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Accepted Manuscript

Positioning metal-organic framework nanoparticles within the context of drug delivery


A comparison with mesoporous silica nanoparticles and dendrimers

Stefan Wuttke, Marjorie Lismont, Alberto Escudero, Bunyarat Rungtaweevoranit,


Wolfgang J. Parak

PII: S0142-9612(17)30039-X
DOI: 10.1016/j.biomaterials.2017.01.025
Reference: JBMT 17908

To appear in: Biomaterials

Please cite this article as: Stefan Wuttke, Marjorie Lismont, Alberto Escudero, Bunyarat
Rungtaweevoranit, Wolfgang J. Parak, Positioning metal-organic framework nanoparticles within
the context of drug delivery A comparison with mesoporous silica nanoparticles and dendrimers,
Biomaterials (2017), doi: 10.1016/j.biomaterials.2017.01.025

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Positioning metal-organic framework nanoparticles within the


context of drug delivery A comparison with mesoporous silica
nanoparticles and dendrimers

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Stefan Wuttke,*a Marjorie Lismont,b Alberto Escudero,c Bunyarat Rungtaweevoranit,d
Wolfgang J. Parak*ce

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a
Department of Chemistry and Center for NanoScience (CeNS), University of Munich (LMU), 81377 Munich, Germany.
b
GRASP-Biophotonics, Department of Physics, Universit de Lige, 4000 Lige, Belgium
c
Department of Physics, Philipps Universitt Marburg, 35032 Marburg, Germany.
d
Department of Chemistry, University of California-Berkeley, Berkeley National Laboratory,

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Kavli Energy NanoSciences Institute at Berkeley, Berkeley, California 94720, USA.
e
CIC Biomagune, San Sebastian, Spain.

Abstract

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Nanotechnology enables the creation of delivery vehicles able to overcome physiologically imposed barriers, allowing new approaches for

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reducing the unwanted side effects of systemic delivery of drug, increasing targeting efficiency and so improving therapy efficacy. Owing
to the considerable advances in material sciences and pharmaceutics, a broad range of different inorganic or organic drug nanocarriers
have been developed. Furthermore, researchers have shown that the combination of inorganic and organic chemistries in one single
material, named metal-organic framework (MOF), offers structural designability at the molecular level together with tunable porosity and
chemical functionalisability. While the MOF size can be controlled at the nanometer scale, these features are of paramount interest in the
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development of the next generation of drug delivery systems. After a short state-of-the-art about MOF technology and within the drug
delivery context, this paper discusses the benefits of using MOF nanoparticles compared to dendrimers and mesoporous silica
nanoparticles in order to understand the challenges that must still be overcome.
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Keywords: Metal-organic framework, mesoporous silica, dendrimer, nanocarrier, drug delivery.


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1. Introduction

In light of the increasing number of publications over the last decade, metal-organic frameworks (MOFs), also
known as porous coordination polymers, have emerged as a promising new class of porous materials. While their
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potential applications in various fields, ranging from gas storage to energy technologies including catalysis, have
been highlighted and reported in several articles and themed issues,[17] MOF materials, and in particular their
nanometric counterparts, still have to be discussed relative to other material classes in terms of their structure-to-
performance relationships. This perspective article thus aims at describing the benefits of using MOF nanoparticles
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(MOF NPs or nanoMOFs) in the field of biomedicine, and putting into perspective their properties in the context of
the ones of other NPs.
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The use of nanoparticles (NPs) relies on their properties that fundamentally differ from those of the
corresponding three-dimensional infinite solids.[8] These properties are size- and surface-dependent and start to
become significant at a length scale below 100 nm, which defines the arbitrary but scientific accepted definition of
nanomaterials and NPs in particular. The most important feature of NPs is their large external surface area, i.e. their
high surface-to-volume ratio, which dominates NPs physicochemical properties. As a consequence of an increased
number of surface atoms, NPs are typically highly chemically reactive, have a lower melting point in comparison to
the bulk material, and tend to form aggregates.[8] The NPs surface interface also drives the interactions of NPs with
their environment. This is a valuable property as the surface-interface can be engineered to improve chemical and
colloidal stability for targeting specific issues, as for example concomitant transport and delivery of bioactive
molecules, which are typical tasks defining the nanocarrier concept.[921] The different nanomaterial classes
developed to date can be categorized into NP either purely organic nanosystems including liposomes, dendrimers,
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micelles, and polymeric capsules, or purely inorganic NPs such as quantum dots, noble metal NPs, iron oxide NPs,
silica NPs and upconversion NPs.[911,18] In general inorganic NPs require an organic surface coating warranting
for colloidal stability, as in the context of biological media also inorganic NPs inevitable will comprise organic
molecules adsorbed to their surface.[8,22] MOF NPs or nanoMOFs define a new class of hybrid nanomaterials as
they consist of inorganic building units (e.g. metal oxide clusters) covalently connected by organic building units
(e.g. organic linkers) at the nanometer level.[2331] Hence, MOF NPs combine the richness of bulk MOF
chemistry with the beneficial surface- and size-dependent properties of the nanoworld (Figure 1). Bringing together

