Metal–Organic Frameworks as Efficient Oral Detoxifying Agents

  • Sara Rojas
    Sara Rojas
    Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, France
    More by Sara Rojas
  • Tarek Baati
    Tarek Baati
    Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, France
    Laboratoire des Substances Naturelles, Institut National de Recherche et d’Analyse Physico-Chimique (INRAP), BiotechPole Sidi Thabet, 2020 Sidi Thabet, Ariana, Tunisie
    More by Tarek Baati
  • Leila Njim
    Leila Njim
    Service d’Anatomie et de Cytologie Pathologiques, CHU de Monastir, Monastir, Tunisie
    More by Leila Njim
  • Lisbeth Manchego
    Lisbeth Manchego
    Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, France
  • Fadoua Neffati
    Fadoua Neffati
    Laboratoire de Biochimie et de Toxicologie, CHU de Monastir, Monastir, Tunisie
  • Nissem Abdeljelil
    Nissem Abdeljelil
    Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, France
    Laboratoire de Biophysique, Faculté de Médecine de Sousse, Université de Sousse, Sousse, Tunisie
  • Saad Saguem
    Saad Saguem
    Laboratoire de Biophysique, Faculté de Médecine de Sousse, Université de Sousse, Sousse, Tunisie
    More by Saad Saguem
  • Christian Serre
    Christian Serre
    Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, France
    Institut des Matériaux Poreux de Paris, FRE 2000 CNRS Ecole Normale Supérieure, Ecole Supérieure de Physique et de Chimie Industrielles de Paris, PSL Research University, 24 rue Lhomond, Paris 75005, France
  • Mohamed Fadhel Najjar
    Mohamed Fadhel Najjar
    Laboratoire de Biochimie et de Toxicologie, CHU de Monastir, Monastir, Tunisie
  • Abdelfateh Zakhama
    Abdelfateh Zakhama
    Service d’Anatomie et de Cytologie Pathologiques, CHU de Monastir, Monastir, Tunisie
  • , and 
  • Patricia Horcajada*
    Patricia Horcajada
    Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, France
    Advanced Porous Materials Unit, IMDEA Energy Institute. Av. Ramón de la Sagra 3, 28935 Móstoles-Madrid, Spain
    *[email protected]
Cite this: J. Am. Chem. Soc. 2018, 140, 30, 9581–9586
Publication Date (Web):July 10, 2018
https://doi.org/10.1021/jacs.8b04435
Copyright © 2018 American Chemical Society
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Abstract

Poisoning and accidental oral intoxication are major health problems worldwide. Considering the insufficient efficacy of the currently available detoxification treatments, a pioneering oral detoxifying adsorbent agent based on a single biocompatible metal–organic framework (MOF) is here proposed for the efficient decontamination of drugs commonly implicated in accidental or voluntary poisoning. Furthermore, the in vivo toxicity and biodistribution of a MOF via oral administration have been investigated for the first time. Orally administered upon a salicylate overdose, this MOF is able to reduce the salicylate gastrointestinal absorption and toxicity more than 40-fold (avoiding histological damage) while exhibiting exceptional gastrointestinal stability (<9% degradation), poor intestinal permeation, and safety.

