of FER– from a FER@MFM-300(Sc) composite is shown as inset. See also Figures S1, S3, and S6.

Microscopic Understanding of the FER@MFM-300(Sc) Interactions

Monte Carlo (MC) and Density Functional Theory (DFT) calculations were further combined to understand the microscopic origin of this slow release. Analysis of the MC configurations for the adsorption of FER– in the dry state revealed that the drug molecule establishes relatively strong hydrogen bonds with the μ-OH functional groups of MFM-300(Sc) via their carboxylic groups with characteristic OCOO- - O distance of ca. 3.0 Å as seen by the corresponding radial distribution functions (RDFs) plotted in Figure S15A. Such an arrangement illustrated in Figure 2A leads to a high DFT-calculated binding energy (−43.5 kcal∙mol−1) that needs to be overcome in order for the molecules to be expelled from the MOF framework. Our MC simulations performed in solution further evidenced that FER– species interact strongly with water via their carboxylic groups with characteristic short OCOO- - OW distance of 2.5 Å as seen by the corresponding RDF plotted in Figure S15B. A fraction of these water molecules equally establishes strong hydrogen bonds with the μ-OH groups of the MOF pore wall with characteristic Ow - Oμ-OH distance of 2.7 Å (Figure S15B). This concerted FER– water and water-MOF interaction scenario offers an optimal scenario to stabilize FER– species in the confined environment, water playing a pivotal role by acting as a bridge between the MOF pore-wall and FER– to retain strongly the drug as can be seen in Figure 2B. One can also notice that besides forming a strong hydrogen bond network, as seen by the high intensity of the peak at 2.8 Å in the RDF corresponding to the Ow – Ow pairs (Figure S15B), the water molecules form side interactions with the other functional groups of FER– (Figures 2B and S15B). DFT simulations further confirmed that such an arrangement of FER– is highly stabilized with a corresponding binding energy of −120 kcal∙mol−1, consistent with a slow release observed experimentally. In line with these computational simulations, the experimental 13C CP MAS spectra (Figure S7) confirm the interaction of FER– within the MOF material. In the spectrum of FER@MFM-300(Sc), the NMR signals originating from FER– are considerably lower in comparison with those for MFM-300(Sc). Two signals are observed in the carboxylate region; the first one at 174.9 ppm is the most intense and is attributable to COO– bonded to Sc+3 in MFM-300(Sc). The second one appears at 170.7 ppm and is attributable to COO– coming from the FER– species. The signal of COO– FER–···Na+ appears at 173.1 ppm, i.e., that COO– shifted 2.4 ppm to stronger fields when adsorbed in MFM-300(Sc) (Figure S7).

Figure 2

Microscopic Illustration of FER– Adsorption in the MFM-300(Sc) Porosity

Representative MC snapshots of the FER– adsorption in MFM-300(Sc) (A) at the dry state, displaying the single-adduct between the FER– carboxylic groups and the μ-OH groups of the pore wall and (B) in solution, showing the FER– interactions with H2O molecules forming either (1) a single adduct with the μ-OH groups of the pore wall or (2) clusters at the center of the pore. Sc, O, C, and H are, respectively, represented in yellow, red, gray, and white. MFM-300(Sc) atoms are shown translucid for clarity. H-bonds are shown in dashed blue lines. Captions associated to the RDFs are described in the text.

See also Figures S2, S7, S13, S14, and S15.

Indeed, the drug adsorption profile accomplishes the desired drug-delivery kinetic for transdermal drug administration applications, where the drug carrier systems are designed normally to release the cargo within 1–7 days.

Cytotoxicity Experiments

Accordingly, the cytotoxicity of MFM-300(Sc) and its components (BPTC−4, Sc+3) were investigated separately, monitoring their impact in the cell viability and proliferation of human dermal fibroblasts (Supplemental Information) (Kalpana et al., 2010). Five different concentration solutions (5, 25, 100, 250, and 500 ppm) of BPTC−4, Sc+3, and MFM-300(Sc) were tested (Supplemental Information). The collected data revealed that both MFM-300(Sc) and Sc+3 did not considerably affect the cell viability, in comparison with positive controls. More than 98% of the cells remain viable after 24 h of incubation at any of the concentrations employed (Figures 3 and S9). This behavior remained almost constant even after 120 h. However, the culture well plates pre-treated with BPTC−4 presented a considerable reduction of cell viability in a dose-dependent way. Since some cells separate from the culture plate when they are not viable, the number of cells was also assessed. The cells treated with MFM-300(Sc) only showed an 80% reduction of the number of live cells at 500 ppm. Cells treated with Sc+3 showed a 120% reduction at 25–500 ppm. Treatments with BPTC−4 decrease considerably the number of cells from 5.5 times at 5 ppm to 8.8 times at 500 ppm. Moreover, the cell images collected on an epifluorescence microscope showed that, even when using only 5 ppm of BPTC−4, in the incubation media, the cells adopt a rounded morphology. This last observation indicates that the fibroblast attachment was not appropriate on the culture wells pre-treated with BPTC−4 (Figures 3 and S9). These results not only demonstrate that Sc+3 and MFM-300(Sc) exhibit an acceptable biocompatibility for topical drug administration but also confirm that BPTC−4 shows a negative cytotoxic effect.

