Triple negative breast cancer: new therapy with metal-organic frameworks

Researchers at the University of Arkansas have developed a new nano drug candidate that kills triple negative breast cancer cells.

Triple negative breast cancer is one of the most aggressive and fatal types of breast cancer. The research will help clinicians target breast cancer cells directly, while avoiding the adverse, toxic side effects of chemotherapy.

Their study was published in June issue of Advanced Therapeutics.

Researchers led by Hassan Beyzavi, assistant professor in the Department of Chemistry and Biochemistry, linked a new class of nanomaterials, called metal-organic frameworks, with the ligands of an already-developed photodynamic therapy drug to create a nano-porous material that targets and kills tumor cells without creating toxicity for normal cells.

Metal-organic frameworks are an emerging class of nanomaterials designed for targeted drug delivery. Ligands are molecules that bind to other molecules.

“With the exception of skin cancers, breast cancer is the most common form of cancer in American women,” said Beyzavi. “As we know, thousands of women die from breast cancer each year.

Patients with triple negative cells are especially vulnerable, because of the toxic side effects of the only approved treatment for this type of cancer.

We’ve addressed this problem by developing a co-formulation that targets cancer cells and has no effect on healthy cells.”

Researchers in Beyzavi’s laboratory focus on developing new, targeted photodynamic therapy drugs. As an alternative to chemotherapy – and with significantly fewer side effects – targeted photodynamic therapy, or PDT, is a noninvasive approach that relies on a photosensitizer that, upon irradiation by light, generates so-called toxic reactive oxygen species, which kill cancer cells.

In recent years, PDT has garnered attention because of its ability to treat tumors without surgery, chemotherapy or radiation.

Beyzavi’s laboratory has specialized in integrating nanomaterials, such as metal-organic frameworks, with PDT and other and therapies. Metal-organic frameworks significantly enhance the effectiveness of PDT.

Doctoral student Yoshie Sakamaki from Beyzavi’s laboratrory prepared the nanomaterials and then bio-conjugated them with ligands of the PDT drug to create nanoporous materials that specifically targeted and killed tumor cells with no toxicity in normal cells.

In addition to cancer treatment, this novel drug delivery system could also be used with magnetic resonance imaging (MRI) or fluorescence imaging, which can track the drug in the body and monitor the progress of cancer treatment.

This collaborative project also included contributions from U of A research groups through Julie Stenken, professor of analytical chemistry; Yuchun Du, associate professor of biological sciences; and Jin-Woo Kim, professor of biological and agricultural engineering.

The American Cancer Society estimated 268,600 new cases of invasive breast cancer in 2019 and 41,760 deaths. Currently there are more than 3.1 million breast cancer survivors in the United States. Since 2007, breast cancer death rates have been steady in women younger than 50 but have continued to decrease in older women.

This decrease is believed to be the result of earlier detection and better treatments.

Triple negative breast cancer is aggressive and lacks estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2, which means it cannot be treated with receptor-targeted therapy.

It is difficult to treat with existing chemotherapy and often requires surgery because it quickly metastasizes throughout the body.

Cytotoxic chemotherapy is the only approved treatment for this type of breast cancer.

More than 80% of women with triple negative breast cancer are treated with chemotherapy regimens that include anthracyclines, such as doxorubicin, which can cause cardiotoxicity as a serious side effect.

Furthermore, chemotherapy treatment of breast cancer cell lines using either 5-FU, cisplatin, paclitaxel, doxorubicin or etoposide have shown multi-drug resistance.

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Synthesis, Functionalization, and Biomedical Applications of MOFs

2.1. MOFs Synthesis and Functionalization

So far, many synthetic methods of MOFs have been reported, such as the solvothermal method, rapid precipitation method, one-pot synthesis, reverse microemulsion, a rapid microwave-assisted method, ultrasonic synthesis, and so on.

The synthesis methods and drug loading characteristics of different MOFs are listed in Table 1. Several types of MOFs are discussed in this article. Table 2 categorizes MOFs and lists representative MOFs.

Table 1 – Synthesis and functionalization of metal organic frameworks.