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both of these worlds leads to a flourishing interdisciplinary field of research based on the interconnection of
chemistry, physics, and material sciences, which can have diverse practical outcomes relevant to in various sectors
of applications and in particular in biomedicine.

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Figure 1. Combination between the MOF world (green) and the nanoparticle world (orange) to implement the generation of MOF nanoparticles (Nano
MOF, blue).
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2. Magic bullet concept and scope of the paper

The development of efficient drug delivery systems is an important topic of biomedical research in order to
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ensure a quicker and forceful therapeutic outcome. Whatever the administration route used to deliver the drug, i.e.
oral, nasal, skin, pulmonary or intravenous, drugs in general have to cross multiple biological barriers in order to
reach their intended site of action (Figure 2).[32,33] Furthermore, systemic drug administration suffers from
critical issues as poor solubility, limited stability, rapid drug metabolism and excretion, undesired side effects, and
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lack of selectivity that result in low drug bioavailability along with inefficient therapeutic results.[34,35] To
overcome those issues but also to control the rate and period of drug delivery while bearing in mind Paul Ehrlichs
magic bullet idea (Figure 2), researchers have made significant progress in the design and synthesis of nanoparticle-
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based drug delivery systems.[3640] However, efforts still need to be made to reach closer to the concept of the
ideal magic bullet, which could be defined as a nanometre-sized delivery platform capable of specifically targeting
diseased tissues, avoiding premature fragmentation and degradation, and facilitating the transfer of a higher drug
amount across the cell membrane (Figure 2).[16] This magic bullet may also include a triggered-release mechanism
allowing the spatial, temporal and dosage controls of drug release upon activation by one or more possible
stimuli.[15,16] Additionally, this ideal nanocarrier could possess the mean to track the drug accumulation in
targeted tissues and to evaluate therapeutic progresses through the use of different kind of imaging agent.[16,41,42]
To successfully achieve nanoparticle-based drug delivery that could reach pharmaceuticals market, the critical
considerations of a biodegradable and nontoxic nanocarrier, made of nontoxic components that are easily cleared
from the body after NP decomposition, must still be taken into account.[43,44] Last but not least, the NP-based
carrier has to be synthesized according to a robust and streamlined formulation process that should ensure high
reproducibility and allow for the ease of a scale-up production at the industrial level.
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Figure 2. Graphical illustration of the magic bullet concept
with its associated properties (upper left). Schematic
representation of the nanocarrier-based drug delivery
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pathway to cancer cells (upper and lower right). After
intravenous administration to a patient (upper right), the
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nanocarriers bind to the specific receptors overexpressed on
cancer cell membrane ((1), lower right); are internalized via
receptor-mediated endocytosis (2); after having escaped
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endosomes, release their cargo into the cytosol (3), which


ends up in the cell nucleus with high concentration (4).
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On the way of designing such a model magic bullet (or advanced NP-based carriers, researchers currently try to
overcome long-standing challenges that are the biocompatible and biodegradable characters of the carrier along
with its efficient and specific biodistribution throughout the body, the hydrophilic or hydrophobic nature of cargos
that should be vectorized, and the incorporation of on-demand and controlled drug release mechanism.[19,45]
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These challenges mainly depend on the structural attributes of NPs, i.e. size, shape, chemical composition, as well
as their physicochemical properties, i.e. surface charge and surface functional groups, colloidal and chemical
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stability. In this context, this paper is aimed at answering the following question: Are MOF NPs eligible as the
next generation of nanocarriers? By describing the beneficial inputs, i.e. structural and physicochemical, of MOF
NPs in comparison to the properties of two well-known delivery vehicles, namely polymeric dendrimers and
mesoporous silica NPs, which are to some extent similar to nanoMOFs from the structural point of view, we intend
to put into perspective what are the properties of MOF NPs that make them unique. For ease of reading, Table 1
summarizes the herein mentioned important properties of the three types of nanocarriers.

