Metal organic framework(MOF)

Metal organic framework(MOF)
2/19/2019 1HOLLOW METAL–ORGANIC-FRAMEWORK MICRO/NANOSTRUCTURES
Presented by:
Khatereh zarkesh
Phd student of pharmaceutics

Preparation of Hollow MOF
1. Exterior-Template Method
Commonly consists of three processes:
1) synthesis of the template,
2) MOF shell cladding,
3) template removal.
the first exteriortemplate method to fabricate hollow-structured ZIF-8
(ZIF: zeolitic imidazolate framework) by using carboxylate-terminated polystyrene (PS) spheres
as the template.

carboxylate-terminated PS spheres were synthesized with a uniform diameter. Subsequent addition of
the PS spheres into a mixture solution containing 2-methylimidazole and Zn(NO3)2 quickly resulted in
formation of ZIF-8 shells on the surfaces of the PS spheres. To further increase the shell thickness, the
second growth was conducted by using fresh ZIF-8 precursor solution. When the ZIF-8 shell was thick
enough, the synthesized PS@ZIF-8 core–shell microspheres were immersed in
N,N′-dimethylformamide (DMF) solution to remove the PS templates, and hollow-structured ZIF-8 was
prepared.

The silica shells were first coated on the surface of Au NPs to form Au NP@silica
core–shell structures. Subsequent growth of ZIF-8 resulted in packaging multiple Au NP@silica
to generate “raisin bun”– like composites. After etching the silica, multicavity hollow
Au NPs@ZIF-8 nanostructures were acquired.

2) Self-Template Method
The self-template method is an advanced template technique, which avoids extra removal of the exterior
templates. Generally, the self-templates have two different types:
1) the intermediate products that spontaneously transform into hollow MOF structures
2) the reactants that act as sacrificial precursors for the formation of hollow MOFs via chemical reactions
Using the other one of the reactants as a template is introduced in the two-phase interface method section.
Similar to hollow metal oxide microspheres, hollow MOFs could be synthesized by self-template method. An easy
way to control the formation process of hollow MOF structures via the self-template method is surface protective
modification of the intermediate products before a subsequent transformation reaction. Use of
poly(vinylpyrrolidone) (PVP) has been reported as a surface protecting agent, followed by etching with HCl, to
prepare hollow Ga-soc-MOF structures.

3. Two-Phase Interface Method
Different from the exterior-template and self-template methods, the two-phase interface
method is more convenient and suitable for large-scale production. Generally, the synthesis of
hollow MOF structures by the two-phase interface method includes three types: gas–liquid,
liquid–liquid, and solid–liquid interface systems.
Among them, the gas–liquid interface system is widely applied, which involves two routes:
1)when the gas phase acts as the matrix, the liquid phase serves as the template (liquid in-gas)
2) when the liquid phase functions as the matrix, the gas phase serves as the template
(gas-in-liquid).

Gas–liquid method via spray-drying synthesis

In liquid–liquid interface synthesis, oil-in-water or water-in-oil emulsions are broadly adopted.
the metal salt in an aqueous phase and the organic ligand in an organic solvent were stored in
two separate syringe needles. Then, the aqueous droplets were added to the organic phase to
generate the interface of two incompatible solutions, where the MOF was grown and the hollow
HKUST-1 microstructures formed.

solid–liquid-interface
MOP solid (UMOM-1) and 1,4-diazabicyclo[2.2.2]octane linker solution were mixed together. Since
the cores did not make contact with the solution, only the external surfaces reacted to form
MOP@MOF core–shell structures (I-a). By a subsequent etching process (I-b′), hollow MOFs of a
single shell were produced. In another method (I-b), epitaxial growth of an MOP precursor solution
on the above core–shell structures produced MOP@MOF@MOP structures. Repeating process I-a,
another MOF shell was formed. As a result, hollow MOFs with double shells were obtained after
etching.