Drug Delivery System	Synthetic Method	Loading Capacity	Release Rate	Achievement	Ref.
DOX @ZIF-8	One-pot synthesis	20%	95% (pH 5–6, 37 °C, 7–9 days)	pH-responsive	[26]
PEG-FA/(DOX+VER)@ZIF-8	One-pot synthesis	8.9% (DOX) 32% (VER)	27.37% (DOX) 76.48% (VER) (pH 5, 37 °C, 24 h)	pH-responsive, Overcoming multidrug resistance	[27]
5-FU+DOX @ZIF-90	Ultrasonic stirring	36.35% (5-FU) 13.5% (DOX)	95% (5-FU, 15 h) 91% (DOX, 25 h) (pH 5, 37 °C)	pH-responsive, Combination therapy	[19]
DOX @ZIF-8 NTs	Template-directed synthesis	350% (drug/mo-fs)	72% (DOX) (pH 5, 37 °C, 50 h)	pH-responsive, Ultra-high drug loading and long-acting cycle	[22]
FA/5-FU @IRMOF-3	Solvothermal method	20.4%	68% (37 °C, 96 h)	pH-responsive, Active targeting	[9]
DOX @TTMOF	One-pot synthesis	14.3%	78% (10 mM DTT, pH 7.4, 37 °C, 140 h)	pH-responsive, Redox responsive	[15]
PD/M-NMOF	AOT microemulsion method	4.3% (MB) 0.69% (dox)	72% (MB) 95% (Dox)	Magnetic-responsive Light-responsive	[28]
PTX/Fe3O4@IRMOF-3	mixed solvent solvothermal method	12.32%	65% (pH 7.4, 37 °C, 100 h)	Magnetic-responsive	[10]
mCGP	solvothermal method	13.5% (glucose oxidase and catalase)	/	Starvation and Photodynamic Therapy	[29]
MB @THA-NMOF-76 @cRGD	rapid microwave-assisted method	3 ug/mg (MB)	/	Light-responsive, Active targeting	[20]
Gd-MTX NCP	microwave heating	79.1% (MTX)	100% (pH 7.4, 37 °C 192 h)	Active targeting	[30]
Fe-MIL-53- NH2-FA-5- FAM/5-FU	a reflux method at low temperature	23%	the gentle release for 25 h in pH 7.4 for 20 h in pH 5	Light-responsive, Magnetic-responsive Active targeting	[31]
ZIF-8/5-FU @FA-CHI- 5-FAM	solvothermal method	51%	complete release (pH 7.4, 37 °C, 45 h pH 5, 37 °C, 21 h)	Light-responsive, pH-responsive, Active targeting	[32]
FA/5-FU @MOF-808	stirring-reflux method	38.42%	60–70% (pH 5, 37 °C, 24 h)	pH-responsive, Active targeting	[33]
FA/5-FU@ NH2-UiO-66	stirring-reflux method	30.26%	60–70% (pH 5, 37 °C, 24 h)	pH-responsive, Active targeting	[33]
CoFe2O4@Mn-MOF	layer to layer method	75 ± 1.22% (Encapsu-lation efficienc-y)	55% (pH 7.4, 37 °C, 20 h)	Magnetic-responsive	[34]
BSA/Cu/NQ NP	protein-nanoreactorv method	13.6%	/	Active targeting	[35]
Fe-soc-MOF@PPy	The liquid-solid- solution (LSS) method	15%	/	Light-responsive	[21]

Table 2 – The molecular formula of the metal organic frameworks (MOFs) that appear in this article.

Classifications	Abbreviations	Examples	The Molecular Formula	Ref
Isoreticular Metal Organic Frameworks	IRMOF-n	IRMOF-3	C24H5N3O13Zn4	[9]
Materials of Institute Lavoisier	MIL-n	NH2-MIL-53 (Fe)	C8H6NO5Fe	[31]
Zeolitic Imidazolate Frameworks	ZIF-n	ZIF-8	C8H10N4Zn	[27]
ZIF-90	C4H4N2OZn	[12]
University of Oslo	UiO-n	NH2-UiO-66	C48H30NO32Zr6	[11]
Zhejiang University	ZJU-n	ZJU-801	C12H4O32Zr6	[36]

Usually, metal organic frameworks are synthesized by solvothermal method, which is one of the most classical methods for the synthesis of MOFs. For instance, Yang and coworkers used solvothermal method to synthesize IRMOF-3 [9].

The folic acid (FA) was then modified on IRMOF-3 by post-synthesis modification. Similarly, Angshuman et al. utilized a mixed solvent solvothermal method to get Fe₃O₄@IRMOF-3 [10].

The material was placed in a mixed solvent of DMF and pure ethanol containing PVP, and then heated at 100 °C for 4 h to obtain a dark brown nano materials. Particle size of synthetic IRMOF-3 was less than 100nm, and the particle size of Fe₃O₄@IRMOF-3 was about 200 nm.

