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Biodegradable therapeutic MOFs for the

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Article in Chemical Communications · July 2010

DOI: 10.1039/c001181a · Source: PubMed

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COMMUNICATION
Biodegradable therapeutic MOFs for the delivery of bioactive moleculesw
Stuart R. Miller,a Daniela Heurtaux,a Tarek Baati,a Patricia Horcajada,a
Jean-Marc Grenècheb and Christian Serre*a
Received 19th January 2010, Accepted 28th April 2010
First published as an Advance Article on the web 13th May 2010
DOI: 10.1039/c001181a
A new metal organic framework (MOF) built up from non-toxic
iron and the therapeutically active linker nicotinic acid, with
pellagra-curative, vasodilating, and antilipemic properties, has
Published on 13 May 2010. Downloaded by INSERM on 12/08/2016 16:07:11.
been isolated and characterised via single crystal methods. The
release of the therapeutic agent, which is a constituent of the
framework, is achieved through the degradation of the hybrid
phase, under simulated physiological conditions, allowing for the
delivery of the bioactive molecule.
Metal Organic Frameworks (MOFs) have generated intense
interest owing to their potential application in catalysis, thin
films, adsorption of gases (CH4, CO2, H2) and separation.1
Another avenue now being explored is the use of MOFs for
biomedical applications.2 Our group has shown that MOFs
can be used as drug controlled delivery systems.2 Morris et al.
have meanwhile reported the delivery of bioactive gas molecules
such as NO from MOFs as an antithrombosis and vasodilation
agent.4 Lin and coworkers proposed the use of Ln or Mn
carboxylate based nanoparticles as imaging agents.5–7 Most of
these MOFs, however, are based on toxic metals (i.e. Co, Ni,
Cr, Gd. . .) and/or linkers. Consequently, there is a need to
obtain biocompatible MOFs for medical applications and also
for other potential applications involving environmental
safety policies and societal concerns. Several examples of
‘‘bioinspired’’ MOFs based on non-toxic endogenous linkers
have been reported to date. For instance, Mantion et al.8 have
described Cu2+ or Ca2+ peptide frameworks built from a
chiral oligovalin derivative. An et al.9 proposed the adsorption
and delivery of a cationic drug (procainamide) from the
cationic zinc adeninate with nevertheless the presence of the
exogenous linker 4,4 0 -biphenyldicarboxylic acid as part of the
framework. Our group has reported previously an iron based
MOF based on a fumarate endogenous linker.10,11 Recently,
this approach was further extended by the use of in vivo non
toxic biodegradable porous iron carboxylates nanocarriers, as
a potential platform for drug delivery and imaging.12 Until
now, drug delivery in porous solids has been achieved through
the encapsulation by soaking of the porous solids in a solution
saturated with the drug.2–9,12,13 The release of the molecule is
thus achieved by desorption in the physiological medium
through an exchange with the aqueous phase and depends
a
Institut Lavoisier, UMR CNRS 8180, University of Versailles-St.
Quentin-en-Yvelines, 45, Avenue des Etats-Unis, 78035, Versailles,
France. E-mail: serre@chimie.uvsq.fr, horcajada@chimie.uvsq.fr
b
Laboratoire de Physique de l’Etat Condensé, UMR CNRS 6087,
Universite´ du Maine, F-72085 Le Mans Cedex 9, France
w Electronic supplementary information (ESI) available: Experimental
details. CCDC 775194. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c001181a
4526 | Chem. Commun., 2010, 46, 4526–4528
View Article Online / Journal Homepage / Table of Contents for this issue
www.rsc.org/chemcomm | ChemComm
on the diffusion rate, drug–matrix interactions and the kinetics
of degradation of the matrix. This method thus strongly
depends on the loading capacity of the solid, its pore size
and volume, the kinetics of release, function of the interactions
and diffusion processes. In addition, the degradation of the
matrix leads to the release of the linker with additional toxicity
issues. An alternative approach, not described before, would
consist of the direct coupling of a bioactive molecule to a metal
to build up a MOF within which the linker is the active
molecule. This would avoid the necessity for the large pore
sizes and volumes required to achieve high drug loadings while
the release of the biomolecule is achieved through the bio-
degradation of the material, with no side effects due to the
release of a non bioactive linker. Here we report the synthesis
and characterisation of the first therapeutically active MOFs,
based on non-toxic iron (LD50 = 30 g kg1)14 and nicotinic
acid (pyridine-3-carboxylic acid, called also niacin or
vitamin B3).15 Nicotinic acid is an endogenous acid with
pellagra-curative, vasodilating and antilipemic properties,
which lowers the total cholesterol, LDL-cholesterol, and
triglyceride levels, while raising HDL-cholesterol levels. MOFs
based on nicotinic acid have been reported previously but
using toxic cations, ruling out investigation into any biological
functionality.16–21 Finally, the delivery of nicotinic acid is
analysed as a function of the degradation of the framework.
The structure of BioMIL-1 comprises a three-dimensionally
connected framework built up from trimeric Fe3N3O13 units
linked together via nicotinate molecules (Fig. 1).z
The trimer building unit, i.e. three iron octahedra shared by
m3-O, is reminiscent of that of the iron(III) acetate precursor,
with an exchange of the acetate anions by nicotinates as
evidenced previously for MIL-88A and MIL-89 solids.10 The
trimeric unit however differs slightly from that observed in
other reported hybrid materials, i.e. MIL-100, MIL-10122 and
the MIL88 series10 as there is no terminal water molecule
Fig. 1 Projection down [001] of BioMIL-1. Iron octahedra, oxygen,
carbon and nitrogen are in orange, red, grey and blue, respectively.
Hydrogen atoms have been omitted for clarity.
This journal is 
c The Royal Society of Chemistry 2010
 View Article Online