Introduction

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Poisoning and accidental intoxication via ingestion have become growing health issues worldwide with both a significant cost and severe health problems, even death. (1,2) Unfortunately, for the vast majority of these poisonings, there are no specific pharmacological antidotes, and currently available detoxification methods (i.e., gastric lavage, activated charcoal, and antidotes) are usually ineffective and even involve severe adverse effects, limiting their use. (3−5) In general, activated charcoal is more effective than gastric emptying. Single doses of oral activated charcoal effectively avoid the gastrointestinal (GI) absorption of many drugs and toxins present in the stomach, preventing their uptake into the blood and subsequent distribution to target organs. (6) However, some toxins present poor affinity for charcoal (e.g., alcohols, hydrocarbons, nicotinic acid, and some metals such as iron or lithium), (7,8) reducing the efficacy of activated charcoal. Although the ability of various nanomaterials (e.g., liposomes, antibody fragments, microemulsions) to capture drugs and other toxins has been reviewed, (9,10) to date only an injectable γ-cyclodextrin (Sugammadex) has reached the clinical stage for the reversal of neuromuscular blockade induced by specific anesthetics. (11) Consequently, there is great interest in the development of safe and effective detoxification treatments.
As selective adsorbents, metal–organic frameworks (MOFs) appear as innovative and promising detoxifying agents. These crystalline hybrid materials, which exhibit exceptional porosity and chemical and structural versatility, have already demonstrated interesting performance in the selective adsorption and removal of hazardous molecules either in water or air. (12−17) Furthermore, certain MOFs have recently emerged in the biomedical field, disclosing interesting features such as important capacities for a large variety of active ingredients and a lack of in vivo toxicity. (18−21) Despite extensive studies for biomedical applications, no biocompatible MOF has been reported to date as an oral drug detoxifying agent. In this regard, only a composite constituted by an activated carbon containing a lanthanide-based MOF has been proposed by Oliveira et al. (22) for the removal of a pesticide in rats.
In this study, we target the oral detoxification of drugs using a single biocompatible MOF. Additionally, the in vivo toxicity and biodistribution of an orally administered MOF are addressed for the first time. The cubic microporous Soc-MOF(Fe) or MIL-127 structure, (23,24) based on octahedral iron(III) trimers and 3,3′,5,5′-azobenzenetetracarboxylate anions (TazBz4–), has been selected as efficient adsorbent. This solid exhibits a priori several advantages: (i) good biocompatibility, based on the endogenous iron cation and proven in vitro (median inhibitory concentration (IC50) > 2.00 and 0.44 mg·mL–1 in the HeLa and J774 cell lines, respectively); (25) (ii) high porosity (Brunauer–Emmett–Teller (BET) surface area SBET = 1400 m2·g–1 and pore volume = 0.7 cm3·g–1), associated with an important adsorption capacity; (iii) high chemical stability at different pH values that might ensure its stability along the GI tract; and (iv) gram-scale synthesis at the macrometric scale, (26) with crystal dimensions larger than the maximum size absorbed by the intestinal mucosa (∼20 μm), (27) preventing its intestinal crossing and potential related toxicity.
On the other hand, we use the salicylate derivative aspirin (acetylsalicylic acid, ASA) as a model overdose pain medication. Although used here as model, pain medication leads the list of most common substances implicated in accidental or voluntary adult poison exposures (11.6% in 2016) (1) and is the second cause of pediatric fatalities (17.5% from 2012 through 2016). (28) For instance, more than 40 000 cases of human exposure to salicylates were reported in emergency departments in the United States in 2004, (29) 44% of which involved children under the age of 6 years. In particular, ASA was involved as a single agent in 45% of the cases. In addition, the detoxification of salicylates nowadays requires repeated doses of activated charcoal to reduce the risk of desorption. (6) Thus, ASA detoxification using MOFs could avoid the need for repeated doses.
We first evaluated the in vitro stability of MIL-127 and its ASA encapsulation capacity under simulated GI conditions. Next, the ASA detoxification efficiency and safety of MIL-127 were orally evaluated in an animal model. Finally, an ex vivo intestinal model was used to assess MIL-127 and ASA bypass across the intestinal barrier.

