Metal-organic Frameworks: Preparation, Sensing, Drug Delivery,

Imaging and Therapy

Wei Huang

1,†

, Ruiqi Wang

2,†

and Yongli Zhang

3,* a

Department of Metallurgy and Materials

，

University of Birmingham Birmingham, U.K.

Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian, China

Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University,Dalian, China

†

These authors contributed equally to this paper

Corresponding author

Keywords: Metal-Organic Frameworks, Preparation, Biomedicine, Application.

Abstract: Metal-organic frameworks (MOFs) materials have been widely used in biomedical field due to their unique

physical-chemical properties. This review summarized the preparation methods for MOFs, including

hydrothermal or solvothermal method, microwave synthesis, ultrasonic synthesis, mechanical method and

aerosol method. The MOFs synthesized by hydrothermal method exhibit uniform morphology. Moreover, the

properties of MOFs can be controlled by changing the concentration of precursors, the types of solvents and

catalysts. For the mechanical method, MOFs can be obtained by the mixing and grinding of raw materials in

a small amount of solvent without external heating. This method is applied for the large-scale production of

MOFs due to the simple operation, high yield and low energy consumption. With the advantages of large

specific surface area, high porosity, easy modification, low toxicity and biodegradability, this review also

focused in various biomedical applications of MOFs, such as fluorescence sensing, drug delivery, bioimaging

and tumor therapy.

1 INTRODUCTION

Metal-organic frameworks (MOFs) are crystalline

porous materials with three-dimensional periodic

structure constructed by coordination bonds between

metal ions or ion clusters and organic molecules

(Jiang, Alezi, Eddaoudi 2021). MOFs, firstly

proposed by O.M. Yaghi et al. in 1995, are also known

as porous coordination polymers (Yaghi, Li 1995).

MOFs have experienced a stage three generations

with rapid development. In the early preparation, the

pore size and stability were limited for the first

generation of MOFs. The significantly improved

stability of frameworks is achieved for the second

generation of MOFs, and the frameworks of MOFs

also remained their integrity even after removing the

guest molecules. For the third-generation MOFs, the

shrinkage and expansion of frameworks further is

attained. And the broad pore size of MOFs, from

micropore to mesopore are realized. Compared with

the traditional nanomaterials, MOFs offer the larger

https://orcid.org/0000-0002-4263-8382

specific surface area, high porosity, framework

flexibility and the controlled pore size by adjusting

the length of organic ligands (Lin, Zhang, Chen 2021,

Kim, Hong 2021, Pallach et al 2021). Moreover, the

uncoordinated unsaturated metal sites can be provided

for surface modification. This allows MOFs is easily

modified and functionalized. Due to their unique

characters, MOFs have been considered as a

promising absorbent or catalyst in gas storage and

separation, catalysis, membrane materials and other

fields (Wu, Lin, Ge, Wu, Xu 2013, Yang, Gates 2019,

Li, Wang, Sun, Lollar, Li, Zhou 2018). Moreover,

MOFs have good biodegradability and

biocompatibility, which can be used as drug carrier,

contrast agent as well as nano enzyme (Sun et al 2020,

Li et al 2020, Robison et al 2019). Therefore, MOFs

play a vital role in the biomedical field. This article

describes the preparation methods and various

applications in different branches of biomedical field

for MOFs.

230

Huang, W., Wang, R. and Zhang, Y.

Metal-organic Frameworks: Preparation, Sensing, Drug Delivery, Imaging and Therapy.

DOI: 10.5220/0011291000003444

In Proceedings of the 2nd Conference on Artiﬁcial Intelligence and Healthcare (CAIH 2021), pages 230-237

ISBN: 978-989-758-594-4

2 PREPARATION FOR MOFS

To obtain MOFs with various structures and functions

for various application, different synthesis methods of

MOFs have been proposed. The main methods

include hydrothermal or solvothermal method,

microwave synthesis, ultrasonic synthesis,

mechanical method and aerosol method and so on.

The synthesized MOFs have a variety of morphologic

features, including crystal and amorphous forms,

which makes MOFs play different functions in

various fields and have broad prospects.

2.1 Hydrothermal and Solvothermal

Methods

The hydrothermal or solvothermal method is one of

the most common preparation routes for MOFs.