present, it having been replaced by the nitrogen from the

nicotinate linker. One residual acetate group per trimer also
remains within the structure. Each iron trimer is thus coordinated
to one acetate group, eight nicotinate linkers with five of them
bonded to the trimer via the carboxylate terminus and the
three others via the nitrogen. Two of the five nicotinate linkers
are connected to the trimer via the carboxylate terminus only,
i.e. leaving the nitrogen terminus free. Projection down the
[100] crystallographic plane of BioMIL-1 shows that the
trimeric iron building units align into undulating chains
(Fig. S1w), connected to each other via nicotinate linkers.
The manner in which the framework arranges itself creates Fig. 2 Transmission Mössbauer spectra of BioMIL-1 recorded
at 77 K.
small cavities within the material which have a potential
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solvent area volume determined by PLATON of 782 Å3.23

71.5 wt%, which is even larger than the total amount of
However, negligible electron density attributable to included
drugs encapsulated in highly porous MOFs such as MIL-101
solvent molecules was observed by the single crystal diffraction
whereas 1.4 g of Ibuprofen ‘‘only’’ was loaded into 1 g of
measurement. IR and TGA coupled with mass spectroscopy
the porous hybrid solid (equivalent Ibuprofen content of
indicate that only free water molecules are present in the
58 wt%).2 Thus, our method would allow the administration
cavities (Fig. S2 and S5w).
of very low doses of the formulation. IR analysis of
Bond distances indicate a mixed valence iron within BioMIL-1
Fe2IIIFe1xIIIFexIIO1y(OH)y[O2C–C5H4N]5[O2CCH3] shows
(Table 1), in agreement with bond valence calculations which
that there is no residual solvent DMF within the material,
give values of 2.9, 3.08 and 2.54 for the iron sites.24
which is in agreement with the thermal analysis of the
To better understand the Fe neighbouring and to confirm
material.
the mixed valence state of BioMIL-1, 57Fe transmission
Finally, the biodegradable character of the as prepared
Mössbauer experiments were carried out on the pure solid as
material, under simulated physiological conditions (phosphate-
a function of temperature. As is illustrated in Fig. 2, BioMIL-1
buffered solution (PBS), pH = 7.4, 37 1C, bidimensional
or Fe2IIIFe1xIIIFexIIO(OH)y[O2C–C5H4N]5[O2CCH3] (x B 0.45)
stirring at 150 rpm) of BioMIL-1 was investigated. Degradation
exhibits a quadrupolar structure which has to be decomposed
of the solid leads to two equilibria in the solution. First, the
into two main components. They are unambiguously attributed
nicotinic linker is its deprotonated form (nicotinate) considering
to HS Fe3+ and HS Fe2+ species, according to their respective
the pKa of nicotinic acid (4.9). Thus, this allowed the
isomer shift values estimated at 0.51 and 1.21 mm s1 at 77 K.
quantification of nicotinate in solution by HPLC through
The complete deconvolution of the hyperfine structure was
the degradation process (Fig. 4; see SIw). The degradation of
established from a series of Mössbauer spectra recorded in situ
the material occurs in about an hour allowing a release of the
at different temperatures with the powdered sample located
nicotinic acid from BioMIL-1. Secondly, according to the
under vacuum in a home-made cryofurnace. This suggests the
chemistry of iron (Pourbaix diagram),25 iron(III) in PBS at
presence of five Fe sites, three attributed to different FeIII sites
pH 7.4 forms insoluble iron phosphates, which is further
and two assigned to FeII sites.
confirmed by X-ray powder diffraction and IR spectroscopy
Please note that their respective absorption areas, which
(see SIw). The fast degradation of BioMIL-1 is similar to the
depend slightly on temperature, make it possible to estimate
one observed for the iron terephthalate MIL-101(Fe) solid
the FeII content at about 15(2)%, which is in fair agreement
with a full degradation in two hours in PBS.26 Degradation
with the mean metal to oxygen bond distances observed for
over one week was however observed with the iron di- or
the material.
tri-carboxylate MIL-88A and MIL-100 solids. Thus, using the
Thermal gravimetric analysis of the material (Fig. S2w)
same metal sub-unit but changing the organic spacer or the
shows that the removal of the guest species occurs at
number of complexing groups per spacer changes drastically
150–200 1C while the departure of the nicotinate species from
the water stability.27
the framework occurs under oxygen atmosphere above ca.
300 1C. Thermal X-ray powder diffraction (XRPD) (Fig. 3)
confirms that the material remains crystalline up to 250 1C
and decomposes at higher temperature, in agreement with
the TGA data. There is a slight change in intensities of
the peaks in agreement with the departure of the occluded
free trapped water molecules. Noteworthily, the content
of active molecule (nicotinic acid) in BioMOF-1 reaches