Hollow-MOF Derivatives
various physical and chemical methods have been utilized to prepare MOF derivatives, which are
assigned to two main catalogs:
1) the pyrolysis process and
2) solid–liquid reaction.
Especially, the pyrolysis process might be further classified into two subcatalogs based on different
gas atmosphere conditions:
1) self-pyrolysis in an inert atmosphere (N2, Ar, etc.),
2) solid–gas reaction in reactive gases/vapors (air, H2S, PH3, etc.).
On the other hand, the solid–liquid reaction upon MOFs with specific chemical reagents such as
acids, alkalis, and metal salts is a rapid chemical process, including chemical etching, ion exchange,
and so on.

1) Derived Hollow Metal Hydroxides: (Chemical reagents such as acids, bases, or metal salts have been used to
break the coordination bonds between the metal ions and organic ligands, inducing the transformation to metal
hydroxides.
2) Derived Hollow Metal Oxides: (Thanks to the abundant metal anodes (Fe, Co, Ni, Zn, Cu, Mg,Ti, Mn, and so
on) inside, MOFs are ideal candidates for constructing various hollow metal oxides. Pyrolysis of MOFs in air is an
easy and rapid way to produce hollow metal oxides. Hollow Fe2O3 was successfully derived from MIL-53(Fe) by
the pyrolysis method.
3) Derived Hollow Carbon Matrixes: (To fabricate a hollow carbon matrix, MOFs need to be subjected to self-
pyrolysis under an inert atmosphere (N2, Ar, etc.), which is different from the pyrolysis-involved synthesis of
hollow metal oxides in air.
4) Hollow Metal Phosphides, Metal Sulfides, and Metal Selenides: Other derivatives, such as hollow metal
phosphides, metal sulfides, and metal selenides, can be acquired with MOF templates through phosphorization,
sulfurization, and selenylation processes, respectively. Lou and co-workers used ZIF-67 nanocrystals as templates
and mixed them with Ni(NO3)2 solution, giving rise to the formation of hollow ZIF-67@Co-Ni LDHs core–shell
nanoboxes.

Porous metal–organic-framework nanoscale carriers as a
potential platform for drug delivery and imaging
2/19/2019 12
POROUS METAL–ORGANIC-FRAMEWORK NANOSCAL CARRIERS AS A POTENTIAL PLATFORM FOR
DRUGDELIVERY AND IMAGING

method
The syntheses of nanoscale porous iron(iii) carboxylates (labelled MIL-n) with different topologies and compositions (iron
trans,trans-muconate (MIL-89), fumarate (MIL-88A), tetramethylterephthalate (MIL-88Bt), terephthalate (MIL-53),
trimesate (MIL-100) and aminoterephthalate (MIL-101 _NH2) were optimized by an appropriate choice of the reaction
conditions (conventional solvothermal or microwave synthesis, solvent, additives, iron source, concentrations, energy,
temperature and time). These porous iron(iii) carboxylates are built up from the assembly of either oxo-centred trimers of
iron octahedra (MIL-88, MIL-89, MIL-100, MIL-101 _NH2) or chains of corner sharing octahedra (MIL-53) and di- or tri-
carboxylate linkers, leading either to microporous flexible solids (MIL-88, MIL-89, MIL-53) or mesoporous rigid
frameworks (MIL-100, MIL-101 _NH2). The structure and composition of the resulting nanoparticles were analysed using
X-ray powder diffraction, thermogravimetric analysis and infrared spectroscopy. In the case of MIL-53, MIL-88A, MIL-89,
MIL-100 and MIL-101_NH2, the synthesis could be carried out in water or ethanol.
2/19/2019 13

2/19/2019 14BUSULFAN (BU), AZIDOTHYMIDINE TRIPHOSPHATE (AZT-TP), CIDOFOVIR

1) Their in vitro degradation under physiological Conditions, in the case of MIL-88A (fumarate) and
MIL-100 (trimesate), a major degradation occurred after seven days of incubation at 37 C. The
nanoparticles lose their crystallinity and release large quantities of their ligands (72 and 58 wt% of
the fumaric and trimesic acids, respectively), indicating a reasonable in vitro degradability of the MOF
nanoparticles.
2) The nanoMOF cytotoxicity, studied in vitro (MTT assay) on mouse macrophages , was low
(57 ±11 µg ml¯ for MIL-88A) and comparable with that of the currently available nanoparticulate
systems.
3) Their comparison with control groups did not show significant differences between them, except a
slight increase in the spleen and liver weights, attributed to the fast sequestration by the
reticuloendothelial organs of the nanoMOFs not protected by a PEG (polyethylene glycol) coating. As
all the body organ weights were back to normality one to three months after injection.
2/19/2019 16