3. MOF nanoparticles as future nanocarriers

MOFs are hybrid materials constructed via strong metal-ligand covalent bonds between inorganic clusters and
organic linkers, which are organized in a periodic way to create porous and crystalline three-dimensional
framework (Figure 3).[5,6,46,47] In general, MOFs can be made of numerous metal ions of the periodic table,
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especially those that are di-, tri- or tetravalent and that form inorganic clusters during the synthesis (Figure 3).[48]
The organic linker, for its part, is preformed before initiating MOF synthesis and its geometry can be easily
changed in linear, triangular or square planar, for instance (Figure 3).[49] Therefore, the pore size and shape of
MOFs is defined by the geometry of both the inorganic clusters and the organic linkers as well as by their
connectivity.[50] The large diversity of inorganic and organic components has allowed for the synthesis of an
abundant number of different MOFs. Currently, the class of MOF material is represented by nearly 20,000 different
structures as reported in Cambridge structure database and studied during the two past decades.[46] Generally,

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MOF crystals are synthesized under either room temperature or solvothermal conditions (i.e. 100C < T < 250C).
A routine solvothermal recipe involves the addition of all the reactants (metal salts, ligands, and solvents) in one
step in sealed vessels followed by the heating, just below subcritical conditions, for some minutes, hours, or days
depending on the MOF type. The temperature is the fundamental parameter as it equilibrates the reacting system to

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allow the spontaneous self-assembly of ordered structures/lattices by enhancing the diffusion of reactants and
optimizing coordination interactions in a thermodynamically favourable way. The main used solvents, beside water,
are alcohols, dialkyl formamides, and pyridine. Although the microwave-assisted method has attracted attention for

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the synthesis of MOF in a quicker way as it speeds up the hydrothermal crystallization, it has rarely been applied to
the synthesis of bulk MOF and is rather best suited to the synthesis of MOF nanoparticles.[48,51]
The use of MOF materials for biomedical applications, and in particular as drug delivery nanovehicles, requires
MOFs to be scaled-down to the nanometer range. Researchers have thus developed different bottom-up approaches

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for MOF nanomaterials synthesis, which allow them to control their nucleation rate and crystallization, and limit
their growth to the nanoscale. These synthetic processes are based on spontaneous precipitation, reverse

