Metal-Organic Frameworks as Efficient Oral Detoxifying Agents

Article abstract of DOI:10.1021/jacs.8b04435

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

Full text of DOI:10.1021/jacs.8b04435

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Article
Metal-Organic Frameworks as efficient oral detoxifying agents
Sara Rojas, Tarek Baati, Leila Njim, Lisbeth Manchego, Fadoua Neffati, Nissem Abdejelil, Saad
Saguem, Christian Serre, Mohamed Fadhel Najjar, Abdelfateh Zakhama, and Patricia Horcajada
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Jul 2018
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MetalꢀOrganic Frameworks as efficient oral detoxifying agents
a
a,b,
c
a
d
a,e
,‡
‡
Sara Rojas, Tarek Baati,
Leila Njim, Lisbeth Manchego, Fadoua Neffati, Nissem Abdejelil,
Saad Saguem,e Christian Serre,a,f Mohamed Fadhel Najjar,d Abdelfateh Zakhama,c Patricia Horcaꢀ
jadaa,g,*
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a
Institut Lavoisier, CNRS UMR 8180. UVSQ, Université ParisꢀSaclay. 45, Av. Des Etats Unis 78035 Versailles Cedex,
France
b
Laboratoire des Substances Naturelles, Institut National de Recherche et d’Analyse PhysicoꢀChimique (INRAP), Bioꢀ
techPole Sidi Thabet Ariana 2020, Tunisie
c Service d'Anatomie et de Cytologie Pathologiques, CHU Monastir, Tunisie
d Laboratoire de Biochimie et de Toxicologie, CHU de Monastir, Tunisie
e Laboratoire de Biophysique, Faculté de Médecine de Sousse, Université de Sousse, Tunisie
f 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, 75005 Paris, France
g Advanced Porous Materials Unit, IMDEA Energy Institute. Av. Ramón de la Sagra 3, 28935 MóstolesꢀMadrid, Spain
‡ These authors contributed equally to this work.
Supporting Information Placeholder
madex) has reached so far the clinical stage for the reversal neuꢀ
romuscular blockade induced by specific anesthetics.11 Conseꢀ
quently, there is a great interest in developing safe and effective
detoxification treatments.
ABSTRACT: Poisoning and accidental oral intoxication is a
major health worldwide problem. Considering the insufficient
efficacy of the currently available detoxification treatments, a
pioneering oral detoxifying adsorbent agent based on a single
biocompatible MetalꢀOrganic Framework (MOF) is here proposed
for the efficient decontamination of drugs commonly implicated
in accidental or voluntary poisoning. Further, the in vivo toxicity
and biodistribution of a MOF via oral administration have been
investigated for the first time. Orally in more than 40 times adꢀ
ministered upon a salicylate overdose, this MOF is able to reduce
the salicylate gastrointestinal absorption and toxicity (avoiding
histological damage), while proving an exceptional gastrointestiꢀ
nal stability (>9% degradation), poor intestinal permeation and
safety.
As selective adsorbents, MetalꢀOrganic Frameworks (MOFs)
appear as innovative and promising detoxifying agents. These
crystalline hybrid materials, exhibiting an exceptional porosity
and chemical and structural versatility, have already proven interꢀ
esting performances on 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 of a
large variety of active ingredients and a lack of in vivo toxicity.18–
21
Despite being extensively studied for biomedical applications,
no biocompatible MOF has been reported so far as oral drug
detoxifying agent. In this regard, only a composite constituted by
an activated carbon containing a LnꢀMOF has been proposed for
the removal of a pesticide in rats by Oliveira et al.22
INTRODUCTION. Poisoning and accidental intoxication via
ingestion has become a growing health worldwide problem 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 blood and subsequent distribution to target organs.6
However, some toxins present poor affinity to charcoal (e.g.