Metal–Organic Framework (MOF)-Based Drug/Cargo
Delivery and Cancer Therapy
2/19/2019
METAL–ORGANIC FRAMEWORK (MOF)-BASED DRUG/CARGO
DELIVERY AND CANCER THERAPY
MING-XUE WU AND YING-WEI YANG*
17

methods for drug-loading
Usually, there are two methods for drug-loading: one method
is a two-step encapsulation of drugs by immersing the prepared
MOFs nanocarriers into drug-containing solutions; the
other is a one-pot encapsulation of drugs.
2/19/2019 18

ZN base
Zn-based MOFs have also been reported as nanocarriers due to the low toxicity of zinc ion. For
example, reported a chiral Zn-based MOF constructed from 5,5′ 5′′-(1,3,5-triazine-2,4,6-triyl) tris
(azanediyl) triisophthalate (TATAT) and Zn2+ for the delivery of anticancer drug 5-fluorouracil (5-Fu).
Adsorption of 5-Fu was achieved by soaking the prepared MOF in 5-Fu containing methanol solutions,
and the hydrogen bonding interactions between 5-Fu and the MOF ensured a loading capacity
of 0.5 g −1.
Drug was released from the drug-loaded MOF by dialyzing the as prepared drug vehicle against
phosphate buffered saline (PBS) solution (pH 7.4) at room temperature, and the drug release process
lasted for a week.
2/19/2019 19

reported the first example of UiO MOFs for co-delivery of cisplatin and pooled siRNAs to enhance
their therapeutic efficacy by overcoming drug resistance in ovarian cancer cells. UiO MOF was
prepared with ZrCl4 and aminotriphenyldicarboxylic acid (amino- TPDC) bridging ligands, in which a
cisplatin prodrug and siRNA were sequentially loaded by encapsulating and coordinating to metal
sites on the MOF surfaces. Green fluorescence was clearly observed in cells incubated with
siRNA/UiO-cis, but not in those treated with siRNA/UiO or UiO-cis, indicating that the developed
siRNA/UiO-cis induce cell apoptosis (Figure 2b–d). All these results demonstrated that such a co-
delivery method would enhance the chemotherapeutic efficacy of cisplatin in vitro .
2/19/2019 20

Stimuli-Responsive MOFs for Drug Delivery
1) pH-Responsive MOFs: reported an Fe (bbi) MOF, constructed from 1,1′-(1,4-butanediyl) bis
(imidazole) (bbi) and ferrous ions by a deposition method. In situ encapsulation of DOX was
achieved by simply adding DOX into the bbi solution and, as expected, the loaded DOX could be
released upon lowering the pH, due to the sensitivity of the coordination bond to the acidic
environment . Thus, a layer of silica was coated on the surface of the MOF to prevent the rapid
decomposition of the hosting material for effective control over the release of DOX. More
importantly, folic acid was conjugated to the surface of the as-prepared nanocomposites for
targeted drug delivery.
2/19/2019 21

1) Another pH-sensitive nanocarrier, poly(acrylic acid)@zeolitic imidazolate framework-8
(PAA@ZIF-8), was prepared by ionexchange between Zn2+ and poly(acrylic acid sodium salt)
(PAAS), followed by reacting with 2-methylimidazole (HMeIM) in methanol solution.
2) a pH-responsive ZIF-8 with uniform 70 nm NPs as a theranostic system.Negatively charged
small molecules such as fluorescein camptothecin (CPT) could be encapsulated into the ZIF-8
NPs by one-pot encapsulation. The performance of pH-responsive release was driven by the
dissociation of the ZIF-8 framework at the acidic designated target.
2/19/2019 22

Magnetically-Responsive MOFs
Candidate nanocarriers base on MOFs for such a delivery approach are usually core–shell
NPs, for example Fe3O4 was often used as a magnetic core with a MOF shell.
2/19/2019 23