Firstly, the raw materials including metal salts,

organic ligand and additives were dissolved in water

or organic solvent. Then the mixture was heated at a

certain temperature and pressure in reaction kettle and

MOFs products can be obtained. Kandiah et al.

synthesized the UiO-66-NH2 by dissolving ZrCl4 and

NH2-H2BDC in dimethylformamide (DMF). The

precursor solution was heated in an oven at 80 °C for

12 hours and kept at 100 °C for 24 hours. The final

product was obtained by washing and purifying

(Kandiah et al 2010). Besides reaction kettle

commonly used in MOFs preparation, Motegi et al.

synthesized MOFs of zirconium-based UiO-66 under

the nitrogen atmosphere using a standard reflux

device (Figure 1). (Motegi et al 2017) The synthesized

MOFs showed excellent hydrothermal stability. This

simple synthesis method can be scaled up to 1 L and

further scaled up to allow industrial production of

high-quality, uniform crystalline UiO-66 materials.

Figure 1: The schematic diagram of MOFs synthesis by

conventional reflux solvothermal method.

2.2 Microwave Synthesis

Microwave synthesis of MOFs refers to the reaction

process forming coordination bonds between metal

ions and organic ligands through the vibration and

friction of molecules of precursor solution under

microwave irradiation. In 2006, Zheng et al.

synthesized cubic Zn-MOF (MOF-5) with lengths

ranging from 200 nm to 4 µm by microwave assisted

method for the first time (Ni, Masel 2006). On the

basis of this work, many MOFs have been

successfully prepared by microwave synthesis. For

example, Li and colleagues reported the synthesis of

Zn-MOF (ZIF-7) using microwave assisted strategy,

in which diethylamine was added to further accelerate

the synthesis of ZIF-7, resulting in a significant

increase in the synthesis efficiency (Li et al 2010).

Taddei et al. reported the high-quality microwave-

assisted synthesis methods for large-scale preparation

of UiO-66, offering a possible way for industrial

production and commercialization of MOFs (Figure

2). (Taddei et al 2017)

Figure 2: The schematic diagram of MOFs synthesis by a

continuous-flow microwave reactor (Taddei et al 2017).

2.3 Ultrasonic Synthesis

In addition to microwave-assisted synthesis,

ultrasound-assisted synthesis is also widely used in

the preparation of MOFs. Ultrasonic wave can not

only facilitate the dissolution of metal salts, organic

ligand and additives, but also promote the binding

between metal ions and ligands due to the local

transient heating and vibration of solution caused by

its cavitation. Moreover, this reaction is only carried

out in very small individual reaction units, therefore,

MOF with small particle size were easily synthesized.

Jun Teng et al. designed and developed a novel small-

sized (about 95 nm) multilayer porous MOFs

(HPMOFs) by combining external ultrasound with the

inherent competitive binding between Co and Zn of

bimetallic Co/Zn-ZIF materials (Figure 3) (Teng et al

2018)

The competitive binding between two metal

ions in bimetallic MOFs was interfered with

ultrasonic in this strategy, in which the two metal ions

not only act as the building units of HPMOF, but also

the regulator of structure and size for HPMOF

nanocrystals. Thus, the small nanocrystals MOFs with

excellent selectivity and stability was achieved.

Metal-organic Frameworks: Preparation, Sensing, Drug Delivery, Imaging and Therapy

231

Figure 3: Growth strategy for the synthesis of MOFs (Teng

et al 2018).

2.4 Mechanical Method

Mechanical method, first proposed by James et al. in

2006, refers that the solid phase precursor can be

extruded and grinded by the use of external

mechanical force, resulting in sufficient contact

between metal ions and ligands (Figure 4) (Yuan et al

2010)

With ball milling method, James et al. quickly

synthesized Cu-MOFs using copper acetate and 4-

picolinic acid as raw materials, which pioneered the

mechanical chemical synthesis of MOFs. Julien et al.

reported Zn-MOFs-74 by mechanical grinding (Julien

et al 2016). X-ray diffraction analysis (XRD) results

of products with different grinding time showed that

the longer the grinding time, the better the

crystallinity of products and the more significant the

characteristic peak.

Figure 4. The schematic diagram of Cu-MOFs synthesis by

ball milling (Yuan et al 2010).