Table 1 Mean Fe–O bond distances

Fe(1) Fe(2) Fe(3) Fig. 3 Thermal X-ray diffraction data under air atmosphere for
BioMIL-1 (lCo = 1.7906 Å). For clarity, X-ray diffraction patterns
Mean Fe–O bond length (Å) 2.05(2) 2.03(2) 2.11(3)
at each multiple of 50 1C are in red.

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c The Royal Society of Chemistry 2010 Chem. Commun., 2010, 46, 4526–4528 | 4527

Fig. 4 Release of nicotinic acid through the degradation of BioMIL-1
Published on 13 May 2010. Downloaded by INSERM on 12/08/2016 16:07:11.
under simulated physiological conditions (PBS pH = 7.4, 37 1C).
The hydrothermal stability of MOFs reflects the nature of
the metal (oxidation state, 3p or transition metal, coordination
number. . .) and the nature of the metal linker bond (M–O or
M–N). Finally, depending on the kinetics of release required
for each application and the nature of the active molecule, it
will be of crucial importance to choose the adequate inorganic
sub-unit to produce a bioactive MOF with a suitable stability.
A biodegradable MOF based on non toxic iron and a
bioactive molecule, i.e. nicotinic acid, has been used to
demonstrate a new method of drug delivery. The mixed
valence iron(II/III) trimers based MOF denoted by BioMIL-1,
composed of a highly active substance content of 75 wt%,
degrades rapidly under physiological conditions to achieve the
release of the biomolecule within a few hours. Although the
release of the therapeutic moiety is extremely quick, we
have successfully demonstrated the use of such a molecule
as an integral framework constituent in MOFs. As most
pharmaceutical drugs possess complexing functions (such as
carboxylates, phosphonates...) this paves the way for the
development of new drug delivery systems based on these
molecules and biocompatible metals.
Authors gratefully acknowledge the EU via the ERC-2007-
209241-BioMOFs for the funding, G. Férey for discussions
and E. Kemnitz for the TGA–mass spectroscopy experiments.
Notes and references
z Crystal data for Fe2IIIFe1xIIIFexIIO1y(OH)y-
[O2C–C5H4N]5[O2CCH3] (x B 0.15), M = 853.54 g mol1, mono-
clinic, space group P21/c, a = 11.064(2) Å, b = 21.464(4) Å,
c = 19.613(3) Å, b = 122.4791, V = 3929.1(12) Å3, Z = 4,
Dc = 1.095 mg m3, F(000) = 1297, T = 293(2) K, 1.61 o y o
29.71, 15 o h o 13, 17 o k o 29, 26 o l o 27, R1 = 0.103,
wR2 = 0.315 for 2737 reflections with Fo > 4s (Fo) and 480
parameters, highest residual e density, 1.43, deepest hole 0.95.
Intensity data from a crystal of dimensions 0.2  0.2  0.1 mm was
obtained on a Siemens SMART diffractometer equipped with a Mo
anode, a graphite monochromator and a CCD camera detector. The
data reduction was performed with SAINT; the absorption correction
was performed with the SADABS software.28 All structures were
4528 | Chem. Commun., 2010, 46, 4526–4528
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solved and refined by full-matrix least-squares techniques, based on
F2, using the SHELX software package.29.
1 (a) G. Férey, Hybrid porous solids: past, present, future, Chem.
Soc. Rev., 2008, 37, 191; (b) Themed issue: Metal–organic frame-