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microemulsion and modulator techniques, which are performed under solvo-thermal, microwaves, or ultrasound
conditions.[2330,52] In this way, the controlled synthesis of well-defined MOF NPs has been demonstrated for
some specific MOF examples. However, dealing with the large variety of MOFs remains the main challenge in the
controlled synthesis of MOF NPs. Indeed, the use of different inorganic and organic building block units can
drastically change synthesis conditions. Therefore, the versatility of MOF chemistry should be managed in the
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context of establishing well-defined synthesis protocols, which are known for many other NPs classes. Amongst
them, polymeric dendrimers (Table 1), which are branched 3D structures composed of polymer repeating units
attached to an inner core and synthesized in a layer-by-layer fashion (expressed in generations),[53,54] and
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mesoporous silica NPs (MSNs) (Table 1), which are material derived from supramolecular assemblies of
surfactants that template the inorganic component,[55] are two established types of NPs currently implemented in
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drug delivery.[34,35,5357] While the first ones are similar and comparable to MOF NPs as they both exhibit
structural variety and are based on a symmetric Lego brick design approach, the second ones feature a tunable
porosity as MOF NPs.
The key feature of MOF NPs in comparison to their bulk counter materials is that their behavior is no longer
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exclusively determined by their inner surface only but also by their outer surface properties through their high
external surface-area-to-volume ratio.[5861] Most importantly, the outer surface needs to provide colloidal
stability in biological environments, which always involve the presence of ions, proteins, etc.[22]. Furthermore,
specific surface coatings can be used to improve the properties of NPs. Besides providing colloidal stability,
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coatings of the outer surface may comprise cell-targeting ligands for improving the biodistribution, as well as may
act as triggerable cap system enabling on-demand controlled release of cargo molecules. However, there is no
obvious feature in MOFs as compared to other NP classes that would suggest the use of completely new surface
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chemical functions. Therefore, surface functionalities anchored on NPs such as MSNs likely can be also applied to
MOF NPs and vice versa. As a consequence, the rest of this perspective paper is focused on the inner rather than
the outer surface of MOFs NPs, as their inner surface gives them properties significantly different to the ones of
other porous NP classes.
In the field of drug delivery, the use of porous nanomaterials has the advantage of confining particle-medicine
interactions to the interior of the particle, while the exterior of the particle deals with the physiological interactions
and global targeting.[45] Through their structures, all three types of the herein cited NPs decouple the drug-particle
and particle-physiological interactions. Even so, the high porosity of MOF materials stands out from the two other
kinds of NPs. Indeed, the near absence of dead volume in MOFs leads to high porosities with ultra-high available
BET (Brunauer, Emmett and Teller) surface area ranging from 1000 to 7000 m2/g [46,6269] namely 6 times
higher than BET surface of MSNs, which ranges from 700 to 1200 m2/g.[55] Therefore, the high porosity of MOF
materials makes them suitable for the implementation of non-covalent carrier vehicles as they should allow the
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entrapment of higher amount of biologically active molecules within their pores.[7074] However, critical issues to
achieve the entrapment of larger molecules into the matrix are the MOF pore diameter and aperture, which are
typically in the range of 0.3 to 5 nm and up to 0.3 to 2 nm, respectively.[46,75,76] This last value makes MSNs
prevail over MOF NPs because MSNs may have larger pore aperture up to 20 nm with a pore size from 2 up to 50
nm.[7780] Nevertheless, in the last years, extensive work has been done to develop MOF scaffolds with extended
structure and thus larger pores. It has been demonstrated that the systematic expansion of the MOF-74 structure,
from its original link of one phenylene ring to eleven rings, allowed for reaching pore apertures between 1.4 and 9.8
nm, themselves allowing for the inclusion of biomolecules ranging from vitamins to proteins.[75] This systematic

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approach, consisting in varying the organic linker length of MOF structure without changing its underlying
topology, is called isoreticular expansion (Figure 3).[50] The challenge of the implementation of this chemical
approach to build MOF NPs relies on the demanding synthesis of extended organic linkers together with solubility
issues, making MOF NPs syntheses expensive and thus decreasing their industrial applicability and economic

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feasibility. Moreover, the low solubility of the organic linker results in a poor biodegradability and consequently,
leads to a higher toxicity. The use of available bio-linkers, as will be discussed later in more detail, is one possible
answer to this challenge. Other solutions could be the increase of the metal vertex size, as demonstrated by using
bioMOF-100, or the induction of MOF biomimetic mineralization, a biologically induced/promoted self-assembly

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process.[9698] In the latter case and under physiological conditions, biomacromolecules such as proteins, DNA,
enzymes, efficiently induce MOF formation and regulate the crystal size, morphology, and crystallinity while being
encapsulated within the framework. Recently, biomineralized HKUST-1 and MIL-88A MOF have demonstrated a
remarkable protective capacity of the encapsulated enzymes activity by far superior to the MSNs one after the

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exposure to extreme conditions.[98]

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Table 1. Summary of the typical properties of dendrimers (D), mesoporous silica NPs (MSN) and MOF NPs. (-) stands for no relevant