The hydrophobic nano-platform encapsulated paclitaxel, which had a drug loading of 12.32% and released 65% under physiological conditions for 4 days. In addition, the brown N₃-UiO-66-NH₂ was synthesized by Nian using solvothermal method [11].

These nanocrystals were consistent in size and had good drug loading properties. However, sometimes nanoparticles synthesized by solvothermal method may have a large particle size, which is not conducive to targeted administration by post-synthesis modification.

Therefore, we need to properly control the ratio of metal ions to organic ligands and the conditions under which the reaction is made to control the size of the particles, thereby promoting the functionalization of the drug-loaded particles.

In the end, we still need to use some characterization methods (particle size distribution, scanning electron microscope, transmission electron microscope) to evaluate the dispersity of the nanoparticles.

The nanoparticles with smaller particle size can be synthesized by the rapid precipitation method, but the nanoparticles obtained by the method are usually cluster-like, have no fixed crystal form, and rarely obtain single crystal.

Christopher synthesized ZIF-90 with different particle sizes (60–90 nm, 200–300 nm, 100–200 nm) by adding different amines (trioctylamine, tributylamine, trimethylamine) (Figure 1) [12]. This method can quickly synthesize metal organic framework particles.

As the reaction temperature increases, the particle size also increases gradually. This method can rapidly synthesize MOF particles, usually constituting a precipitate at the moment of amine addition.

One-pot synthesis method is also widely developed in the preparation of metal organic frameworks. The most well-known ZIF-8 can be synthesized in this way. Shi prepared CQ@ZIF-8 by one-pot method with a drug-loading of 18% [13].

The particles were regular octahedral structures with an average particle size of 250 nm. ZIF-8 is consistent under physiological conditions and is easily degraded under acidic conditions. These features are beneficial to the targeted transport of the nanoparticles. Coincidentally, Song also synthesized the photosensitizing target formulation ZnPc@ZIF-8/CTAB by the same method, with a drug-loading of 29.5% [14].

After the release of the photosensitizer ZnPc, the intracellular reactive oxygen species increased, thereby producing an anticancer effect. The one-step synthesis of ZIF-8-based nano drug loading systems is appropriate and can target weak acidic environments, and it has attracted much attention as a host for delivering both hydrophilic and hydrophobic drugs. In addition, one-pot synthesis was administered by Wang et al. who obtained the tumor targeting MOF of pH response and redox response (DOX@TTMOF) [15].

Additionally, Shi and coworkers developed Ce-MOF by one-step synthesis [16]. They then combined ATP aptamer to the Ce-MOF modified on the bare gold electrode. ATP aptamer could detect serum ATP in tumor patients by electrochemical impedance spectroscopy. The precise diagnosis of tumors is the basis of accurate tumor treatment.

In addition, Su et al. obtained UiO-66@AgNCs@Apt@DOX by one-pot encapsulation, who’s loading efficiency was twice that of two separate processes [17]. All of the above demonstrate the simplicity and efficiency of one-step synthesis. One-step synthesis has been the choice of most researchers for the development of drug-loaded MOFs.

However, when a part of the metal organic frameworks was used for drug loading, it is often requested that the drugs have a strong interaction with the carrier to achieve a high drug loading capacity. For example, ZIF-8 can be successfully used in one-step synthesis and drug delivery only if the transported drugs have an acidic group.

However, not all effective drugs have acid groups, which greatly affects the use of ZIF-8 as a drug carrier. Therefore, a strategy is urgently needed to compensate for this shortcoming. Zhang et al. wanted to load Cytarabine (Ara) with ZIF-8, but because of the lack of a drug-acting group, it was not possible to achieve high drug loading capacity [18]. Therefore, they proposed that Cytarabine (Ara) combined with New indocyanine green (IR820) to form a prodrug together encapsulated in ZIF-8, this strategy greatly increased the drug loading capacity, which suggests that we can strengthen affinity between the carriers and the drugs by structural modification or other methods to increase the drug loading capacity of MOFs.

Other methods are also provided for the synthesis of metal organic frameworks. Zhang and his group used vigorously stirring in combination with ultrasonic condition to synthesize ZIF-90 [19]. In this way, they synthesized ZIF-90 with a particle size of less than 300 nm to serve as drug carriers.