Results and Discussion

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The structural, textural, and compositional integrity of MIL-127 was initially confirmed (see the PXRD, FTIR, and N2 sorption analyses disclosed in Supporting Information (SI) section 2) under simulated GI conditions, mimicking both gastric (HCl, pH 1.2 at 37 °C for 2 h) and intestinal (Ringer medium based on a phosphate-buffered saline solution, pH 6.0 at 37 °C for 24 h) conditions found in healthy vertebrates. (30) It should be noted that this digestion model simulates the composition, pH, residence time, and temperature conditions in the different portions of the human digestive tract. (31)
Next, to select the most suitable dose of MIL-127 to be administered upon an ASA overdose, different ASA concentrations were put in contact with a fixed amount of MIL-127 (ASA:MIL-127 ratio = 1.5:1 and 3:1) in gastric medium followed by intestinal conditions, mimicking the GI transit (SI section 3). The ASA removal and matrix chemical stability were monitored by quantifying the release of the MIL-127 constitutive organic linker (H4TazBz) and ASA to the medium by HPLC (see SI section 1). It should be noted here that because of the important GI hydrolysis of ASA to salicylic acid (SA) (i.e., 2 and 20% under simulated gastric conditions for 2 h and intestinal conditions for 24 h, respectively; Figure S5), both salicylate derivatives were considered for the quantification. Under GI conditions (Figure 1), MIL-127 can adsorb 25.2% of the total salicylates at a 3:1 ratio (corresponding to 8.6% + 16.6% under the gastric and intestinal conditions, respectively) and 39.4% at a 1.5:1 ratio (corresponding to 13.6% + 25.8% under the gastric and intestinal conditions, respectively). Therefore, as expected, the most suitable detoxifying dose of MIL-127 corresponds to the highest MOF content (i.e., ASA:MIL-127 = 1.5:1), which is able to remove ∼40% of the salicylates. However, the drug loading (grams of drug entrapped per gram of MIL-127) did not depend on the amount of MOF, reaching in both cases a maximum ASA capacity of around 0.14 g·g–1. It is also interesting to mention that after the medium exchange (from gastric medium to intestinal medium), no release of salicylates was detected, indicating excellent affinity of the drug for the MIL-127 matrix and suggesting good stability of the adsorbent under GI conditions. The chemical (<2% degradation; Figure 1) and structural (Figure S6) integrity of MIL-127 was further confirmed after its incubation in gastric (2 h) and intestinal (24 h) media supplemented with ASA, regardless of the ASA:MIL-127 ratio. Finally, the MIL-127 adsorption capacity was compared with those of other adsorbent materials: a commonly used commercial activated charcoal (Norit) and two archetypical zirconium terephthalate MOFs (UiO-66 and UiO-66-NH2) (32,33) (Table S2). Although the activated charcoal works better as a detoxifying agent than MIL-127 in the gastric medium (94 vs 13% efficiency), it releases a significant amount of the adsorbed salicylates when it passes to intestinal conditions (11%). In contrast, the MIL-127 adsorbent, which exhibits similar ASA removal after 26 h under GI conditions compared to active charcoal (ca. 34%), is able to retain its salicylate cargo along the GI tract. Further comparison with the other benchmarked MOF structures, which are known for their chemical robustness and high adsorption capacity, showed that MIL-127 adsorbs salicylates more efficiently than UiO-66 and UiO-66-NH2 (33% vs 6 and 9%, respectively).

Figure 1

Figure 1. Evolution of salicylate removal (left, black) and MIL-127 matrix degradation (right, red) under simulated GI conditions (the blue and green backgrounds represent gastric and intestinal media, respectively). Different ASA:MIL-127 ratios were studied: 3:1 (triangles) and 1.5:1 (circles). The concentrations of salicylates have been normalized for an easier comparison.

