Applications of Metal Organic Frameworks in Drug Delivery and

Therapy

Yubo Li

1,a,

†

, Guanlin Peng

2,b,*,

†

and Yuezhou Yu

3,c,

†

Wuhan Britain-China School, Wuhan 430022, China

Bi Academy, Chongqing 400010, China

Jiangsu Tianyi High School, Wuxi 214171, China

Corresponding author

†

These authors contributed equally

Keywords:

Metal Organic Framework, Drug Delivery, Antibody, Therapy.

Abstract:

Metal organic frameworks (MOFs) are organic-inorganic mixtures formed from metal ions and organic

ligands under relatively mild conditions. MOFs are widely used as drug carriers due to their low toxicity, high

drug load, good biocompatibility, and functional diversity. Stimulus-responsive MOFs materials have

attracted extensive attention in the field of drug delivery materials and biological applications. This article

highlights the different types of stimulus-responsive MOFs materials, including pH-Responsive MOFs,

magnetically-responsive MOFs, ion-responsive MOFs, temperature-responsive MOFs, and pressure-

responsive MOFs. MOFs materials are very effective as intermediates for drug transport. In this thesis, we

mainly studied the advantages of MOFs as intermediates. It is stable and can be safely degraded, and it makes

the antibody easier to attach, and have strong plasticity.

1 INTRODUCTION

MOFs are organic-inorganic mixtures formed from

metal ions and organic ligands under relatively mild

conditions (Batten, Champness, Chen, 2013). The

stability of MOF is influenced by many factors,

including the operational environment, metal ions,

organic ligands, coordinate geometry of metal

ligands, hydrophobicity of interstitial surfaces. The

study of MOF stability helps rationalize the influence

of several factors and design stable framework

structures wisely. The relatively volatile coordination

relationships of the skeletal support structure are seen

as the cause of the limited stability of the MOF.

Therefore, the stable structure of the MOF would

need to be highly coordinated. They have been

extensively studied in the basic fields of catalytic

intermediates capture and energy transfer and the

potential practical applications such as gas storage

and separation, heterogeneous catalysis, chemical

sensing, biomedical applications, and proton

conduction (Chughtai, Ahmad, Younus, 2015). Many

early MOFs made from divalent metals, such as Zn2+

or Cu2+, showed extremely high porosity and

showed promise for widespread use, but ultimately

proved unsuitable for harsh conditions due to stability

issues (Eddaoudi, Kim, Rosi, 2002); (Deng, Doonan,

Furukawa, 2010).

Drug delivery systems (DDS) are typical of the

research achievements about new preparations and

dosage forms in modern pharmacy, the crystallization

of modern scientific and technological progress. The

system has made great progress in the theoretical

system, design of new preparation and preparation

process, and application in clinical treatment, mainly

including oral slow and controlled release system,

transdermal drug delivery system, and targeted drug

delivery system. Recent research about this topic has

made a big process because people have already

found an almost perfect carrier for drug delivery,

which is MOFs. MOFs are regarded as the perfect

material because they have many advantages that

other carriers do not have (Neuberger, Schöpf,

Hofmann, 2005).

Compared with other organic porous materials

and inorganic materials, MOFs have the following

characteristics. Firstly, MOF materials are highly

adjustable. MOFs are a hybrid porous material whose

pore surface properties can be adjusted to suit drug

Li, Y., Peng, G. and Yu, Y.

Applications of Metal Organic Frameworks in Drug Delivery and Therapy.

DOI: 10.5220/0011216100003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 455-460

ISBN: 978-989-758-595-1

455

delivery needs. Secondly, partial MOFs can be

adjusted according to needs so that their toxicity to

the human body is controlled in an acceptable range

to achieve a relatively stable carrier. Because active

functional groups can be inserted into the surface of

MOFs, it is easier to modify the surface to meet the

use requirements. Thirdly, the drug can be loaded by

introducing functional ingredients or changing the

body's flexibility, and then the speed and size of its

release can be controlled. Finally, MOFs can achieve

the purpose of making targeted drugs by introducing

stable special materials. By changing the NMOFs

after the contact surface, MOFs can be transformed

into a method that can make it have the advantages of

nanosensors. For example, the targeting and

bioavailability of drugs can be improved, the stability

of drugs can be increased, the efficacy can be

improved, and the toxic and side reactions can be

reduced. It can also make the drug into the human

body at all levels of the tiny blood vessels, and

pathological tissue cells play a therapeutic role.