data, ( ) stands for yes, (~) stands for needs to be improved and () stands for no. (#) Figure reproduced from ref [193].
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Besides the high loading capacities ensured by the NPs large inner surface area, the precise and selective
chemical modification of the internal pore system is another key point in the achievement of an effective drug
delivery system. This one allows for controlling the host (nanocarrier) guest (drug) interaction, itself driving the
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diffusional transport, delivery kinetics and stability of the drug.[99] Dendrimers and MSNs mainly display
hydrophobic pore cavities.[57,90] This limits the physical encapsulation, i.e. loading process, to hydrophobic
molecules only if no additional internal modification of the NPs is achieved. However, by carefully selecting the
organic linker involved in the synthesis of MOF NPs, these ones may have either hydrophobic or hydrophilic pore
cavities,[70,72] therefore enlarging the panel of cargo molecules that can be integrated in and transported by the
nanovehicle. Drug loading in dendrimers, achieved through adsorption or conjugation, is limited due, amongst
others things, to their small size ranging from 1 to 10 nm and thus most of dendrimers suffer from low drug-to-
dendrimer ratios.[54,56,57] Higher loading capacities have been reported for MSNs and MOF NPs, which result
from bigger NPs size and larger pore volumes, around 2 cm3/g in both cases, obtained by changing the length of the
templating surfactant[55] or the length of the organic linker used in MSNs and MOF NPs synthesis, respectively.
Besides the adsorption through electrostatic interactions or hydrogen bonds, drugs may also be covalently
incorporated in these nanocarriers using co-condensation process for MSNs, pre-functionalized organic linkers for
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MOF NPs, and post-synthetic covalent grafting methods for both MSNs and MOF NPs.[16,100102] In contrast to
the two first approaches that allow guest molecules one-pot incorporation[103,104] while the particles are forming,
post-synthetic modifications (PSMs) take place after the formation of the material. The pore surface designability of
MOF materials includes the use of organic linkers that are pre-functionalized with various small organic groups, as
-NH2, -OH, -Cl, -Br, or -N3 for example, that serve as anchoring points for further covalent attachment of cargo
molecules (Figure 3).[100,105107] While this approach targets the organic part of the MOF scaffold, one may also
consider the use of the coordinatively unsaturated metal sites (CUSs) as functionalization points.[108] This strategy
relies on Lewis acid-base interactions, where CUSs of the MOF are the Lewis acid sites while functional molecules,
containing chelating agents or electron rich molecules, serve as Lewis bases (Figure 3). Finally, MOF chemistry

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still offers the possibility of building block substitution, which involves the replacement of the organic or inorganic
structural components of the MOF via organic linker or ions exchange (i.e. transmetalation, Figure 3).[109111]
While PSM of MSNs is limited to silanol chemistry to introduce the functional groups to the exposed silica surface,
the richness of available organic functional groups combined with the presence of accessible CUSs or the exchange

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of linkers or ions enlarge the possibilities of pore surface designability compared to the two other NPs classes.
Although a large variety of therapeutic agents, as ibuprofen, doxorubicin, busulfan, caffeine, azidothymidine
triphosphate, cisplatin, etc. have already been covalently or non-covalently encapsulated within NMOFs[70,112

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116] and for some of them inside dendrimers[54,81,117] and MSNs as well,[55,118,119] a deep comparison of the
resulting loading capacities is delicate as these ones depend strongly on the physicochemical properties of the
nanocarrier (i.e. NPs size, pore size and morphology, pore surface chemistry, and the available surface area), on the
drug nature (i.e. hydrophobic, hydrophilic, or amphiphilic), on the drug containing solvent, and on the