The oral detoxification ability of MIL-127 was then evaluated in vivo using the best ASA:MIL-127 ratio (i.e., 1.5:1). Considering both the safe dose and median lethal oral dose (LD50) of ASA in rats (ca. 3 and 900–1200 mg·kg–1, respectively), (34,35) we orally administered more than 10 times the safe oral dose of ASA (350 mg·kg–1), which might be enough to determine the detoxification efficiency of MIL-127 in a drug overdose without causing euthanasia and/or distress of the animal. After 1 h of the ASA overdose, the MIL-127 adsorbent (1 g·kg–1) was orally administered (SI section 4). Remarkably, after 24 h, the plasma and urine concentrations of salicylates, as determined by HPLC (SI section 4), were reduced 3-fold in the presence of MIL-127 (Table 1), reaching similar results as previously published for the adsorption of ASA by activated carbon. (36) Similarly, the salicylate concentrations in different portions of the small intestine, which are associated with higher villi and microvilli absorptive surface area, (37) were around 30 times lower after the administration of MIL-127 compared with the ASA control group (Table 1 and Figure S9). These findings unequivocally prove the lower GI absorption of salicylates and thus the efficiency of MIL-127 in the detoxification of ASA-overdosed rats.
Table 1. Salicylate Concentrations in Plasma, Urine, and Small Intestine
 ASA concentration (mg·mL–1)
 without MIL-127with MIL-127
plasma0.21 ± 0.110.07 ± 0.04
urine15.8 ± 7.46.4 ± 2.2
duodenum0.144 ± 0.0060.02 ± 0.01
jejunum0.46 ± 0.010.016 ± 0.007
ileum0.5 ± 0.10.019 ± 0.007
We further evaluated the intestinal barrier bypass of ASA ex vivo with Ussing diffusion chambers. Briefly, two compartments (donor and receptor) separated by an intestinal biopsy (i.e., jejunum) were filled with simulated intestinal media (i.e., Ringer), and ASA was incubated in the presence or absence of MIL-127 in the donor compartment. The transport was monitored by quantifying the salicylates in the receptor chamber (SI section 6). Remarkably, the presence of MIL-127 (1 or 2 mg·mL–1) drastically reduced (>40-fold) the intestinal absorption of salicylates (Figure 2). The above in vivo and ex vivo results highlighted for the first time the unique properties of MOFs as efficient oral drug detoxifying agents in living beings.

Figure 2

Figure 2. Salicylate ex vivo intestinal bypass in the presence of MIL-127 (1 or 2 mg·mL–1).

To address the benefit–risk balance of MIL-127 in ASA overdose treatment, different parameters (animal behavior, body and organ masses, biomarkers, etc.) were evaluated. First, no behavioral changes or significant differences in body or organ masses were noted in any of the groups (Figure S10). The macroscopic aspect of the organs was totally normal, without hypertrophy, cell necrosis, or color change.
Microscopic examination of stomach, jejunum, and liver showed a protective effect of MIL-127 against ASA overdose. Stomach histological sections of control groups revealed a normal architecture consisting of mucosa (M) separated from submucosa (SM) by a thin muscularis mucosa (MM) (SI section 5 and Figure S11). The mucosa consists of superficial foveolar epithelium (F) and deeper gastric glands (Gg). Each foveolar serves as a conduit for gastric secretions to be released into the lumen (L). Microscopic examinations of stomachs of the ASA group showed an evident toxicity, highlighted by the formation of mucosal erosions with cellular desquamation and necrosis of the foveolar epithelium mucosal epithelium (yellow arrows), as reported for ASA histological damage. (38) In addition, ASA alters the stomach mucus coating, and the tissues become damaged from exposure to acid, inducing the formation of ulcers. Hence, MIL-127 seems to limit this effect, as confirmed by the normal stomach mucosal architecture free from any pathological changes that was observed in the [email protected] and MIL-127 groups, both of which are similar to the control. This finding confirmed the gastroprotective effect of MIL-127 particles, which were observed to be located in the stomach lumen and in the mucosa on the surface of the foveolar epithelium (Figure S11, black arrows). Likewise, jejunum histological sections showed an important amount of MIL-127 particles around the intestinal microvilli, which might prevent intestinal absorption of salicylates (Figure 3b,d, black arrows). Similarly to the stomach, ASA overdoses (ASA group) produced important toxicity with focal erosions in the intestinal mucosa, showing extensive damage and abnormalities in the tissue structure (see SI section 5 for further details). (38) In particular, we observed destruction and transformation of villi into edema accompanied by loss and disorganization of the enterocyte surface and brush border with a partial edema of the lamina propria and microvilli enlargement associated with lightened contents. Notably, these deleterious effects are not present in the MIL-127-treated group. Furthermore, the [email protected] group showed reasonably well-preserved jejunum epithelia without any histological lesions. Although the normal villi were lost in the form of villus fusion and swelling (Figure 3, [email protected], red arrows), no destruction of the enterocyte surface and brush border was observed, again supporting the protective effect of the MIL-127 adsorbent. These results are of particular importance since they rule out the gastric and intestinal toxicity of MIL-127 that remains adhered to the microvilli, working as an ASA detoxifying and gastric and intestinal mucosa protecting agent.