alcohols, hydrocarbons, nicotinic acid, and some metals 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 only an injectable γꢀcyclodextrine (Sugam-
In this study, we pioneering target the oral detoxification of
drugs using a single biocompatible MOF. Additionally, the in vivo
toxicity and biodistribution of a MOF orally administered will be
addressed for the first time. The cubic microporous SocꢀMOF(Fe)
or MILꢀ127 structure,23,24 based on iron(III) octahedra trimers and
3,3´,5,5´ꢀazobenzenetetracarboxylate anions (TazBz4ꢀ), has been
selected as efficient adsorbent. This solid exhibits a priori several
advantages: i) a good biocompatibility, as based on the endogeꢀ
nous iron cation and as proven in vitro (inhibitory concentration
50; IC50 > 2.00 and 0.44 mg·mLꢀ1 in HeLa and J774 cell lines,
respectively),25 ii) a high porosity (BrunaeurꢀEmmettꢀTeller surꢀ
face area SBET = 1400 m2 gꢀ1 and pore volume = 0.7 cm3·gꢀ1),
associated with an important adsorption capacity, iii) a high
chemical stability under different pH values that might insure its
stability along the GI tract, and iv) a gramꢀscale synthesis at the
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macrometric scale,26 with crystal dimensions larger than the maxꢀ
imum size absorbed by the intestinal mucosa (∼20 µm),27 preventꢀ
ing its intestinal crossing and potential related toxicity.
tion capacity was compared with other adsorbent materials: a
commonly used commercial activated charcoal (Norit®) and two
archetypical Zrꢀterephthalate MOFs (UiOꢀ66 and UiOꢀ66ꢀ
NH2)32,33 (SI, Table S2). Although the active charcoal works
better as detoxifying agent under gastric media than MILꢀ127 (94
vs. 13% efficiency), it releases a significant amount of the adꢀ
sorbed salicylates when passing to intestinal conditions (11%). In
contrast, MILꢀ127 adsorbent, exhibiting a similar ASA removal
after 26 hꢀGI conditions than active charcoal (ca. 34%), is able to
retain its salicylate cargo along the GI tract. Further comparison
with other benchmarked MOF structures, known by their chemiꢀ
cal robustness and high adsorption capacity, shows that MILꢀ127
adsorbs more efficiently salicylates than UiOꢀ66 and UiOꢀ66ꢀNH2
(33% vs. 6 and 9%, respectively).
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On the other hand, we use the salicylate derivative aspirin (acetylꢀ
salicylic acid or ASA) as model overdose pain medication. Altꢀ
hough here used as model, pain medication leads the list of most
common substances implicated in accidental or voluntary adult
poison exposures (11.6%, Poison Statistics US National Data
2016), being the second cause of pediatric fatalities (17.5%, US
Poison Control from 2012 through 2016).1,28 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
these involving children under the age of 6 years. In particular,
ASA was involved as a single agent in 45% of the cases. In addiꢀ
tion, the detoxification of salicylates requires nowadays from
repeated doses of activated charcoal to reduce the risk of desorpꢀ
tion.6 Thus, the ASA detoxification by using MOFs could avoid
needing repeated doses.
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Thus, we firstly evaluated the in vitro stability of MILꢀ127 and
its ASA encapsulation capacity under simulated GI conditions.
Secondly, the ASA detoxification efficiency and safety of MILꢀ
127 were orally evaluated in an animal model. Finally, an ex vivo
intestinal model was used to assess the MILꢀ127 and ASA bypass
across the intestinal barrier.
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RESULTS AND DISCUSSION. The structural, textural and
compositional integrity of the MILꢀ127 was initially confirmed
(see PXRD, FTIR and N2 sorption analyses disclosed in Supportꢀ
ing InformationꢀSI, Section 2) under simulated GI conditions,
mimicking both gastric (HCl, pH = 1.2 at 37 ºC for 2 h) and intesꢀ
tinal conditions found in healthy vertebrates (Ringer medium
based on a phosphate buffer saline solution pH = 6.0 at 37 ºC for
24 h).30 Note that this digestion model simulates the composition,
pH, residence time and temperature conditions in the different
portions of the human digestive tract.31
1.5:1
1
3:1
0.5
0
0
5
10
15
20
25
Time (h)
Figure 1. Evolution of salicylates removal (left, black) and MILꢀ127
matrix degradation (right, red) under simulated GI conditions (blue and
green background represents respectively gastric and intestinal media).