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encapsulation process. All these parameters should be taken into account to establish loading capacity and
efficiency, the calculation and the unit of which requiring to be standardized to allow accurate and relevant
comparison.
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For an optimal nanocarrier, a high drug loading is not a necessary and sufficient condition to guarantee an
effective therapeutic outcome but an on-demand triggerable drug release is required to precisely control drug
release profile in terms of timing, duration, and magnitude.[12,15,120,121] Indeed, depending on drug properties,
especially its polarity and its circulation as well as on the degradation rate of the cargo itself, weak physical
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interactions between the drug and the pore surface may be not enough to ensure that the drug is not prematurely
released before reaching its site of action.[83] The design of stimuli responsive nanosystems that recognize their
environment and react in a dynamic way has been widely investigated over the last years to better control drug
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release, avoid premature release and burst effect (i.e. important drug release within the first minutes). There are two
main approaches to achieve stimuli-responsive-based triggerable drug release: covalent linking of the drug to the
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pore surface through cleavable bonds or functionalization of the nanocarrier external surface using sheddable
coatings,[122] as cap system (i.e. lipid bilayer, polymer, oligonucleotides) or pore gating systems (i.e. protein, iron
oxide NPs, Au NPs).[16,35] Various similar external and internal stimuli such as temperature, pH, solvent polarity,
molecular recognition, electric and magnetic field, and light, have been reported for triggered drug release with
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dendrimers,[123125] MSNs,[16,35,83,89,118] and MOF NPs.[126129] In any case, different release profiles
were observed depending on the drug type, the drug diffusion rate, the nature of the host-guest interaction, and the
material kinetics degradation. Therefore, nanocarriers should subsequently be designed for a particular disease, i.e.
a given drug molecule, and the host-guest interaction should be adjusted for desired drug loading and release
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properties to achieve an optimal therapy outcome.[25,130] The only advantage of NMOF compared to MSNs and
dendrimers for the design of stimuli-responsive drug delivery relies on the large tailorability of MOF scaffold-guest
interaction, resulting from the huge number of available MOF structures and the versatility of MOF chemical
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functionalization approach (Figure 3), which could greatly enlarge in the future the range of encapsulated drugs, i.e.
hydrophilic and amphiphilic drugs that require further functionalizations for MSNs and dendrimers.
Additionally to the drug encapsulation, this PSM of the nanocarrier internal pore system offers the possibility to
incorporate additional labels, e.g. fluorescent dye or imaging contrast agents,[131,132] which help to localize the
nanocarrier and to evaluate its therapeutic effect and in this way, to develop multifunctional MOF NPs. Besides
drug delivery NPs capability and in order to study drug biodistribution, therapeutic outcome, and NPs fate, imaging
modalities are required. The integration of these ones in the design of MOF NPs can be achieved with all labels
commonly used for other NPs classes: fluorescent, magnetic or radioactive agents. However, the specific advantage
of the MOF class is the feasibility of synthesizing MOF that integrates the imaging label within its own scaffold by
selecting paramagnetic metallic building unit that will act as contrast agent for magnetic resonance imaging (MRI).
This approach was successfully illustrated by the synthesis of Gd(III) [133136] and Fe(III) [70,137] MOF NPs,
which have been used for imaging their MRI relaxivity in biological fluids. This ability of NMOF to be functional
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due to its construction leaves more space for drug loading and eventually removes one further labelling step
compared to MSNs[55,101,138] and dendrimers.[139141]
Multifunctional MOF materials have recently been developed by introducing heterogeneity within order:[142]
Basically, the synthesis of MOFs, based on the use of an increasing number of building units, maintains the definite
order of the MOF backbone, while the distribution of the building units is disordered.[143147] By synthesizing
MOF-5 type structures, containing up to eight distinct functionalities, it has been demonstrated that the whole is
greater than the sum of the part. For example, one of these MOF-5 exhibits up to 400 % higher selectivity for gas
separation compared to their monofunctionalized counterparts.[147] This provides more tangible evidence that
MOFs offer numerous functionalization strategies allowing for tuning their internal surface properties along with

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molecular framework host-guest interactions. This may also be controlled by the flexibility that breathing MOFs
display, also called soft porous crystals or flexible MOFs.[59,61,93,148150] Without losing the underlying
crystalline order, these MOFs are able to change their structure, most of the time through adsorption or desorption
of the guest. The interaction of the guest molecule with the matrix, in place of diffusion processes, mainly governs

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drug-releasing profiles, which can last over days. It is worth mentioning that using this type of MOFs can reduce
burst release behavior and consequently makes MOFs suitable as storage vehicles that would be potentially able to
deliver drugs over days.[25,27]

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Figure 3. Schematic drawings of the different modification approaches used to endow a MOF with additional functionality. These approaches can be
classified in two main concepts: in the first one, at least one building block is modified before MOF synthesis (left), while in the second approach, the
structure is synthesized first and then subjected to further post-synthetic modifications (PSM, right).

As a result of the periodic arrangement of connected organic and inorganic parts, MOFs are crystalline
materials, a major feature that do not exhibit their amorphous homologues, the so-called nanoscale coordination
polymers (NCPs). Even though, MOF crystallinity facilitates the material characterization by use of X-ray
diffraction technique,[151] one may debate how much the detailed knowledge of the exact positions of the building
units is advantageous for their potential use as carriers in drug delivery. In light of MOF industrial applicability as
drug delivery systems, this property may be highly useful concerning quality control. In addition, the symmetrical
arrangement of the building blocks certifies well-ordered pores with well-defined size, while in the case of MSNs
random pore size distributions, i.e. disordered or worm-like, are often observed especially as the pore diameter
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becomes larger. Therefore, the production of crystalline MOF structures could potentially allow better reproducible
drug loading and release profiles than MSNs and dendrimers.
In regard to biological applications, a critical consideration is that the nanoformulation does not impose any
health risks as such the NPs should be constructed with intrinsically nontoxic building blocks.[152] Still, even if
NPs are made of biocompatible, i.e. intrinsically nontoxic, building units, it does not necessarily mean that they are
per se nontoxic.[22,43,44,153155] Potential toxicity may originate from the particulate nature of the NPs, which
could for example open up different entry portals for the material into cell or may cause catalytic effects due to the
increased surface-to-volume ratio, in other words due to the highest amount of reachable surface atoms.[8] This
toxicity is not related to intrinsic toxicity of the building blocks that composed the material. MSNs are known for