Figure 3

Figure 3. Histological sections of rat jejunum after 24 h of 10% glucose (negative control), MIL-127, ASA (positive control), and [email protected] administration.

Examination the livers of the MIL-127 and glucose control groups revealed a normal parenchyma architecture without any apparent change in the hepatocyte structure (Figure S12). In contrast, neutrophil infiltrations were observed in the liver upon ASA overdose (Figure S12c, yellow arrows), suggesting an acute inflammation due to the accumulation of ASA. (39,40) Treatment with MIL-127 reduced the hepatotoxic effect of ASA, as shown by the decrease in neutrophil infiltrations in the livers of the [email protected] group. In addition, hepatocellular toxicity was assessed by the activity of typical biomarkers of hepatic cytolysis (alanine and aspartate aminotransferases, ALT and AST, respectively). (41) ALT and AST activities significantly increased in the ASA, MIL-127, and [email protected] groups (Figure S17). If high ASA doses are considered to be hepatotoxic, (39,40) iron accumulation upon intestinal absorption (see the discussion of biodistribution below) can also lead to transient higher transaminase activity, as previously reported for intravenously administered Fe-based MOFs. (42) Also, it is known that ASA induces a significant increase in intestinal amylase and lipase, (43) and similar values, higher than that for the control group, were observed for both the ASA and [email protected] groups. Although intestinal absorption of ASA is reduced in the presence of MIL-127, the ASA hepatotoxicity is not fully avoided.
Having proved the safety and efficiency of MIL-127 as an oral ASA detoxifying agent, we investigated the in vivo fate of the adsorbent, which is a critical point for its future application. First, the integrity of the MIL-127 adsorbent along the GI tract was evaluated by recovering the content within all of the GI portions. Despite the quite aggressive GI conditions (e.g., pH, the presence of competing highly complexant groups such as phosphates, enzymes, intestinal motility), MIL-127 possesses remarkably high stability, retaining its crystalline structure all along the GI tract, as confirmed by PXRD (Figures S2 and S13). Further chemical analyses of the GI contents by HPLC demonstrated that only 8.7% of the material was degraded. Moreover, MIL-127 exhibited more than 10-fold lower degradation in the presence of ASA compared with singly administered MIL-127 (Table S3), suggesting stabilization of MIL-127 by a potential “template” effect of the encapsulated salicylates. In addition, considering the ASA blood concentration (Table 1), we were able to estimate the number of salicylate molecules adsorbed per metal node cluster as 1.05. The possible coordination of approximately one salicylate to the iron trimer makes the metal sites less accessible to water molecules and therefore might stabilize the MIL-127 solid. In addition, the presence of intact MIL-127 particles was visually confirmed in the entire GI tract from the stomach to the colon as well as in feces; crystalline (see the PXRD patterns in Figure 4) and well-faceted cubic particles were observed by field-emission-gun scanning electron microscopy (FEG-SEM) (Figure S14). (26) Furthermore, the iron levels in feces were determined by inductively coupled plasma atomic emission spectroscopy (ICP-OES), which showed a 5-times higher iron concentration than for the negative control group (6.9 ± 3.5 vs 1.3 ± 0.3 mg·g–1, respectively), in concordance with the fecal excretion of the MIL-127 particles.

Figure 4

Figure 4. PXRD patterns of MIL-127 material during passage through the entire GI tract, showing that MIL-127 remains stable along the GI tract. Data were collected using a high-throughput Bruker D8 Advance diffractometer.