Different ASA:MILꢀ127 ratios have been studied: 3:1 (triangles) and 1.5:1
(circles). Note that concentration of salicylates has been normalized for an
easier comparison.
Then, to select the most suitable dose of MILꢀ127 to be adminꢀ
istered upon an ASA overdose, different ASA concentrations
were put in contact with a fix amount of MILꢀ127 (ASA:MILꢀ127
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 quantiꢀ
fying the release of the MILꢀ127 constitutive organic linker
(H4TazBz) and ASA to the media by HPLC (see SI, Section 1).
Note here that due to the important GI hydrolysis of ASA to
salicylic acid (SA) (i.e. 2 and 20% under simulated gastric condiꢀ
tions for 2 h and intestinal conditions for 24 h, respectively; SI,
Figure S5), both salicylate derivatives were considered for the
quantification. Under GI conditions (Figure 1), MILꢀ127 can
adsorb 25.2% of the total salicylates using a 3:1 ratio (correspondꢀ
ing to 8.6% + 16.6% in the gastric and intestinal conditions, reꢀ
spectively) and 39.4% with a ratio 1.5:1 (corresponding to 13.6%
+ 25.8% in the gastric and intestinal conditions, respectively).
Therefore, as expected, the most suitable detoxifying dose of
MILꢀ127 corresponds to the highest MOF ratio (i.e. ASA:MILꢀ
127 = 1.5:1) able to remove ∼40% of salicylates. However, the
drug loading (grams of drug entrapped per gram of MILꢀ127) did
not depend on the amount of MOF, reaching in both cases a maxꢀ
imum ASA capacity of around 0.14 g·gꢀ1. It is also interesting to
mention that after the medium exchange (from gastric to intestinal
one), no release of salicylates was detected, supporting an excelꢀ
lent affinity of the drug by the MILꢀ127 matrix and suggesting a
good stability of the adsorbent under GI conditions. The chemical
(< 2% of degradation; Figure 1) and structural (SI, Figure S6)
integrity of MILꢀ127 was further confirmed after its incubation in
gastric (2 h) and intestinal (24 h) media supplemented with ASA,
regardless the ASA:MILꢀ127 ratio. Finally, the MILꢀ127 adsorpꢀ
The oral detoxification ability of MILꢀ127 was then in vivo
evaluated using the best ASA:MILꢀ127 ratio (i.e. 1.5:1). Considꢀ
ering both the safety and lethal 50 oral (LD50) doses of ASA in
rats (ca. 3 mg·Kgꢀ1 and 900 – 1200 mg·Kgꢀ1, respectively),34,35 we
have orally administered more than 10 times the safety oral dose
of ASA (350 mg·Kgꢀ1), which might be enough to determine the
detoxification efficiency of MILꢀ127 in a drug overdose without
causing euthanasia and/or distress of the animal. After 1 h of the
ASA overdose, 1 g·Kgꢀ1 of the MILꢀ127 adsorbent was orally
administered (SI, Section 4). Remarkably, after 24 h, the plasma
and urine concentration of salicylates, determined by HPLC (SI,
Section 4), was reduced three times in presence of the MILꢀ127
(Table 1), reaching similar results as previously published for the
adsorption of ASA by activated carbon.36 Similarly, salicylates
concentration 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 the
MILꢀ127 when compared with the ASA control group (Table 1,
and SI Figure S9). These findings unequivocally prove the lower
GI absorption of salicylates and thus, the efficiency of the MILꢀ
127 on the detoxification of ASA overdosed rats.
Table 1. Salicylates concentration in plasma, urine and small intestine.