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their relatively good biocompatibility and in particular it has also been shown that bare MSNs, featuring silanol
groups at their surface, dissolve fairly rapidly under physiological conditions and produce soluble silicic acid
species, which were found to be nontoxic.[35] Regarding dendrimers, their cationic derivatives are in general less
biocompatible than their anionic counterparts.[54] Moreover, dendrimers of lower generation would be relatively

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more biocompatible than higher generation ones.[54] In the case of MOF, researchers have tried to select metal ions
and organic linker building blocks that are known for their low toxicity to achieve better biocompatibility. MOFs
assembled from biocompatible building units define a subgroup in MOF family known as BioMOFs or MBioFs

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(Metal-biomolecule frameworks).[94,95] Some interesting BioMOFs or MBioFs have already been reported in
literature. For example, the engineered Bio-MIL-series (MIL standing for Materials of Institute Lavoisier) is well-
known.[95,156,157] A zinc-adeninate building unit was used to develop the Bio-MOF-100 structure.[96] The
spherical ferritin proteins have been used as nodes in the framework.[158] MOFs have also been made with Mg(II)

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or Ca(II) as metal clusters, which are linked by neutral bridging ligand.[159] These examples are just some amongst
many others, about which deeper information can be found in reviews.[25,43,160,161] Over the two last decades,

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nanosafety research has emphasized that NPs cytotoxicity could not be only reduced to their individual
physicochemical properties, such as chemical composition and stability, colloidal stability, size, shape, and surface
charge nor to the interaction with their biological environment through the formation of adsorbed biomolecules
layer (i.e. protein corona) when coming in contact with complex fluids as blood. These properties are closely
interconnected and should be taken as a whole, specific to each NP formulation, which therefore requires
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systematic and reliable in vitro and in vivo studies as soon as NPs toxicity is concerned. As those experiments are
time and money consuming before achieving statistically relevant and reliable results, each NP class community
explores, in a stepwise way, different toxicological aspects for various NP formulations of their class. This makes
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the comparison between NP classes (i.e. MOF NPs, MSNs, and dendrimers) and between nanocarriers in the same
class (i.e. two different MOF NPs) quiet delicate. Concerning MOF NPs, first in vitro results, obtained for several
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MOF NP formulations, attest them a low cytotoxicity.[126,162,163,103,164] So far, the evaluation of the in vivo
toxicity has been focused on iron-based MOF NPs that degrade after some time into their building block units (i.e.
iron and organic linker), which are removed from the organism with no evidence of toxicological impact.[165,166]
Hopefully, the great variety of different building block units together with the various ways of changing the MOF
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NP individual physicochemical properties give MOF community a glimpse of generating ultimately low toxic
formulations.
Closely associated with the toxic impact of NPs is the question of their biodegradability. MOFs are by far less
stable then dendrimers and MSNs as most structures already decompose in contact with humidity. However, due to
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the huge variety of different MOF structures, with a huge spectrum of different chemical properties, some of them
are stable under aqueous conditions for a certain time or totally stable. The intrinsic instability of MOFs under
physiological conditions can be slowed down with external surface coatings[137,167] long enough to allow the
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nanocarrier for fulfilling his task before it degrades. This biodegradability has already been demonstrated in vivo
for iron based-MOFs.[165,166]
The next step in the improvement of versatile MOF chemistry would consist in using active pharmaceutical
molecules as building unit of the framework. Indeed, this kind of architecture would be valuable towards making
MOF NPs bioactive by themselves. In the development of such active BioMOFs, some structures have been
recently reported, such as the assembly of zinc ions with cis-platin and oxaliplatin bisphosphonate ligands[168] or
curcumin-based MOFs.[169] Another approach targets the incorporation of a NO functionality into the MOF
scaffold and the controlled release of this gaseous biomolecule.[170173] Very recently, the development of
photosensitive molecules-based MOF NPs (e.g. MOF containing a porphyrin-based linker) has moved towards
photodynamic therapy applications with so far promising biological outcomes.[174179] However, all these works
are still in their infancy and intensified efforts using this approach are expected in the future.
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Finally and from a structural point of view, the last requirement for NPs to be applicable in biomedical concerns
is that the nanovehicle, in the best case, should be stable until its task of delivery is fulfilled, meaning that their
structural intactness should be maintained to avoid molecules leaching until they reach the targeted site. After
having accomplished its task, it should decompose into its small and nontoxic building units, which can be cleared
out of the body, ensuring no long-term toxic effect. In addition to the good biocompatibility of MSNs, their high
thermal, chemical, and mechanical stabilities confer them a relatively low degradation rate,[89] which depends on
particles size, functionalization, and pore morphology as well as on the degree of silica condensation.[35]
Moreover, their colloidal stability under physiological conditions should still be improved while dendrimers are
comparatively stable in biological environment. Considering MOF NPs, their stability also strongly depends on