MOFs have essentially large surface areas, highly

ordered porosity, and clear structures that give these

materials the ability to load and release different

cargoes, especially therapeutic agents (Ma, Moulton,

2011).

This review will focus on the development of

MOFs in the field of controlled drug release and

effective cancer treatment, including drug

nanocarriers and cancer treatment systems composed

of single MOFs, stimulus-responsive MOFs, and

multifunctional MOFs. This document also covers

basic methods for the application of MOF to biology.

Finally, the development prospects and challenges of

MOF are under discussion.

2 STIMULI-RESPONSIVE MOFs

FOR DRUG DELIVERY

Stimulus-responsive MOFs materials have attracted

extensive attention in the field of drug delivery

materials, especially in the field of biological

applications. As a result, Stimulus-responsive MOFs

have become popular candidate materials for

controlling drug release. Generally, stimulus-

response MOFs can be divided into single stimulus-

response types and multiple stimulus-response types.

Next, we will discuss the main response methods for

these two MOFs (Feng, Wang, Zhang, 2019).

2.1 Single-Stimuli-Responsive MOFs

for Drug Delivery

2.1.1 pH-Responsive MOFs

All porous MOF nanosensors are stimulated by

external stimulation. However, the pH-responsive

MOF is the most widely studied, especially in cancer

treatment, because acidic bonds are particularly

sensitive to the tumor microenvironment and

coordination external doctor many studies have

investigated the pH response of MOF to drug delivery

and cancer therapy (Freeman, Arrott, Watson, 1960).

Recently, Qian's group described an interesting

cationic nanocarrier, ZJU-101 (Zhejiang University,

ZJU) MOF, for delivering the anionic drug diclofenac

sodium. The cation material of the body is in

zirconium and 2,2′-bipyridine-5,5′-dicarboxylate

(BPYDC) ligand. And the high carrying capacity of

diclofenac sodium was 0.546 g/g. The release rate of

diclofenac sodium in inflammatory tissues (pH = 5.4)

was higher than that in normal tissues (pH = 7.4)

because the ion exchange between the anions in PBS

and the drug is more frequent under acidic conditions.

As a result, the coulomb interaction between the

cation ZJU-101 and the anionic drug is weakened. As

a result, diclofenac sodium-sensitive to pH is

expected to be a promising carrier of anti-

inflammatory drugs (Angelos, Khashab, Yang,

2009).

2.1.2 Magnetically-Responsive MOFs

Due to the potential benefits of magnetic response

systems with respect to magnetic separation,

magnetic targeting, magnetic resonance imaging

(MRI) and magnetic hyperthermia, drug delivery is

quite diverse. Therefore, the administration of

magnetic drugs is a unique strategy for improving the

therapeutic effect of concentrating the drug delivery

probe at the tumor site. Since the method was first

proposed by Watson et al. in the 1960s, many MOFs

materials have been found to have good magnetic

properties and can be used for drug separation and

drug delivery (Cavka, Jakobsen, Olsbye, 2008);

(Hergt, Dutz, Müller, 2006); (Jurgons, Seliger,

Hilpert, 2006); (Kumar, Mohammad, 2011). In 2014,

Guan and colleagues reported on a one-step in situ

pyrolysis method for producing γ-Fe

@MOF. In

their work, γ-Fe

@MIL-53 (LA) demonstrated its

potential for controlled magnetic separation and drug

liberation. As anticipated, magnetic nanocomposites

showed a controlled release behavior in 37 salines.

That is, the capsule IBU is fully released after 7 days

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

456

in 3 stages. About 30% of the drug is released rapidly

within the first 3 hours in the first stage. Then 50% of

the drug was released within 2 days. Finally, the

remaining 20 percent of the drug was released within

five days. This confirms that magnetic γ-

@MIL-53 (AL) is a feasible drug delivery

material (Lee, Hyeon, 2012).