ASA
ASA@MILꢀ127
0.07±0.04
6.4±2.2
0.02±0.01
0.016±0.007
0.019±0.007
Plasma (mg·mLꢀ1)
Urine (mg·mLꢀ1)
0.21±0.11
15.8±7.4
0.144±0.006
0.46±0.01
0.5±0.1
Duodenum (mg·mLꢀ1)
Jejunum (mg·mLꢀ1)
Ileum (mg·mLꢀ1)
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Section 5).38 In particular, we can observe destruction and transꢀ
formation of villi into edema accompanied by loss and disorganiꢀ
zation of enterocytes surface and brush border with a partial edeꢀ
ma of the lamina propria and a microvilli enlargement associated
with lightened contents. Notably, these deleterious effects are not
present in the MILꢀ127 treated group. Further, the ASA@MILꢀ
127 group showed reasonably wellꢀpreserved jejunum epithelia
without any histological lesion. Although the normal villi were
lost in the form of villus fusion and swelling and fusion of villus
(Fig.3, ASA@MILꢀ127 red arrows), any destruction of the enterꢀ
ocytes surface and brush border was observed, supporting again
the protective effect of the MILꢀ127 adsorbent. These results are
of particular importance since they rule out the gastric and intestiꢀ
nal toxicity of MILꢀ127 that remains adhered on the microvilli,
working as ASA detoxifying and gastric and intestinal mucosa
protective agent.
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We further ex vivo evaluated the intestinal barrier bypass of
ASA by means of the Ussing diffusion chambers. Briefly, two
compartments (donor and receptor), separated by an intestinal
biopsy (i.e. jejunum), are filled with simulated intestinal media
(i.e. Ringer), incubating the ASA in presence or not of the MILꢀ
127 in the donor compartment and monitoring the transport by
quantifying the salicylates in the receptor chamber (SI, Section 6).
Remarkably, the presence of 1 or 2 mg·mLꢀ1 of MILꢀ127 drastiꢀ
cally reduced (more than 40 times) the intestinal absorption of
salicylates (Figure 2). The above in vivo and ex vivo results highꢀ
lighted for the first time the unique properties of MOFs in terms
of efficient oral drug detoxifying agents in living beings.
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Liver examination of MILꢀ127 and glucose control group reꢀ
vealed a normal parenchyma architecture without any apparent
change in the hepatocytes structure (SI, Figure S12). In contrast,
neutrophils infiltrations were observed in the liver upon ASA
overdose (Figure S12(c), yellow arrows), suggesting an acute
inflammation due to the accumulation of ASA.39,40 The treatment
with MILꢀ127 reduced the hepatotoxic effect of ASA, as shown
by the decrease of neutrophils infiltrations in liver of ASA@MILꢀ
127 group. In addition, hepatocellular toxicity was assessed by the
activity of typical biomarkers of hepatic cytolysis (alanine and
aspartate aminotransferasesꢀALT and AST, respectively).41 ALT
and AST activities significantly increase in the ASA, MILꢀ127
and ASA@MILꢀ127 groups (SI, Figure S17). If ASA highꢀdoses
are considered as hepatotoxic,39,40 iron accumulation upon intestiꢀ
nal absorption (see biodistribution below) can also lead to transiꢀ
ent higher transaminase activity, as previously reported for intraꢀ
venously administered FeꢀMOFs.42 Also, it is known that ASA
induces a significant increase in the intestinal amylase and
lipase,43 observing similar values, higher than the control group,
for both the ASA and ASA@MILꢀ127 groups. Although intestinal
absorption of ASA is reduced in presence of MILꢀ127, the ASA
hepatotoxicity is not fully avoided.
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0
AAS
MIL127 (1mg/ml) MIL127 (2mg/ml)
MILꢀ127 MILꢀ127
40
20
0
ASA
(1 mg—mLꢀ1
)
(2 mg—mLꢀ1)
AAS
ASA
MIL127 (1mg/ml)
MILꢀ127
MIL127 (2mg/ml)
MILꢀ127
(2 mg—mLꢀ1
)
(1 mg—mLꢀ1
)
Figure 2. Salicylates ex vivo intestinal bypass in presence of 1 or 2
mg·mLꢀ1 of MILꢀ127.