2.5 Aerosol Method

For the spray pyrolysis or aerosol flow strategy, the

precursor solution was transformed from liquid to

nano/micro droplets or aerosols using spray tools, and

transported to the heating region by the mean of

flowing carrier gas. Under high temperature, final

nanomaterials can be prepared by the condensation

and reaction of reactants due to rapidly volatilization

of the solvent in the droplets. In this process, each

droplet can act as a single reactor in which do not

interfere with each other, leading to a good dispersion

of MOFs. In 2013, Arnau et al. synthesized Cu-MOF

(HKUST-1, MOF-199) with hollow sphere structure

by spray method.20 Additionally, based on this

method, Arnau et al. also synthesized NOTT-100,

MIL-88A, MOF-14, UiO-66 and other MOFs. In

2018, Ceren et al prepared a spherical porous Zr-

MOFs (UiO-66-NH2) by continuous-flow spray-

drying (Figure 5) (Avci-Camur et al 2018). By

adjusting the concentration of acetic acid as an

additive, the specific surface area and water

absorption values of the resulting microbeads were

comparable to those obtained using other methods. In

addition, this work demonstrates the possibility of

spray drying for large-scale production of high yield

UiO-66-NH2. Spray pyrolysis has become a green

method for rapid preparation of MOFs, offering a

bright prospect in the synthesis of MOFs and other

nanomaterials (Garzón-Tovar et al 2016).

Figure 5. The schematic diagram of the set-up for the

aqueous continuous-flow spray-drying synthesis of Zr-

MOFs

(Avci-Camur et al 2018).

3 APPLICATIONS IN SENSING,

DRUG DELIVERY, IMAGING,

AND THERAPY FOR MOFS

With the potential of adjustable pore structure, large

surface area, large internal pore volume, and

multifunctional surface modification, MOFs have

been widely used in biomedical applications, such as

fluorescence sensor, drug delivery, bioimaging, and

tumor therapy (Figure 6) (Lai et al 2021)

CAIH 2021 - Conference on Artiﬁcial Intelligence and Healthcare

232

Figure 6: Biomedical applications of MOFs

(Lai et al

2021).

3.1 Fluorescence Sensor

Fluorescent sensing materials, as the core materials of

light-emitting diodes and various solid-state sensors,

are widely applied in our daily life. It is known that

many small organic molecules can emit fluorescence.

The introduction of these small molecules or

functional groups into the pore structure of MOFs can

not only control the fluorescence properties of

materials, but also explore the luminescence and

electron transport mechanism of materials. Therefore,

the design and synthesis of MOFs with fluorescence

properties have attracted more attention in recent

years. Researches have shown that amino

functionalized UiO-66 can selectively probe

phosphate ions in aqueous solution, with obvious

fluorescence response in the range of 5-150 µM, and

a good linear relationship between fluorescence

intensity and phosphate ion concentration (Zhao et al

2015). The theoretical detection line can reach up to

1.25 µM, which is far below the emission standard of

phosphate ions. Similarly, azide (-N3) and nitro (-

NO2) functionalized UiO-66 (UiO-66-N3 and UiO-

66-NO2) can also be used as fluorescent probes for

rapid and selective detection of H2S, even below the

concentration of H2S in the human body (Bai et al

2016)

3.2 Drug Delivery

MOFs, as a drug delivery platform, have attracted

considerable attention in recent years due to their

unique properties. The stable porous structure and

large specific surface area favor the load of a large

number of drug molecules by physical adsorption or

bonding reactions. The toxicity of MOFs can be

controlled by changing the type of ions. In addition,

the coordination bonds can degrade in a low pH

environment. MOFs can be passively targeted at

tumor sites by enhanced permeability and retention

(EPR) effect. Moreover, the targeting of MOFs can be

increased by functional surface modification, such as

cell membranes, proteins, organic polymers and so on.

For the MOFs-based drug delivery system, the

selectivity to lesions and selective aggregation of

drugs can be improved, which can reasonably control

the distribution of drugs in vivo, and avoid the toxic

and side effects caused by unnecessary drug diffusion.