2.1.3 Ion-responsive MOFs

Ion-responsive MOFs open up new drug delivery

pathways. The strong electrostatic interaction

between the drug and the frame enables it to control

the diffusion and release of the drug in the drug

carrier. Therefore, the strong electrostatic interaction

between ionic drugs and ion frames is particularly

interesting because the release of ionic drugs is a

chemically stimulated reaction process that occurs

only in ion exchange. For example, Tamames-Tabar

et al. investigated the cytotoxicity of MOFs

containing Fe, Zn, or Zr central metals on human

cervical cancer cell lines (HeLa) and mouse

macrophages (J774). The cytotoxicity of Fe-MOFs

was less than that of Zn-MOFs and Zr-MOFs.

Although Zn and Fe are trace elements found in the

human body, Zn ions can compete with Fe and Ca

ions to bind ion channels, alter metabolism, and

damage cells. Gao et al. demonstrated Fe-MOFs'

relative biocompatibility by finding that more than

80% of human aortic smooth muscle cells survived

exposure to 200 μg/mL Fe-Mil-53-NH2-FA-5-

FAM/5-FU. Similarly, nh2-MIL-88 (Fe) or NH2-MIL

88(Fe)/Br was incubated at 2000 μg/mL. More than

90% of human primary corneal epithelial cells remain

active, and Fe-MOF exhibits relatively low

cytotoxicity as an imaging agent. The IC50 of MIL-

88A(Fe) on J774 cells was 57±11 μg/mL. Mil-100

(Fe) showed no cytotoxicity to human leukemia cell

line CCRF-CEM and human multiple myeloma cell

line RMI-8226 at 10 mm. By intravenous

administration of 220 mg/kg of Fe-MOFs MIL, the

concentrations of MIL-100 and MIL-88A, MIL-100

and MIL-88B-4CH3 were reduced, supporting the

explanation of MOFs. These things have successfully

become practical iron (Wu, Zhou, Li, 2014).

2.1.4 Temperature-responsive MOFs

In general, temperature-sensitive nanotransporters

are materials that are sensitive to small temperature

variations at a physiological temperature of 37. Sada

et al. demonstrated a switchable UIO-66 PNIPAM

nanocarrier by immersing UIO-66-PNIPam in a guest

solution and loading L2L m-catechol, caffeine, and

procaine into the nanocarrier (Fig. 1a), and then

evaluated the release behavior at 25 oC or 40 oC (Fig.

1b). As expected, the release increases to 25 and stops

at almost 40 (Fig. 1c), indicating that the controlled

release results in temperature changes. In recent

years, two zinc MOFs were synthesized. The anti-

cancer drug MTX was loaded into both MOFs by

single immersion, and the loading amounts of ZJU-

64 and ZJU-64-CHS were 13.45% and 10.63%,

respectively. ZJU-64 and ZJU-64-CH loaded with

MTX were released at 37 oC for 72 h with the same

amount of release, but at 60 oC for 1.5 h and 6 h,

respectively, indicating that ZJU-64 and ZJU-64-CH

have potential application value as temperature-

sensitive drug carriers (Wu, Yang, 2017); (Nagata,

Kokado, Sada, 2015).

Figure 1: a) The controlled release profiles of UiO-66-PNIPAM. b) Release behavior of drug-loaded UiO-66-PNIPAM in the

water at 25 °C and 40 °C for seven days. c) Temperature-responsive release behavior of UiO-66-PNIPAM resorufin in water

at 572 nm (Lin, Hu, Yu, 2016).

Applications of Metal Organic Frameworks in Drug Delivery and Therapy

457

2.1.5 Pressure-responsive MOFs

To avoid premature drug release before reaching

pathological tissues, several effective, responsive

MOFs have been developed to prolong drug release

time and significantly improve treatment outcomes.