The 24 h biodistribution of MIL-127 was also investigated by quantifying the iron in the plasma, stomach, duodenum, jejunum, ileum, heart, liver, spleen, and kidneys by atomic absorption spectroscopy (AAS) (Figures S15 and S16). Except for the duodenum and jejunum, the iron levels were found to be normal, with no significant difference compared with the negative control group, ruling out important GI absorption of MIL-127 and/or its constitutive iron cation. However, statistical analysis of the Fe content confirmed significant differences (p < 0.05) in the duodenum and jejunum. Since iron absorption mainly occurs in the duodenum and upper jejunum, (44) this result suggests partial degradation of MIL-127 (8.7% at the ileum level; see above) and then slight iron absorption within this region of the small intestine.
Finally, we evaluated ex vivo (i.e., with Ussing chambers) the intestinal barrier bypass of MIL-127 and its constitutive organic ligand H4TazBz as well as their potential toxicity over the intestine (SI section 6). MIL-127 (1 mg·mL–1) or the corresponding amount of the H4TazBz ligand were incubated in the donor compartment of the Ussing permeation chamber using as the biological barrier jejunum and ileum biopsies, since they are associated with a high absorption capacity. It is worth mentioning that very low ligand concentrations are able to cross the intestine (0.1 and 2 μg·mL–1, corresponding to ca. 0.01 to 0.30% of the initial dose; Figure S18). Furthermore, the diffusion flux (F) and the apparent permeability of the membrane (Papp) for MIL-127 and H4TazBz ligand were calculated (Table 2). (45,46) Very low values were observed regardless the intestine section. Interestingly, MIL-127 exhibits an even lower permeation flux than the free ligand (ca. 0.05 vs 1.1 μg·cm–2·h–1 in both intestinal sections), probably due to progressive leaching of the linker from MIL-127 to the medium. In addition, the large particle size of MIL-127 (ca. 28 μm) is in agreement with a lower intestinal transport via enterocytes, as previously demonstrated for other particles. (47) Furthermore, the H4TazBz ligand exhibits very low permeation compared with other known small, uncharged solutes like caffeine (0.001 vs 7.2 cm·h–1, respectively). (48) Both the high chemical stability of MIL-127 and the low ligand permeation rule out important intestinal absorption of the MIL-127, preventing any severe toxicity associated with its accumulation within the body.
Table 2. Diffusion Flux (F) and Permeability Coefficient Parameter of the Membrane (Papp)
 jejunumileum
 H4TazBzMIL-127H4TazBzMIL-127
F (μg·cm–2·h–1)1.050.051.120.04
Papp (cm·h–1)0.00140.00130.00100.0011
Furthermore, the viability of the intestinal membrane was checked by measuring the transepithelial resistance (TEER), which is accepted as a good model for determining the membrane integrity after the transport of chemicals. (49) For this purpose, upon intestinal bypass of MIL-127 and H4TazBz, the conductivity of this polarized membrane was studied via modulation of the ion channels (Figure S19). The response of the membrane to the addition of forskolin or biotin, which modifies the voltage-dependent K+ of a healthy membrane, supports the lack of toxicity of both MIL-127 and the H4TazBz ligand.

Conclusions

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MIL-127, which combines exceptional GI stability and important drug adsorbent capacity, is a promising safe and efficient oral detoxification treatment. Upon a salicylate overdose, MIL-127 is able to drastically reduce its intestinal absorption more than 40-fold (decreasing by a third the ASA concentration in blood), avoiding associated histological damage. In addition, except for a minor GI degradation (<9%) and subsequent slight iron absorption in the duodenum and jejunum, the integrity of MIL-127 is preserved along the GI tract, and the MOF is excreted in the feces without any sign of severe toxicity. Further biodistribution studies demonstrated a lack of intestinal absorption of MIL-127 due to its large particle size, high structural and chemical stability, and poor intestinal permeation of both MIL-127 and its constitutive ligand. These results open fascinating perspectives for the safe and efficient treatment of poisoning and accidental intoxication using biocompatible MOFs.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b04435.