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their respective structure and so far, the chemical, structural, and colloidal stabilities[180,181] of only few
nanoMOFs have been recently investigated under biological relevant conditions.[25,27,70,88,168,182,183] The
decomposition of MOF NPs and the resulting long-term toxicity could be improved by building biodegradable
MOF NPs that could decompose into their biocompatible components. Complete removal of the MOFs NPs from

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the body would strongly help to reduce chronic toxicity. This gives a clear advantage over inorganic NPs, which
typically cannot be fully degraded to be small enough for renal excretion, though some partial degradation has been
reported.[184,185] However, also organic dendrimers may be designed from biodegradable materials and thus may

SC
go along the same strategy.[186] Generally speaking, the stability and toxicity of nanomaterials under physiological
conditions and in vivo are often neglected and more experimentations are needed to guarantee that the stability will
be maintained in living tissues.[89] This will obviously rely on the development of effective external surface
functionalization strategies,[85,88,182,183,187192] which will also be responsible for the efficient targeting of the

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nanocarrier along with its improved biodistribution.

4. Conclusion and outlook


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Taken all together, MOF NPs appear as a very promising drug delivery platform that still needs to be fully
exploited to get closer to the concept of a magic bullet with universally improved properties as compared to other
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NP classes used in drug delivery. Their key advantage is their hybrid nature relying on the synergistic combination
of inorganic and organic chemistry that allows very high porosities and the incorporation of a large variety of
functional groups. On one hand, their assembly from preformed molecular building blocks, similar to dendrimers,
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offers huge structural diversity. On the other hand, their porous nature, better defined than the one of MSNs,
facilitates reproducible loading and release of drugs, which may be also controlled by the composition of MOF
NPs. Due to the possibility of using biocompatible building blocks and degradable linkage allowing for
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decomposition into fragments small enough for renal excretion, MOF NPs likely may go ahead in obtaining more
biocompatible NPs, which would be a major advantage with respect to future clinical applications. However,
targeted delivery problems associated with other NP types may remain and should be also addressed in the future.
Degradation, stability and toxicity of MOF NPs should be considered as important parameters in their design
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optimization, bearing in mind that moving in one direction could solve a particular problem but may often lead to
another issue. Therefore, it is crucial to identify the right NP parameters for the intended indication, in other
words the key characteristics and critical components that dictate the performances of the nanosystem.[32] The
synthesis of nanoMOFs is beginning to be mastered, underlining the young age of this research field but also
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leaving plenty of room for new creative insights.


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Acknowledgements

Parts of this work were funded by the European Commission (project FutureNanoNeeds to WJP). SW is grateful
for financial support from the Deutsche Forschungsgemeinschaft (DFG) through DFG-project WU 622/4-1. ML is
grateful for the financial support of a Concerted Research Action from the University of Lige, Belgium (CRA2015
Project icFlow). Finally, the authors would like to thank Prof. Omar M. Yaghi (UC Berkeley) for his valuable
constructive comments.
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*Corresponding author: Tel.: stefan.wuttke@cup.lmu.de and wolfgang.parak@physik.uni-marburg.de

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