Figure 3

Cytotoxicity Experiments of MFM-300(Sc), Sc+3, and BPTC−4

(A) Viable (green/calcein positives) and dead (red/EthD-1 positives) cells seeded on culture well plates pre-treated with different concentrations of MFM-300(Sc), Sc(III) and BPTC−4.

(B) Viable cell percentage and (C) total number of viable cells. ANOVA test and Sidak's multiple comparisons test. ∗p < 0.05, ∗∗p < 0.005, ∗∗∗p < 0.0005 and ∗∗∗∗p < 0.00005. Scale bars correspond to 100 μm.

See also Figures S9 and S12.

These findings encouraged us to investigate the transdermal permeability of FER– upon the topical administration of this antioxidant using FER@MFM-300(Sc) as a drug carrier. An active ingredient will exert its effect on its therapeutic target by releasing it from its pharmaceutical form, and it will subsequently arrive at its site of action.

Evaluation of the Antioxidant Effect of FER– Released from the MFM-300(Sc) Matrix

The ex vivo permeation assays were carried out on Franz diffusion cells using low back human tissue (Figures 4A and S10). This tissue was obtained from a female donor, who underwent aesthetic surgery, and it was employed with the prior consent of the donor (Supplemental Information, Figure S10). The Franz chambers consist of two compartments (donor and receptor) separated by the skin membrane (Figure 4A). The skin was placed in the donor compartment, where the stratum corneum (SC) was exposed to a suspension of FER@MFM-300(Sc) (41.4 mg mL−1) (Figures 4B and S10). The receptor compartment was filled with PBS (phosphate-buffered saline) at 37°C and kept under stirring (500 rpm) for 87 h. Afterward, the receptor medium was sampled to determine the amount of antioxidant diffused across the skin barrier (referred as systemic diffusion). As a control test, this permeation experiment was also performed using an aqueous suspension of FA (6.68 mg mL−1) (Figure 4C). Then, once completed the permeation assay, the skin samples were further analyzed to determine the biodistribution of the antioxidant within the skin layers. The tape stripping technique was employed to remove the SC layer of each skin sample (Binder et al., 2019, Escobar-Chávez et al., 2008, Esposito et al., 2018, Limcharoen et al., 2019). Then, these tape stripping samples and the remaining part of each skin sample were analyzed to estimate the amount of the antioxidant retained in the SC and in the inner layers of the skin. The data collected show that, when using the FER@MFM-300(Sc) system, ca. 10.40% of the cargo permeates through the skin to the systemic compartment, whereas in the system with an aqueous suspension of free FA only ca. 5.71% of the drug reaches the receptor compartment (Figures 4B and 4C), presumably because of oxidation and poor solubility of free FA in the skin. Interestingly, the amount of the antioxidant retained in the SC when using the FER@MFM-300(Sc) formulation and free FA is comparable ca. 0.20% and almost negligible, respectively. The carrier (MFM-300(Sc)) was retained in the SC as demonstrated by the size of the crystals (Figure S8). In addition, the quantity of the drug retained in the dermal and epidermal layers is around 0.29% when using FER@MFM-300(Sc) and 0.39% in the case of free FA. The permeation fluxes determined for FER– and FER@MFM-300(Sc) were 12.1 × 10−4 and 5.9 × 10−4 (nmol·cm−2·h−1), respectively. These findings demonstrate that our carrier material (MFM-300(Sc)) improves the permeation of the drug through the human skin, in comparison with the free FA. Such differences might be attributed to the promotion in the absorption of FER– inside FER@MFM-300(Sc) possibly by transcellular or paracellular routes. In addition, there is a higher availability of the drug when it is administrated as the ion FER– species than when it is administrated directly as the protonated species (FA).

Figure 4

Ex Vivo Permeation Experiments of Free and Entrapped FER–

(A–C) (A) Structural design of a Franz diffusion cell and schematic representation of the skin layers; (B) ex vivo permeation experiments of FER– using the FER@MFM-300(Sc) formulation, and amount of antioxidant (%) retained within the skin and released in the receptor chamber (systemic); and (C) ex vivo permeation experiments using an aqueous suspension of free FA and percentage of antioxidant retained within the skin and released in the receptor chamber (systemic).

See also Figures S8, S10, and S11.