To address the benefitꢀrisk balance of the MILꢀ127 in ASA
overdose treatment, different parameters (animal behavior, body
and organs weight, biomarkers, etc.) were evaluated. First, no
behavioral changes or significant differences in body or organs
weight were noted in all groups (SI, Figure S10). The macroscopꢀ
ic 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 MILꢀ127 against ASA overdose.
Stomach histological sections of control groups revealed a normal
architecture consisting of mucosa (M) which is separated from
submucosa (SM) by a thin muscularis mucosa (MM) (SI, Section
5, Fig S11). The mucosa consists of superficial foveolar epitheliꢀ
um (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 stomach of the ASA group shows an
evident toxicity, highlighted by the formation of mucosal erosions
with cellular desquamation and necrosis of the foveolar epitheliꢀ
um mucosal epithelium (yellow arrows) as reported for ASA
histological damage.38 In addition, the ASA alters the stomach
mucus coating and the tissues become damaged from exposure to
acid, inducing the formation of ulcers. Hence, MILꢀ127 seems to
limit this effect as confirming by the normal stomach mucosal
architecture, free from any pathological changes observed in the
ASA@MILꢀ127 and MILꢀ127 groups both are similar to the
control. This funding confirmed the gastroprotective effect of
MILꢀ127 particles, which are shown to be located in the stomach
lumen and in the mucosa on the surface of the foveolar epithelium
(SI, Fig. S11, black arrows). Likewise, jejunum histological secꢀ
tions showed an important amount of MILꢀ127 particles around
the intestinal microvilli, which might prevent the salicylates intesꢀ
tinal absorption (Fig. 3(b,d), black arrows). Similarly to 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 for further details,
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troscopy (ICPꢀOES) in feces, observing a 5ꢀtimes higher iron
Glucose
concentration than the negative control group (1.3 ± 0.3 vs. 6.9 ±
3.5 mg·gꢀ1), which is in concordance with the fecal excretion of
the MILꢀ127 particles.
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Stomach
MILꢀ127
Duodenum
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Jejunum
Ileum
Colon
Feces
ASA
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2θ (º)
Figure 4. PXRD patterns of MILꢀ127 material after passing through the
entire GI tract. MILꢀ127 remains stable along the GI track. Data were
collected using the highꢀthroughput Bruker D8 Advance diffractometer.
ASA@MILꢀ127
The 24 h biodistribution of MILꢀ127 was also investigated by
quantifying the iron (by atomic absorption spectroscopy (AAS),
SI, Figure S15ꢀ16) in plasma, stomach, duodenum, jejunum,
ileum, heart, liver, spleen, and kidneys. Except for duodenum and
jejunum, iron levels were found to be normal, with no significant
difference when compared with the negative control group, ruling
out an important GI absorption of the MILꢀ127 and/or its constituꢀ
tive iron cation. However, statistical analysis of the Fe content
confirmed significant differences (p < 0.05) in duodenum and
jejunum. Considering that iron absorption mainly occurs in the
duodenum and upper jejunum,44 this result suggests a partial
degradation of MILꢀ127 (8.7% at the ileum level, see above) and
then, a slight iron absorption within this small intestine region.
Figure 3. Histological sections of rat jejunum after 24 h of 10% glucose
(negative control), MILꢀ127, ASA (positive control), and ASA@MILꢀ127
administration.