In addition, the usage of nano-drug delivery platform

can also regulate the biological metabolism of drugs

and control drug release by chemical switch, leading

to the improved efficiency of drug treatment. It is

expected to achieve controlled release of drugs when

some small drug molecules are encapsulated in MOFs

with low toxicity.

Furthermore, some studies have shown that the

combination of different organic functional groups in

the structure of MOFs can achieve the regulation of

the types of drug loading and sustained release effects.

Cunha et al. found that the loading capacity of UiO-

66-X (X = H, CH

, NH

, NO

, Cl, Br) modified by

different organic functional groups was very different

for different drug small molecules (Cunha et al 2013).

In 2017, Deng group found that the type and content

of functional groups modified on the organic ligand of

MIL-101 (Fe) can affect the slow-release effect of the

drug by changing the interaction between small

molecules and pore channels (Dong et al 2017).

3.3 Bioimaging

MOFs can be used as contrast agents in biological

imaging to enhance the imaging signal of magnetic

resonance (MRI), fluorescence imaging (FOI) and X-

ray computed tomography (CT). The high-resolution

images for the structure of the living body structure

can be provided by the detection the radiofrequency

signals of protons inside organisms using external

magnetic fields, gradient fields and radio waves. The

contrast ratio of images can be further improved due

to the change in the transverse and longitudinal

relaxation rates of protons by the usage of MOFs.

MRI contrast agents include two types: one is a

positive contrast agent that shortens the longitudinal

relaxation time (T1) of the water proton, and the other

is a negative contrast agent that reduces the transverse

relaxation time (T2) of the water proton (Wu, Jiang,

Roy 2016). MRI contrast agents were evaluated by the

Metal-organic Frameworks: Preparation, Sensing, Drug Delivery, Imaging and Therapy

233

longitudinal and transverse relaxation rates of protons

(r1 and r2), and the type of contrast agents can be

determined by the ratio of r2/r1. The contrast agent is

positive or T1 relaxation when r2/r1 is small, which

usually contains paramagnetic transition metal ions

(such as Gd

or Mn

). In the case of large r2/r1, the

contrast agent is negative or called T2 relaxation, and

often contain superparamagnetic materials. Lin et al.

reported a Gd-based MOFs as a T1 imaging contrast

agent with a r1 of 35.8 mM

-1

.(Rieter et al 2006)

Moreover, such nanoparticle also exhibits T2 imaging

capability with a r2 of 55.6 mM

-1

. Horcajada et al.

synthesized Fe

-MOFs (MIL-88A) with a r2 of about

50 mM

-1

, which reveals the promising application

for T2 magnetic resonance imaging as contrast agent

(Lin, Rieter, Taylor 2009).

FOI has been extensively used in the diagnosis of

tumors and diseases because of its non-invasive

ability to distinguish diseased tissues. At present, FOI

using MOFs can be achieved by recombination with

fluorescent particles or by linking and adsorbing

fluorescent molecules. Tang et al. designed a MOFs

coated upconverting nanoparticles (NaYF

: Yb,

Er@Fe-MIL) that exhibit both the fluorescence

characteristics of the core and the T2-weighted

magnetic resonance imaging characteristics of the

MOFs shell (Tang et al 2015). In addition, MOFs also

have the inherent fluorescence properties. It is

reported that Mn

[Co(CN)

]

@SiO

exhibits green

fluorescence at 488 nm single photon excitation, and

blue fluorescence at 720 nm two-photon excitation.

This two-photon fluorescence imaging show a greater

penetration depth, less photobleaching and light

damage and higher resolution than single-photon

fluorescence imaging (Huang et al 2013).

CT imaging refers that the fault or cross section

image of the detected object can be drawn using the

attenuation signal of X-ray in different beam paths.

The improved contrast of CT imaging is achieved by

using the contrast agent with high X-ray attenuation.

Lin et al. prepared two MOFs with high Zr (37 wt%)

and Hf (57 wt%), respectively (Dekrafft et al 2012).

Zr with an atomic number of 40 and Hf with an atomic

number as high as 72 can be used as a component of

CT contrast agent. MOFs, modified with PEG with an

enhanced biocompatibility, showed negative

enhancement of CT signal in liver and spleen after

intravenous injection of 15 minutes on in vivo CT

imaging of mice. Zhang et al. reported a MOFs

nanocrystal (UiO-PDF) with iodine-boron

dipyrrolimethylene (I

-BDP) that can be used as CT

contrast agent. In addition, the CT imaging

capabilities of MOFs by combining with other CT

contrast agents such as noble metal material can be

realized (Zhang et al 2017).