works, Chem. Soc. Rev., 2009, 38, 1201.
2 P. Horcajada, C. Serre, M. Vallet-Regi, M. Sebban, F. Taulelle and
G. Férey, Angew. Chem., Int. Ed., 2006, 45, 5974; P. Horcajada,
C. Serre, G. Maurin, N. A. Ramsahye, F. Balas, M. Vallet-Regi,
M. Sebban, F. Taulelle and G. Férey, J. Am. Chem. Soc., 2008,
130, 6774.
3 N. J. Hinks, A. C. McKinlay, B. Xiao, P. S. Wheatley and
R. E. Morris, Microporous Mesoporous Mater., 2010, 129, 330.
4 W. J. Rieter, K. M. L. Taylor, H. An and W. Lin, J. Am. Chem.
Soc., 2006, 128, 9024.
5 K. M. L. Taylor, A. Jin and W. Lin, Angew. Chem., Int. Ed., 2008,
47, 7722.
6 K. M. L. Taylor, A. Jin and W. Lin, J. Am. Chem. Soc., 2008, 130,
14358.
7 A. Mantion, L. Massu, P. Rabu, C. Palivan, L. B. McCusker and
A. Taubert, J. Am. Chem. Soc., 2008, 130, 2517.
8 J. An, S. J. Geib and N. L. Rosi, J. Am. Chem. Soc., 2009, 131, 8376.
9 C. Serre, F. Millange, S. Surblé and G. Férey, Angew. Chem.,
Int. Ed., 2004, 43, 6285.
10 S. Surblé, C. Serre, C. Mellot-Draznieks, F. Millange and
G. Feréy, Chem. Commun., 2006, 284.
11 M. Vallet-Regı́, F. Balas and D. Arcos, Angew. Chem., Int. Ed.,
2007, 46, 7548.
12 P. Horcajada, T. Chalati, C. Serre, B. Gillet, C. Sebrie, T. Baati,
J. F. Eubank, D. Heurtaux, P. Clayette, C. Kreuz, J.-S. Chang,
Y. K. Hwang, V. Marsaud, P.-N. Bories, L. Cynober, S. Gil,
G. Férey and P. Couvreur, Nat. Mater., 2010, 9, 172.
13 H. Zhang, Y. Kim and P. K. Dutta, Microporous Mesoporous
Mater., 2006, 88, 312.
14 P. Horcajada, C. Serre, G. Maurin, N. A. Ramsahye, F. Balas,
M. Vallet-Regi, M. Sabban, F. Taulelle and G. Férey, J. Am.
Chem. Soc., 2008, 130, 6774.
15 M. Knip and W. P. Moore, Diabetologia, 2000, 43, 1337.
16 J. Y. Yu and E. Kohler, Inorg. Chem. Commun., 2002, 8, 600.
17 J. Lou, F. Jiang, R. Wang, L. Han, Z. Lin, R. Cao and M. Hong,
J. Mol. Struct., 2004, 1–3, 211.
18 W.-J. Feng, G.-P. Zhou, X.-F. Zheng, Y.-G. Liu and Y. Xu, Acta
Crystallogr., Sect. E: Struct. Rep. Online, 2006, 62, m2033–2035.
19 Y. S. Song, Y. Bing and Z. X. Chen, J. Solid State Chem., 2006,
179, 4037.
20 J. Y. Lu and A. M. Babb, Inorg. Chem. Commun., 2001, 4, 716.
21 C. T. Dziobkowski, T. J. Wrobleski and D. B. Brown, Inorg.
Chem., 1982, 21, 671.
22 G. Férey, C. Serre, C. Mellot-Draznieks, F. Millange, S. Surblé,
J. Dutour and I. Margiolaki, Angew. Chem., Int. Ed., 2004, 43, 6296.
23 A. L. Spek, J. Appl. Crystallogr., 2003, 36, 7.
24 N. E. Brese and M. O’Keeffe, Acta Crystallogr., Sect. B: Struct.
Sci., 1991, 47, 192.
25 M. Pourbaix, Atlas of Electrochemical Equilibria in Aqueous
Solutions, National Association of Corrosion Engineers, Houston,
Tex., 2nd English edn, 1974.
26 K. M. L. Taylor-Pashow, J. D. Rocca, Z. Xie, S. Tran and W. Lin,
J. Am. Chem. Soc., 2009, 131, 14261.
27 J. J. Low, A. I. Benin, P. Jakubczak, J. F. Abrahamian,
S. A. Faheem and R. R. Willis, J. Am. Chem. Soc., 2009, 131,
15834.
28 Bruker, SADABS SAINT and SMART, Bruker AXS Inc,
Madison, Wisconsin, USA, 2002.
29 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr.,
2008, 64, 112.
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c The Royal Society of Chemistry 2010