Once proved the safety and efficiency of MILꢀ127 as oral ASA
detoxifying agent, we investigated the in vivo fate of the adsorꢀ
bent, as a critical point for its future application. First, the integriꢀ
ty of the MILꢀ127 adsorbent was evaluated along the GI tract by
recovering the content within all the GI portions. Despite the quite
aggressive GI conditions (e.g. pH, presence of competing highly
complexant groups such as phosphates, enzymes, intestinal motiliꢀ
ty), MILꢀ127 possesses a remarkably high stability, retaining its
crystalline structure all along the GI tract, as confirmed by PXRD
(SI, Figures 4 and S13). Further chemical analyses of the GI
contents by HPLC demonstrated that only 8.7% of the material
was degraded. Moreover, MILꢀ127 exhibited more than 10 times
lower degradation in presence of ASA when compared with the
single administrated MILꢀ127 (SI, Table S3), suggesting the MILꢀ
127 stabilization by a potential “template” effect of the encapsuꢀ
lated salicylates. In addition, considering the ASA blood concenꢀ
tration (Table 1), we can estimate the salicylate molecules adꢀ
sorbed per metal node cluster, corresponding to 1.05. The possiꢀ
ble coordination of around one salicylate to the iron trimer makes
the metal sites less accessible to water molecules and therefore,
might stabilize the MILꢀ127 solid. In addition, the presence of
intact MILꢀ127 particles was visually confirmed in the entire GI
track (from stomach to colon) as well as in feces, observing crysꢀ
talline (see PXRD patterns in SI, Figure 4) and wellꢀfaceted cubic
particles by fieldꢀemissionꢀgun scanning electron microscopy
(FEGꢀSEM in SI, Figure S14).26 Furthermore, the iron levels were
determined by inductively coupled plasma atomic emission specꢀ
Finally, we evaluated ex vivo (i.e. Ussing chambers) the intestiꢀ
nal barrier bypass of MILꢀ127 and its constitutive organic ligand
H4TazBz, as well as their potential toxicity over the intestine (SI,
Section 6). 1 mg·mLꢀ1 of MILꢀ127 or the corresponding amount
of the H4TazBz ligand were incubated in the donor compartment
of the Ussing permeation chamber using as 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·mLꢀ1,
corresponding to ca. 0.01 ad 0.30% of the initial dose; SI, Figure
S18). Furthermore, the diffusion flux (F) and the apparent permeꢀ
ability of the membrane (Papp) for MILꢀ127 and H4TazBz ligand
were calculated (Table 2),45,46 observing very low values, regardꢀ
less the intestine section. Interestingly, MILꢀ127 exhibits an even
lower permeation flux than the free ligand (ca. 0.05 vs. 1.1 µg·cmꢀ
2·hꢀ1 in both intestinal sections), probably due to the progressive
leaching of the linker from the MILꢀ127 to the medium. In addiꢀ
tion, the large particle size of MILꢀ127 (ca. 28 µm) is in agreeꢀ
ment with a lower intestinal transport via enterocytes, as previousꢀ
ly demonstrated for other particles.47 Furthermore, the H4TazBz
ligand exhibits a very low permeation when compared with other
known small uncharged solutes like caffeine (0.001 cm·hꢀ1 vs. 7.2
cm·hꢀ1).48 Both the high chemical stability of MILꢀ127 and the
low ligand permeation rule out an important intestinal absorption
of the MILꢀ127, preventing any severe toxicity associated with its
accumulation within the body.
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Journal of the American Chemical Society
Poisoning in the Developing World. QJM 2000, 93, 715–731.
Table 2. Diffusion flux (F) and permeability coefficient parameter of
the membrane (P)
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Graham, L. M.; Nguyen, T. M.; Lee, S. B. Nanodetoxification:
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Watson, W. A.; Cremer, K. F.; Chapman, J. A. Gastrointestinal
Obstruction Associated With MultipleꢀDose Activated Charcoal.