The performance of contrast agent with the high

ordinal number metal can be effectively improved.

Meanwhile, MOFs with controllable particle size can

be selectively enriched in tumor sites by EPR effect,

which can further improve the diagnostic efficiency

of tumor.

3.4 Photothermal, Photodynamic,

Microwave Hyperthermia, And

Synergistic Therapy

3.4.1 Photothermal Therapy

Photothermal therapy mean that the thermal damage

and apoptosis of tumor cells due to the local warming

of tumor sites occur by the usage of near-infrared

(NIR) laser irradiation. The photothermal agents that

easily accumulate in tumor sites are usually selected

as auxiliary agents in clinical practice, because of

simple tumors is insensitive to the absorption of near

infrared golden light. Common photothermal agents

include metal compounds (MoS2, Co9Se8), noble

metal nanomaterials (gold nanoparticles), carbon

nanomaterials (graphene), organic fluorescent dyes

(IR825, ICG) and MOFs. Particularly, MOFs have

attracted wide attention due to their functionalization

and biodegradation. Cai et al. developed a MIL-100

(Fe) nMOF using hyaluronic acid (HA) as a surface

modification for targeted therapy of tumors.35 The

MOFs loaded with the indocyanine green (ICG) also

was used for image-guided photothermal tumor

therapy, which exhibited high ICG loading (40%),

strong NIR absorption and photostability. In vitro and

in vivo studies clearly revealed that

MOFs@HA@ICG with a good photothermal

therapeutic effect showed high cellular uptake in

MCF-7 cells and increased accumulation in xenograft

tumors.36 In addition, Wang et al. reported a polymer-

MOF hybrid that is Zr MOF (UiO-66) particle

modified by polyaniline (PAN) (UiO-66@PAN) as a

nanoplatform for photothermal therapy of tumors.

Under laser irradiation, the temperature of UiO-

66@PAN solution at a concentration of 100 µg mL-1

increased to 57.2 °C, which was sufficient to

effectively kill malignant tumor cells. In cell

experiments, this platform shows non-cytotoxicity in

mouse colon cancer CT26 and human colon cancer

HTC116 cell lines. However, the cell death rate

reached 70 % after laser irradiation. In vivo

experiments shows that tumors treated with UiO-

66@PAN and NIR radiation completely retreated

CAIH 2021 - Conference on Artiﬁcial Intelligence and Healthcare

234

after 10 days, demonstrating the promising prospect

of UiO-66@PAN for photothermal therapy of tumors.

3.4.2 Photodynamic Therapy

Photodynamic therapy (PDT) is an important method

in clinical treatment of tumor. In the PDT, oxygen can

be converted into reactive oxygen species (ROS)

using photosensitizers under laser irradiation,

resulting the tumor cell death. PDT, with high

selectivity, small side effects, no trauma and

restorability, has attracted more attention in the

clinical. Lu et al. synthesized Al-Mn mixed MOFs

(Mn-MOF) with Mn as the active center to enhance

the photodynamic effect.37 The ROS produced by

Mn-MOF under light irradiation can be detected using

ROS detection reagent, DCFH as a probe. It is

confirmed that the fluorescence intensity of ROS

probe increased threefold after irradiation, indicating

that Mn-MOF has good photosensitivity and can be

used as a photosensitizer of PDT.

Based on the easy modification and

functionalization of MOFs materials, Zhang et al.

reported a simple and universal strategy for the

enhancement of PDT (Zhang et al 2018). The

platinum nano-enzymes with high catalase activity

and stability can be uniformly decorated in the

photosensitizer MOF. Therefore, the formation of

singlet oxygen for hypoxic tumor sites under laser

irradiation is promoted by the release of O

activated

by H

catalyzed by platinum nano-enzymes,

resulting tumor cells death.