Ion-Responsive MOFs
In such drug carriers, strong electrostatic interactions between the drugs and the frameworks
control the diffusion and release of drugs. Thus, the strong electrostatic interactions between
ionic drugs and ionic frameworks have attracted particular interest because the release of ionic
drugs is a chemical stimuli-responsive process taking place only through ion exchange.
Yang and co-workers developed a cationic drug carrier, MOF- 74-Fe(III), through the oxidation of
neutral MOF-74-Fe(II). The cationic MOF exhibited around 15.9 wt% of the loading capacity of
ibuprofen anions.
2/19/2019 24

Temperature-Responsive MOFs
Poly(N-isopropyl acrylamide) (PNIPAM) is a promising building block for thermosensitive drug
nanocarriers that possess a lower critical solution temperature.When the temperature is
lowered to below its cloud point (Tc, around 32 °C), PNIPAM exhibits hydrophilicity and tends to
dissolve in water; however, it also forms an aggregate. Accordingly, Sada et al. demonstrated a
switchable UiO-66- PNIPAM nanocarrier.
2/19/2019 25

Resorufin, caffeine, and procainamide were loaded in the nanocarrier by soaking the UiO-66-
PNIPAM in guest solutions, then the release behaviors were assessed at 25 °C or 40 °C . As
expected, the amount of released drug increased at 25 °C and almost halted at 40 °C , which
indicated that controlled release was driven by temperature variation.
2/19/2019 26

Pressure-Responsive MOFs
Recently, Qian and co-workers reported a Zr-based MOF builted from (2E,2E′)-3,3′-(2-fluoro-1,4-
phenylene) diacrylic acid (F-H2PDA) and zirconium cluster with high model drug diclofenac
sodium (DS) loading capacity of 58.80 wt% due to its enhanced polarity and extended organic
spacer. The Dsrelease kinetics of such drug-loaded MOF could be adjusted through varying
pressure, resulting in a prolonged release time between 2–8 days. Such formulation showed a
new method for responsive MOF-based drug delivery.
2/19/2019 27

dual stimuli-responsive
UMCM-1-NH2 was used as the host material to store cargoes of guest molecules, followed by
modification of carboxylatopillar arene (CP5) as a dual stimuli-responsive gatekeeper linked by
positively-charged pyridinium (Py) stalks (CP5-capped UMCM- 1-NH–Py). In acidic tumor tissues
or tumor cells, the gatekeeper of CP5 tended to be neutral, which weakened the noncovalent
binding interactions between CP5 and the stalk, leading to unblocking of the MOF followed by
the release of cargo. Upon addition of a competitive binding agent (methylviologen salts), which
possess a higher binding affinity to CP5 than Py, CP5 was detached from the stalks, which caused
the release of cargo. We integrated pH- and/or competitive binding agent-responsive strategies
into a single drug nanocarrier , where the CP5-capped drug nanocarrier showed high
encapsulation efficiency, negligible premature release, negligible cytotoxicity, desirable
biodegradability, and biocompatibility.
2/19/2019
MING-XUE WU AND YING-WEI YANG*
29

2/19/2019
30

developed a triply-responsive theranostic hybrid platform based on CP5-gated Zr-MOFs.
Positively charged quaternary ammonium salt stalks were tethered on UiO-66-NH2 via post-
synthetic modification, and then negatively charged CP5 was encircled on the stalks sitting on
the surface of the MOF through host–guest complexation. Controlled release experiments
verified that the prepared therapeutic platform was promising for potential bone regeneration
and bone cancer therapy because lower pH and higher concentration of Ca2+ in osteoclasts and
tumor cells could stimulate the release of the therapeutic agents via pH-responsiveness and
Ca2+-competitive responsiveness. Furthermore, high temperatures could damage and kill cancer
cells as well as weaken host–guest interactions to prompt gradually release of the therapeutic
molecule (5-Fu). Furthermore, the triply-responsive drug nanocarrier possessed desirable
properties, including negligible premature release, non-cytotoxicity, and good biocompatibility.
2/19/2019 31
Triply-responsive theranostic

2/19/2019 HOLLOW METAL–ORGANIC-FRAMEWORK MICRO/NANOSTRUCTURES 32

Multiple-stimuli responsive
2/19/2019 33

Multifunctional MOFs for Cancer
Theranostics
2/19/2019 34

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