  • Full details of the synthetic procedures, biological simulated media, stability studies (PXRD, FTIR, and N2 sorption measurements), HPLC determinations, in vitro tests, and in vivo biodistribution and ex vivo intestinal permeation studies (PDF)

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Author Information

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  • Corresponding Author
    • Patricia Horcajada - Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, FranceAdvanced Porous Materials Unit, IMDEA Energy Institute. Av. Ramón de la Sagra 3, 28935 Móstoles-Madrid, Spainhttp://orcid.org/0000-0002-6544-5911 Email: [email protected]
  • Authors
    • Sara Rojas - Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, Francehttp://orcid.org/0000-0002-7874-2122
    • Tarek Baati - Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, FranceLaboratoire des Substances Naturelles, Institut National de Recherche et d’Analyse Physico-Chimique (INRAP), BiotechPole Sidi Thabet, 2020 Sidi Thabet, Ariana, Tunisie
    • Leila Njim - Service d’Anatomie et de Cytologie Pathologiques, CHU de Monastir, Monastir, Tunisie
    • Lisbeth Manchego - Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, France
    • Fadoua Neffati - Laboratoire de Biochimie et de Toxicologie, CHU de Monastir, Monastir, Tunisie
    • Nissem Abdeljelil - Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, FranceLaboratoire de Biophysique, Faculté de Médecine de Sousse, Université de Sousse, Sousse, Tunisie
    • Saad Saguem - Laboratoire de Biophysique, Faculté de Médecine de Sousse, Université de Sousse, Sousse, Tunisie
    • Christian Serre - Institut Lavoisier, CNRS UMR 8180, UVSQ, Université Paris-Saclay, 45 Av. Des Etats Unis, Versailles 78035 Cedex, FranceInstitut des Matériaux Poreux de Paris, FRE 2000 CNRS Ecole Normale Supérieure, Ecole Supérieure de Physique et de Chimie Industrielles de Paris, PSL Research University, 24 rue Lhomond, Paris 75005, France
    • Mohamed Fadhel Najjar - Laboratoire de Biochimie et de Toxicologie, CHU de Monastir, Monastir, Tunisie
    • Abdelfateh Zakhama - Service d’Anatomie et de Cytologie Pathologiques, CHU de Monastir, Monastir, Tunisie
  • Author Contributions

    S.R. and T.B. contributed equally.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was supported by UniverSud Paris (ref: 2010–25) and CNRS/DGRST (ref: 24432) projects. S.R. and P.H. acknowledge the Marie Sklodowska-Curie Programme (MSCA-IF-EF-ST-2015-705529). P.H. acknowledges the Spanish Ramón y Cajal Programme (Grant Agreement 2014-16823) and the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA Grant Agreement 291803. The authors acknowledge Laura García for the ICP-OES characterizations and Carine Livage for the FEG-SEM observations.

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  • Abstract

    Figure 1

    Figure 1. Evolution of salicylate removal (left, black) and MIL-127 matrix degradation (right, red) under simulated GI conditions (the blue and green backgrounds represent gastric and intestinal media, respectively). Different ASA:MIL-127 ratios were studied: 3:1 (triangles) and 1.5:1 (circles). The concentrations of salicylates have been normalized for an easier comparison.

    Figure 2

    Figure 2. Salicylate ex vivo intestinal bypass in the presence of MIL-127 (1 or 2 mg·mL–1).

    Figure 3

    Figure 3. Histological sections of rat jejunum after 24 h of 10% glucose (negative control), MIL-127, ASA (positive control), and [email protected] administration.

    Figure 4

    Figure 4. PXRD patterns of MIL-127 material during passage through the entire GI tract, showing that MIL-127 remains stable along the GI tract. Data were collected using a high-throughput Bruker D8 Advance diffractometer.

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