3.4.3 Microwave Hyperthermia

Microwave hyperthermia of tumor (MWT) also is a

treatment method that induces apoptosis by means of

local heating at the tumor site. Compared with

photothermal therapy, a lot of heat can be generated

by the high-speed oscillatory friction between

polarized ions and dipoles in the radiation zone

induced by high-speed alternating electric field

generated by microwave (MW) as a heat source in the

microwave hyperthermia. Microwave hyperthermia

has the advantages of low cost, low toxicity and small

wound. However, the tumor cannot be accurately

located by a single microwave therapy. Meanwhile,

the temperature changes of the edge zone caused by

the gradient of the thermal field is not enough to

eliminate the tumor cells, resulting in the occurrence

of recurrence. To solve this problem, the concept of

microwave sensitizer was proposed. Microwave

sensitizer exhibit high microwave-heat conversion

efficiency, which is based on the ion domain

limitation. Compared with inorganic nanomaterials,

many studies have proved that MOFs materials can be

used as excellent microwave sensitizer in clinical

microwave hyperthermia of tumors. Zhou et al.

prepared Zr-MOF-PEG-TPP@DOX with

mitochondrial targeting ability as MW sensitizer, by

loaded chemotherapy drug doxorubicin (DOX) with a

porous zirconium-based MOF nanocubes (Zr-MOF,

UiO-66) modified by triphenyl phosphate (TPP) and

polyethylene glycol (PEG).39 The local temperature

of H22 tumor-bearing mice treated with Zr-MOF-

PEG-TPP@DOX increase to 50.8 °C after 5 min

microwave irradiation, which meets the requirements

of local temperature rise for thermal therapy. Tumor

growth also proved the good tumor inhibition effect

of this nanoplatform.

3.4.4 Synergistic Therapy

Besides the catalytic activity, photosensitivity or

microwave sensitization of MOFs, combine with

different therapies, the good loading performance and

functionalization of MOF materials can be used to

achieve the synergistic treatment, which can

effectively enhance the lethality for tumors. For

instance, MOF materials loaded with chemotherapy

drugs (such as adriamycin, cisplatin), cooperated with

chemotherapy, hyperthermia and kinetic therapy,

become an effective synergistic treatment. Ma et al.

reported that Zr-MOF with degradation and release of

terephthalic acid in acidic tumor microenvironment,

was used to inhibit carboxylic anhydrase (CAIX)

induced by hypoxic factor HIF-1α.40 Moreover, Zr-

MOF loaded with the chemotherapy drug quercetin

(QU) can also improve the radiotherapy sensitivity of

QU used for the inhibition of hypoxic factor, which

realizes the inhibition of hypoxic and chemotherapy.

As one of the important research fields in clinical

tumor treatment, the combination of immunotherapy

and MOF materials has attracted more attention. Lin

et al. reported a novel dihydroporphyrin-based MOF

nanomaterial (TBC-Hf), which encapsulated with an

inhibitor of IDOi for the immunomodulatory enzyme

IDO within the framework (Figure 7).41 The

synthesized IDOi@TBC-Hf can be used for the

synergistic treatment of photodynamic therapy and

immunotherapy. Based on this treatment, the effective

tumor suppression in colorectal cancer models is

achieved, and increased T cells in the tumor

microenvironment were detected after inhibiting IDO

and activating the immune system, which provides a

new idea for the clinical treatment of cancers.

Metal-organic Frameworks: Preparation, Sensing, Drug Delivery, Imaging and Therapy

235

Figure 7: In vivo anticancer efficacy of IDOi@TBC-Hf.41.

4 CONCLUSIONS

The unique properties of MOF, such as tunable pore

structure, large surface areas, high drug loading, easy

modification and functionalization, make it a potential

candidate in the biomedical field. This review

provides a more systematic understanding for the

preparation methods and bio-applications of MOFs.

However, limitation and challenges still exist for

MOF, such as standardization of preparation methods,

large-scale preparation, biocompatibility and

biodegradability. These factors limit the application of

MOF in biological field. Therefore, a simple and

stable preparation strategy with uniform size and high

yield of biocompatible MOFs is urgently developed.

Additionally, compared to biomedical application of

MOFs, the research on the biological effect of MOF

materials have received less attention. Therefore, it is

of great significance to clarify the biological effect of

MOF materials for safe application. In summary,

although the research based on MOF has made great

progress, it still faces challenges related to its

toxicology, clinical application and large-scale

production technology.

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