J. Emerg. Med. 1986, 4, 401–407.
1
2
3
4
Jejunum
Ileum
MILꢀ127
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H4TazBz
MILꢀ127
0.05
H4TazBz
1.12
F (µg·cmꢀ2·hꢀ1)
Papp (cm·hꢀ1)
1.05
0.04
5
6
7
8
9
0.0014
0.0013
0.0010
0.0011
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Neuvonen, P. J.; Olkkola, K. T. Oral Activated Charcoal in the
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Furthermore, the viability of the intestinal membrane was
checked by measuring the transepithelial resistance (TEER),
which is accepted as good model for determining the membrane
integrity after the transport of chemicals.49 For this purpose, upon
the intestinal bypass of the MILꢀ127 and H4TazBz, the conductivꢀ
ity of this polarized membrane was studied via the modulation of
the ion channels (SI, Figure S19). The response of the membrane
to the addition of forskolin or biotin, which modifies the voltageꢀ
dependent K+ of a healthy membrane, supports the lack of toxicity
of both, MOF and H4TazBz ligand.
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CONCLUSIONS. In conclusion, MILꢀ127, combining an exꢀ
ceptional GI stability and an important drug adsorbent capacity, is
a promising safe and efficient oral detoxification treatment. Upon
a salicylate overdose, MILꢀ127 is able to drastically reduced more
than 40 times its intestinal absorption (decreasing a third the ASA
concentration in blood), avoiding associated histological damages.
In addition, except for a minor GI degradation (< 9%) and subseꢀ
quent slight iron absorption in duodenum and jejunum, the integꢀ
rity of MILꢀ127 was preserved along the GI tract, being excreted
by feces without any sign of severe toxicity. Further biodistribuꢀ
tion studies demonstrated a lack of intestinal absorption of MILꢀ
127, due to its large particle size, high structural and chemical
stability and poor intestinal permeation of both MILꢀ127 and its
constitutive ligand. These results open fascinating perspectives for
the safe and efficient treatment of poisoning and accidental intoxꢀ
ications using biocompatible MOFs.
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A Review of the Recent
Advances in the Field of Organic Pollutants Removal and
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Wang, B.; Lv, X. L.; Feng, D.; Xie, L. H.; Zhang, J.; Li, M.;
Xie, Y.; Li, J. R.; Zhou, H. C. Highly Stable Zr(IV)ꢀBased
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Zeng, T.; Zhang, X.; Wang, S.; Niu, H.; Cai, Y. Spatial
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SimonꢀYarza, T.; GiménezꢀMarqués, M.; Mrimi, R.; Mielcarek,
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Wu, M. X.; Yang, Y. W. Metal–Organic Framework (MOF)ꢀ
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Asensio, M. C.; Salles, F.; Lozano, M. V.; Guillevic, M.;
SimónꢀVázquez, R.; GonzálezꢀFernández, A.; Serre, C.; Alonso,
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information provides full details of the synthetic
procedures, biological simulated media, stability studies (PXRD,
FTIR, N2 sorption measurements), HPLC determinations, in vitro
tests, in vivo biodistribution and ex vivo intestinal permeation
studies.
AUTHOR INFORMATION
Corresponding Author
*patricia.horcajada@imdea.org
ACKNOWLEDGMENT
This works was supported by UniverSud Paris (ref: 2010–25) and
CNRS/DGRST ref: 24432) projects. SR and PH acknowledge the
Marie SklodowskaꢀCurie Programme (MSCAꢀIFꢀEFꢀSTꢀ2015ꢀ
705529). PH acknowledges the Spanish Ramón y Cajal Proꢀ
gramme (grant agreement no. 2014ꢀ16823) and the People Proꢀ
gramme (Marie Curie Actions) of the European Union’s Seventh
Framework Programme (FP7/2007ꢀ2013) under REA grant
agreement no. 291803. Authors would like to acknowledge Laura
García for the ICPꢀOES characterizations, Carine Livage for the
FEGꢀSEM observations and Carmen Sanchez for the cover art
design.
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Drug overdose
Detoxification
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MILꢀ127(Fe)
In vivo experiments
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Poisoning and accidental intoxication via ingestion is a major worldwide public health problem that causes
both a significant cost and severe health problems, even death. In this study, we pioneering target the oral
detoxification of drugs using a single biocompatible MOF.
81x41mm (150 x 150 DPI)
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