In addition to the stimulus-response MOFs

mentioned above, pressure is also used to control

drug release. For example, Qian and colleagues

documented a Zr-based MOF constructed from

(2E,2E)-3,3-(2-fluoro-1,4-benzene) diacrylic acid (F-

H2PDA) and zirconium clusters with a loading

capacity of 58.80 wt% of high-model drug diclofenac

sodium (DS). Different pressures can adjust the

release kinetics of MOF-loaded DS, and the release

time can be extended to 2-8 days. This demonstrates

the effectiveness of stress control drug release

(Nagata, Kokado, Sada, 2015).

2.2 Multiple-Stimuli-responsive MOFs

for Drug Administration

Because of the intricacy of the human environment,

the capacity to precisely convey drugs in people

utilizing single incitement responsive MOF materials

is restricted. Notwithstanding, multi-boost reaction

MOFs can be utilized as a superior choice to further

develop drug load limit and chemotherapy

proficiency (Jiang, Zhang, Hu, 2016); (Ogoshi,

Kanai, Fujinami, 2008); (Strutt, Zhang, Schneebeli,

2014); (Zhang, Zhao, 2013).

By incorporating pH esteem and additionally

serious restricting response techniques into a solitary

medication nanocervator (Fig. 2), the medication

nanocervator with CPS as the terminal has high

embodiment proficiency, unimportant early delivery,

immaterial cytotoxicity, and optimal biodegradability

and biocompatibility. In the R bunch, MOF

multistimulus delicate nanocervors with CP5 ring as

the guard were additionally examined. For instance,

another CP5-covered UIO-66-NH5-FU nanocarrier

was reported. In this work, UIO-66-NHH is adjusted

by the emphatically charged quaternary ammonium

salt Astals (Q) through the contrarily charged CP5

ring arrangement pseudotaxane goes about as an

energizer with responsive supramolecular gating to

direct medication discharge. Because of the great

partiality among zinc and fluorouracil, zinc * can be

utilized as a cutthroat glue to trigger delivery by

specialists. Furthermore, the expanded temperature

will likewise debilitate the non-covalent bond

cooperation among CP5 and the stem, in this manner

animating medication discharge. Thusly, cp5-gated

MOF-based double boost responsive medication

nanocarriers give new freedoms to treating focal

sensory system sicknesses. (Si, Xin, Li, 2015)

Figure 2: Schematic delineation of double improvements responsive DDS dependent on UMCM-1-NH2 NMOF gated by

pillararenes. Recreated under the details of the CC-BY-NC-3-0 unported license (Doane, Burda, 2012).

3 MOFs FOR ANTIBODY

TRANSPORT

As a biological drug, the antibody is an important part

of immunotherapy and plays an important role in

scientific research, medical diagnosis and disease

treatment. However, many biological drugs,

including antibodies, have disadvantages such as

poor internal stability, easy aggregation and easy

degradation, which greatly reduce the efficacy.

Polymer is one of the most commonly used carriers

to maintain antibody stability, but polymer has certain

immunogenicity and lacks biosafety. Therefore, it is

imperative to develop a simple and efficient biologic

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

458

drug stabilization material. So we found that MOFs

are intermediates for drug transport. The advantages

of MOFs as intermediates are as follows.

3.1 Stability and Security Degradation

Yao Chen of Nankai University, and Shengqian Ma,

of the University of South Florida used MOFs as a

protective layer to prevent antibodies from

accumulating or inactivating in complex

environments in the body. The protected antibody has

good thermal, chemical and mechanical stability and

can stay at 4↔50 °C, 25 °C min-1 when temperature

changes rapidly. More importantly, with the right

stimulus, antibodies can be fully released within 10

seconds. At the same time, MOFs are almost all

degraded, avoiding the immunogenicity and

biosafety problems of residual materials (Tan, Song,

Zhang, 2016).

3.2 Antibody Adhesion

MOFs are widely welcomed as drug carriers in the

biomedical field. MOFs is an ideal drug carrier. On

the one hand, there are many ways to bind drug

molecules to MOFs nanoparticles differently. On the

other hand, the combination of drugs and MOFs

nanoparticles can be adjusted to improve the drug

adsorption rate of MOFs nanoparticles. Abhik et al.

synthesized and used Fe

@MIL-100 to load the

anticancer drug doxorubicin. The study structure

showed that Fe

@MIL-100 could improve the

drug loading rate of adriamycin and achieve the

purpose of drug release. Zhou et al. Ni@MOFs-74

(Ni) were synthesized by the one-pot method, and it

was found that Ni@MOFs-74 (Ni) has high porosity

and strong magnetic properties, which can greatly

improve drug loading rate. The results showed that

Ni@MOFS-74 (Ni) loaded ibuprofen up to 4.1 mg/g.

