Cytotoxicity of nanoscaled metal–organic
frameworks†
Cristina Tamames-Tabar,‡
ab
Denise Cunha,‡
a
Edurne Imbuluzqueta,‡
b
Florence Ragon,
a
Christian Serre,
a
Mar
´
ıa J. Blanco-Prieto§
*
b
and Patricia Horcajada§
*
a
A series of fourteen porous Metal–Organic Frameworks (MOFs) with different compositions (Fe, Zn, and Zr;
carboxylates or imidazolates) and structures have been successfully synthesised at the nanoscale and fully
characterised by XRPD, FTIR, TGA, N
2
porosimetry, TEM, DLS and z-potential. Their toxicological
assessment was performed using two different cell lines: human epithelial cells from foetal cervical
carcinoma (HeLa) and murine macrophage cell line (J774). It appears that MOF nanoparticles (NPs)
exhibit low cytotoxicity, comparable to those of other commercialised nanoparticulate systems, the less
toxic being the Fe carboxylate and the more toxic being the zinc imidazolate NPs. The cytotoxicity
values, higher in J774 cells than in HeLa cells, are mainly function of their composition and cell
internalisation capacity. Finally, cell uptake of one of the most relevant Fe-MOF-NPs for drug
vectorisation has been investigated by confocal microscopy studies, and indicates a faster kinetics of cell
penetration within J774 compared to HeLa cells.
Introduction
Metal–Organic Frameworks or MOFs are still considered as
being a hot research topic in material chemistry
1
as illustrated
through their highly porous hybrid character built from inor-
ganic units and organic polycomplexing linkers. Their easily
tuneable structure, composition and porosity allow careful
switching of their physico-chemical properties. This huge
chemical and structural versatility makes them promising
candidates for main relevant applications such as gas storage,
separation, heat transformation, catalysis and sensing, among
others.
1,2
Recently, their use in biomedicine has been
proposed,
3
including contrast agents for imaging techniques
4
and the encapsulation for controlled delivery of molecules,
such as drugs,
5
cosmetics
6
and biologically active gases (NO,
H
2
S, etc.).
7
The control of MOF particle size in the nanometric range
8
has paved the way for their use in nanotechnology.
9
It is
noteworthy that nanoscale non-toxic porous iron(III)-based
MOFs with engineered cores and surfaces have been proposed
as nanocarriers for the controlled delivery of antitumoral and
anti-HIV drugs, with additional imaging properties.
9b,10
Also,
they enable the progressive release of the drug into the cells.
9b
However, prior to any bioapplication of MOF nanoparticles
(NPs), their toxicity has to be established.
11
Until now, the
available toxicity information remains very scarce, mostly
related either to the inorganic and organic precursors or in vitro
cytotoxicity studies.
12
For instance, Liu and co-workers have
reported values of the half maximal inhibitory concentration
(IC
50
) of 46 mg mL
1
for the silica-coated MIL-101_NH
2
-Br-
BODIPY NPs on human colon adenocarcinoma cells (HT-29).
13
However, both the uorophore moiety and the silica coating of
these NPs might also inuence their cytotoxicity.
10
Additionally,
the in vitro toxicity of lanthanide-based MOFs
14
was carried out
in human colon adenocarninoma (HT-29) and in acute
lymphoblastic leukaemia human cells, showing important
cytotoxicity values (IC
50
10 and 15 mg mL
1
, respectively) due
a priori to the linkers’ antitumoral own activity.
Finally, the only reported in vivo studies so far concern the
intravenous injection of high doses (up to 220 mg kg
1
) of three
porous iron(III) carboxylate NPs based on different organic
linkers. All the studied parameters (serum, enzymatic, histo-
logical, etc.) evidenced a lack of severe acute and subacute
(150 mg kg
1
for four consecutive days) toxicity. NPs were
rapidly captured by the liver and spleen and then, degraded into
their constitutive components (iron and carboxylate ligand),
allowing the direct removal in around 15 days of iron and
exogenous linkers by the urine and faeces without any
a
Institut Lavoisier, UMR CNRS 8180, Universit´ e de Versailles
Saint-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex,
France. E-mail: horcajada@chimie.uvsq.fr; Fax: +33 (0)139256652; Tel: +33 (0)1
39254371
b
Departamento de Farmacia y Tecnolog´ ıa Farmac´ eutica, Facultad de Farmacia,
Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain. E-mail: mjblanco@
unav.es; Fax: +34 948425649; Tel: +34 948425600 ext. 6519
† Electronic supplementary information (ESI) available: Synthesis of the
non-commercialised linkers, the MOF syntheses and the MOF characterisation.
See DOI: 10.1039/c3tb20832j
‡ These authors contributed equally to this work.
§ These authors are equal senior authors.
Cite this: J. Mater. Chem. B, 2014, 2,
262
Received 10th June 2013
Accepted 25th October 2013
DOI: 10.1039/c3tb20832j
www.rsc.org/MaterialsB
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