Thus, the poor solubility of FA in the aqueous suspension, as well as its propensity to oxidize, reduces the concentration of the available molecular species retarding the permeation through the skin layers. The therapeutic reach of the permeation of FER– from FER@MFM-300(Sc) in the epidermis-dermis region, systemic, or deposition from the SC, also implies the subsequent prolonged release for up to 5 days of the cargo with the innocuous biodegradation of the carrier, a requirement of special interest for chronic clinical conditions.

Evidence of non-permeation of FER@MFM-300(Sc) was recorded by SEM studies before and after the tape stripping technique owing to the particle size of FER@MFM-300(Sc) (5 × 13 μm), which corroborates the new system as only for modified release and not for permeation (Figure S11). It is worth to emphasize that, for this model with real human skin, we did not perform more repetition experiments to achieve a certain level of statistics because of the limitations of achieving reproducible samples (same origin of the human skin: ideally same patient, same area of extraction, age of the donor, sex, ethnicity, etc.). More than focusing on the absolute permeation values of FER–, it is very significant the trends that we show.

Finally, to examine if the therapeutic drug preserved its antioxidant pharmacological effects after the long-term release process, the antioxidant efficacy, of FER– released from the microporous carrier (MFM-300(Sc)), was tested by monitoring the reactive oxygen species (ROS) produced in dermal skin fibroblasts upon being treated with H2O2. First, the release of the antioxidant was performed by soaking the MOF composite (FER@MFM-300(Sc)) in the cell culture media for 5 days. Then, the fibroblasts were pre-treated with this incubation media for 20 min. Subsequently, the cells were exposed to H2O2 for 20 min to induce the oxidative stress. The efficacy of the antioxidant in protecting skin fibroblasts from H2O2-induced ROS toxicity was determined using CellRox flow cytometry assay (see Supplemental Information, Figure S9). The results obtained demonstrated that the unstained condition marks 100% of cells without ROS expression (CellRox+), dead cells (7-AAD+), or doubly marked (CellRox/7-AAD+). In the basal state (without H2O2 treatment), only 0.2% of the cells remain unlabeled and 67.5% show ROS expression, whereas, as expected, the cells incubated with H2O2 present an increase in ROS production (88.7%), the unlabeled population decreases (0.6%), and the population with dead cells and ROS + showed 10.7%. However, when the cells were treated with FER@MFM-300(Sc) (100 ppm) the percentage of unstained cells (without ROS or dead cell staining) increase considerably (25.9%) in comparison with the values observed in the basal state (0.6%). This fact confirms that the FER– released from FER@MFM-300(Sc) maintains its bio-functionality by scavenging ROS species. Another result shows that only the application of the MFM-300(Sc) to the cells increase the unlabeled cells from 0.6% to 1.3%, suggesting that the MFM-300(Sc) exhibits an unexpected antioxidant capacity. These findings suggest that FER@MFM-300(Sc) not only allows the long-term sustained release of FER– but also enhances the bio-preservation of dermal skin fibroblasts during the delivery process.

In summary, this work demonstrates that MFM-300(Sc) is an efficient drug carrier by virtue of its excellent biocompatibility in human skin cells, remarkable stability under physiological conditions, and adequate controlled release for topical applications. The incorporation of FER– into MFM-300(Sc), in comparison with other well-known or even commercial materials like hydrotalcites (Lima et al., 2013), provided a longer-term controlled release through human skin. MFM-300(Sc) also demonstrated a higher chemical stability in comparison with typical MOF DDSs like MIL-100 and MIL-101(Horcajada et al., 2006, Li et al., 2017). This particular chemical stability for MFM-300(Sc) provides a benchmark material for future investigations in order to compare with other MOF carries, particularly those constructed with Sc(III) metal centers. In addition, our study reveals that this material improves the systemic delivery of ferulate leading to the controlled and sustained long-term delivery of the cargo, which avoids both the degradation of ferulate, and the continuous re-application of the drug during, relatively, a long time. These findings pave the way toward the extended use of Sc(III)-based MOFs as drug carriers.

Limitations of the Study

In this study, the topical drug bioavailability was assessed by in vitro experiments using a two-chamber Franz cell. The main disadvantage of this system is that it does not consider the in vivo skin processes and does not mimic accurately the living state of the skin. For instance, the skin normally functions under air from the environment. However, during the permeation studies, SC is typically exposed to wet conditions for prolonged periods. On the other hand, the current work was limited to the release of FER–. Future efforts should test other drugs in order to drive the extended use of Sc(III)-based MOFs as drug carriers.

Resource Availability

Lead Contact

Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Ilich A. Ibarra (argel@unam.mx).

Materials Availability

This study did not generate new unique reagents.

Data and Code Availability

All the data needed to evaluate the conclusions of this work are detailed in the main text and/or the Supplemental Information. Additional data related to this paper may be requested from Ilich A. Ibarra (argel@unam.mx).

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.