Lazaro et al. used Zr-MOFs combined with

dichloroacetic acid and 5-fluorouracil to enhance in

vitro cytotoxicity (Tan, Song, Zhang, 2016).

3.3 Highly Modifiability

MOFs has good material modification property. The

remaining uncoordinated carboxyl groups in MOFs

are derived. Under the activation of EDC and SULfo-

NHS, antibody molecules were covalently modified

by peptide bonds, and a kind of antibody

functionalized MOFs material was developed. Then

MOFs materials were grown in situ on ZnO

substrates to construct a cell recognition and capture

platform. The captured cells were observed and

counted by ESEM and confocal fluorescence

microscopy. Several factors affecting the capture of

tumor cells by antibody-functionalized MOFs

materials were studied, including co-incubation time,

cell concentration, material morphology and different

cell lines. EpCAM antibody modified MOFs have a

strong specific capture ability for EPCAM-positive

cell lines, and the capture efficiency is greatly

affected by cell concentration and material

morphology. McF-7 cells are preferentially attached

to the needle-like structure of the material. Europium

complex is superior to antibody-functionalized

ZnMOFs in biocompatibility. In addition, the

cytotoxicity of ZnMOFs depends on the amount of

material used. In contrast, the cytotoxicity of the Eu

complex did not change significantly over the range

of concentrations used in the experiment (Tan, Song,

Zhang, 2016).

4 CONCLUSION

In summary, stimulus-responsive MOF materials can

be divided into single stimulus response and multi-

stimulus response. The single stimulus response

includes pH-Responsive MOFs, magnetically-

responsive MOFs, ion-responsive MOFs,

temperature-responsive MOFs and pressure-

responsive MOFs. Magnetic response system has

great advantages in magnetic separation, magnetic

targeting and magnetic resonance imaging. Specific

advantages are reflected in the accurate release of

drugs, accurate imaging and other aspects. The strong

electrostatic interaction between drug and frame

makes MOF material have many advantages in drug

delivery and release. In addition to stimulus-

responsive MOF materials, pressure can also be used

to control drugs. They stand out in the field of drug

delivery because of their strong drug loading

capability, high microbial capacity and easy

functional properties.

More efficient synthesis for MOF materials is a

very promising research direction. The traditional

synthesis method has a long reaction time, high

reaction temperature, large organic solvent, and

complex reaction equipment, which has become the

bottleneck.

REFERENCES

Angelos S, Khashab N M, Yang Y W, et al. (2009) pH

clock-operated mechanized nanoparticles. Journal of

the American Chemical Society, 131(36): 12912-

Applications of Metal Organic Frameworks in Drug Delivery and Therapy

459

12914.

Batten S R, Champness N R, Chen X -M, et al. (2013)

Terminology of metal-organic frameworks and

coordination polymers (IUPAC Recommendations

2013). Pure Appl. Chem., 85: 1715-1724.

Chughtai A H, Ahmad N, Younus H A, et al. (2015) Metal–

organic frameworks: Versatile heterogeneous catalysts

for efficient catalytic organic transformations. Chem

Soc Rev, 44(19): 6804-6849.

Cavka J H, Jakobsen S, Olsbye U, et al. (2008) A new

zirconium inorganic building brick forming metal

organic frameworks with exceptional stability. Journal

of the American Chemical Society, 130(42): 13850-

13851.

Deng H, Doonan C J, Furukawa H, et al. (2010) Multiple

functional groups of varying ratios in metal-organic

frameworks. Science, 327(5967): 846-850.

Doane T L, Burda C. (2012) The unique role of

nanoparticles in nanomedicine: imaging, drug delivery

and therapy. Chemical Society Reviews, 41(7): 2885-

2911.

