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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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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 on the diffusion rate, drug–matrix interactions and the kinetics
iron and the therapeutically active linker nicotinic acid, with of degradation of the matrix. This method thus strongly
pellagra-curative, vasodilating, and antilipemic properties, has depends on the loading capacity of the solid, its pore size
Published on 13 May 2010. Downloaded by INSERM on 12/08/2016 16:07:11.

been isolated and characterised via single crystal methods. The and volume, the kinetics of release, function of the interactions
release of the therapeutic agent, which is a constituent of the and diffusion processes. In addition, the degradation of the
framework, is achieved through the degradation of the hybrid matrix leads to the release of the linker with additional toxicity
phase, under simulated physiological conditions, allowing for the issues. An alternative approach, not described before, would
delivery of the bioactive molecule. consist of the direct coupling of a bioactive molecule to a metal
to build up a MOF within which the linker is the active
Metal Organic Frameworks (MOFs) have generated intense molecule. This would avoid the necessity for the large pore
interest owing to their potential application in catalysis, thin sizes and volumes required to achieve high drug loadings while
films, adsorption of gases (CH4, CO2, H2) and separation.1 the release of the biomolecule is achieved through the bio-
Another avenue now being explored is the use of MOFs for degradation of the material, with no side effects due to the
biomedical applications.2 Our group has shown that MOFs release of a non bioactive linker. Here we report the synthesis
can be used as drug controlled delivery systems.2 Morris et al. and characterisation of the first therapeutically active MOFs,
have meanwhile reported the delivery of bioactive gas molecules based on non-toxic iron (LD50 = 30 g kg1)14 and nicotinic
such as NO from MOFs as an antithrombosis and vasodilation acid (pyridine-3-carboxylic acid, called also niacin or
agent.4 Lin and coworkers proposed the use of Ln or Mn vitamin B3).15 Nicotinic acid is an endogenous acid with
carboxylate based nanoparticles as imaging agents.5–7 Most of pellagra-curative, vasodilating and antilipemic properties,
these MOFs, however, are based on toxic metals (i.e. Co, Ni, which lowers the total cholesterol, LDL-cholesterol, and
Cr, Gd. . .) and/or linkers. Consequently, there is a need to triglyceride levels, while raising HDL-cholesterol levels. MOFs
obtain biocompatible MOFs for medical applications and also based on nicotinic acid have been reported previously but
for other potential applications involving environmental using toxic cations, ruling out investigation into any biological
safety policies and societal concerns. Several examples of functionality.16–21 Finally, the delivery of nicotinic acid is
‘‘bioinspired’’ MOFs based on non-toxic endogenous linkers analysed as a function of the degradation of the framework.
have been reported to date. For instance, Mantion et al.8 have The structure of BioMIL-1 comprises a three-dimensionally
described Cu2+ or Ca2+ peptide frameworks built from a connected framework built up from trimeric Fe3N3O13 units
chiral oligovalin derivative. An et al.9 proposed the adsorption linked together via nicotinate molecules (Fig. 1).z
and delivery of a cationic drug (procainamide) from the The trimer building unit, i.e. three iron octahedra shared by
cationic zinc adeninate with nevertheless the presence of the m3-O, is reminiscent of that of the iron(III) acetate precursor,
exogenous linker 4,4 0 -biphenyldicarboxylic acid as part of the with an exchange of the acetate anions by nicotinates as
framework. Our group has reported previously an iron based evidenced previously for MIL-88A and MIL-89 solids.10 The
MOF based on a fumarate endogenous linker.10,11 Recently, trimeric unit however differs slightly from that observed in
this approach was further extended by the use of in vivo non other reported hybrid materials, i.e. MIL-100, MIL-10122 and
toxic biodegradable porous iron carboxylates nanocarriers, as the MIL88 series10 as there is no terminal water molecule
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 Fig. 1 Projection down [001] of BioMIL-1. Iron octahedra, oxygen,
details. CCDC 775194. For ESI and crystallographic data in CIF or carbon and nitrogen are in orange, red, grey and blue, respectively.
other electronic format see DOI: 10.1039/c001181a Hydrogen atoms have been omitted for clarity.

4526 | Chem. Commun., 2010, 46, 4526–4528 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.

This journal is 
c The Royal Society of Chemistry 2010 Chem. Commun., 2010, 46, 4526–4528 | 4527
 View Article Online

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4528 | Chem. Commun., 2010, 46, 4526–4528 This journal is 

c The Royal Society of Chemistry 2010

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