Eddaoudi M, Kim J, Rosi N, et al. (2002) Systematic design

of pore size and functionality in isoreticular MOFs and

their application in methane storage. Science,

295(5554): 469-472.

Feng Y, Wang H, Zhang S, et al. (2019)

Antibodies@MOFs: an in vitro protective coating for

preparation and storage of biopharmaceuticals.

Advanced Materials, 31(2): 1805148.

Freeman M W, Arrott A, Watson J H L. (1960) Magnetism

in medicine. Journal of Applied Physics, 31(5): S404-

S405.

Hergt R, Dutz S, Müller R, et al. (2006) Magnetic particle

hyperthermia: nanoparticle magnetism and materials

development for cancer therapy. Journal of Physics:

Condensed Matter, 18(38): S2919.

Jurgons R, Seliger C, Hilpert A, et al. (2006) Drug loaded

magnetic nanoparticles for cancer therapy. Journal of

Physics: Condensed Matter, 18(38): S2893.

Jiang K, Zhang L, Hu Q, et al. (2016) Pressure controlled

drug release in a Zr-cluster-based MOF. Journal of

Materials Chemistry B, 4(39): 6398-6401.

Kumar C S S R, Mohammad F. (2011) Magnetic

nanomaterials for hyperthermia-based therapy and

controlled drug delivery. Advanced drug delivery

reviews, 63(9): 789-808.

Lee N, Hyeon T. (2012) Designed synthesis of uniformly

sized iron oxide nanoparticles for efficient magnetic

resonance imaging contrast agents. Chemical Society

Reviews, 41(7): 2575-2589.

Lin W, Hu Q, Yu J, et al. (2016) Low cytotoxic metal-

organic frameworks as temperature-responsive drug

carriers. ChemPlusChem, 81(8): 804.

Ma Z, Moulton B. (2011) Recent advances of discrete

coordination complexes and coordination polymers in

drug delivery. Coordination Chemistry Reviews,

255(15-16): 1623-1641.

Neuberger T, Schöpf B, Hofmann H, et al. (2005)

Superparamagnetic nanoparticles for biomedical

applications: possibilities and limitations of a new drug

delivery system. Journal of Magnetism and Magnetic

materials, 293(1): 483-496.

Nagata S, Kokado K, Sada K. (2015) Metal-organic

framework tethering PNIPAM for ON-OFF controlled

release in solution. Chemical Communications, 51(41):

8614-8617.

Nagata S, Kokado K, Sada K. (2015) Metal-organic

framework tethering PNIPAM for ON0OFF controlled

release in solution. Chemical Communications, 51(41):

8614-8617.

Ogoshi T, Kanai S, Fujinami S, et al. (2008) para-Bridged

symmetrical pillar [5] arenes: their Lewis acid

catalyzed synthesis and host–guest property. Journal of

the American Chemical Society, 130(15): 5022-5023.

Strutt N L, Zhang H, Schneebeli S T, et al. (2014)

Functionalizing pillar [n] arenes. Accounts of chemical

research, 47(8): 2631-2642.

Si W, Xin P, Li Z T, et al. (2015) Tubular unimolecular

transmembrane channels: construction strategy and

transport activities. Accounts of chemical research,

48(6): 1612-1619.

Tan L L, Song N, Zhang S X A, et al. (2016) Ca

, pH and

thermo triple-responsive mechanized Zr-based MOFs

for on-command drug release in bone diseases. Journal

of Materials Chemistry B, 4(1): 135-140.

Wu Y, Zhou M, Li S, et al. (2014) Magnetic metal-organic

frameworks: γ‐Fe2O3@MOFs via confined in situ

pyrolysis method for drug delivery. Small, 10(14):

2927-2936.

Wu M X, Yang Y W. (2017) Metal-organic framework

(MOF)‐based drug/cargo delivery and cancer therapy.

Advanced Materials, 29(23): 1606134.

Zhang H, Zhao Y. (2013) Pillararene‐based assemblies:

Design principle, preparation and applications.

Chemistry-A European Journal, 19(50): 16862-16879.

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

460