They used ZIF-90 to load both 5-FU and DOX, which improved the efficacy and overcame the problem of drug resistance. In addition, this drug delivery system could rely on pH for targeted drug delivery.

A rapid microwave-assisted method was utilized by Jia et al. who synthesized MB@THA-NMOF-76@cRGD (HTHA = 4,4,4-trifluoro-1-(9-hexylcarbazol-3-yl)-1,3-butanedione, MB = methylene blue, NMOF = nanoscale metal−organic framework, and cRGD = cyclic ArgGly-Asp peptide) [20].

his drug loading system has an average particle size of 89 nm and good uniformity. Through x-ray diffraction, scanning electron microscope, and thermogravimetric analysis, it was proved that the components of the system were modified.

The author also studied its stability and found that the system is highly resistant to light and acid. The liquid-solid-solution (LSS) method was reported by Cai who synthesized Fe-soc-MOF to achieve photothermal therapy [21].

The nanosystem has a particle size of about 100 nanometers, which is much smaller than those synthesized by other methods. Another unique approach was introduced by Yu et al. who employed a template-directed synthesis strategy [22].

In brief, this strategy relied on the growth of skeletal and interconnected ZIF-8 crystals on a long and soft filamentous micelle, which was finally removed by extraction to obtain zif-8 hollow nanotubes.

This nanotube had an ultra-high drug loading rate of 350% and was effective in avoiding the reticuloendothelial system (RES), forming a long-acting cycle (about one week). Cao used a surfactant to assist synthesize ZIF-8 hollow nanospheres and encapsulated 10-HydroxyCamptothecin (HCPT) for tumor therapy [23]. It provided a new idea for the synthesis of MOFs.

With the in-depth study of MOFs, single nanocarriers often have certain defects, accompanied by low drug loading, burst release, and so on. The poor biocompatibility of some metal organic frameworks also limits their clinical application. In recent years, researchers have worked to solve these problems.

In this context, composite nanocarriers have been shown to be better for the treatment of cancer. For example, MnCo-MOF has strong toxicity and its application in vivo is dangerous. Wang and colleagues developed a polydopamine hybrid nanogels [24].

The nanosystem could effectively reduce the toxicity of the MOFs and improve the photothermal conversion efficiency of the photosensitizer. In vitro and in vivo experiments show that the materials had good biocompatibility and excellent photothermal effect. This strategy suggests that we can extend it to therapeutic applications of other MOFs.

Other than this, Abhik and coworkers studied the effects of complexes of Fe3O4 nanoparticles and MOFs on the drug loading and releasing behaviors [25]. They found that the drug loading of the composite was higher than that of a single nanocarrier.

The materials had not burst release behavior, and the loaded doxorubicin could be released for 25 days. Even in the first few days, Fe3O4@MIL-100 did not have any sudden release behavior.

All the above experiments are excellent examples of MOFs-based composite materials for targeted anti-cancer treatment. This indicates that we can further develop multifunctional composite materials based on MOFs to conduct anti-cancer research at a higher level.

Properties of Metal Organic Frameworks Regarding Drug Delivery Applications

The metal organic frameworks usually have a large specific surface area, a large pore diameter, good biocompatibility, non-toxic to the human body and easy to be metabolized. Therefore, MOFs are suitable as carriers for drug delivery.

In order to increase the drug loading capacity, control the rate of drug release, and deliver the drug to the destination accurately, we need to rationally adjust the pore size, particle size, stability, and other properties of the MOFs. Here, we only briefly introduce the three basic characteristics of MOFs that need to consider as drug carriers.

The Effect of Pore Size of MOFs on the Drug Loading Capacity

Although the pore size of MOFs is adjustable, its regulation ability is restricted. Generally, a larger pore size means a higher drug loading capacity. In recent years, some researchers have prepared hollow MOFs to pursuit higher drug loading capacity and multi-functional targeted drug delivery.

For example, Gao et al. synthesized hollow ZIF-8, which had a drug loading capacity of 51% and modified three substances [32]. In addition, we can also modify the pore size of MOFs by changing organic ligands to improve drug loading capacity.

In recent years, there have been few studies in this field, which provides a new direction for our future research, to study the effects of metal organic framework nanoparticles with different pore sizes on drug loading performance.

Particle Size Control to Achieve Functional Transfer of MOFs and Improve Biocompatibility

Particle size is another important property of drug-loaded MOFs. The particle size can determine the targeting ability of the drug delivery system. When the particle size is around 100 nm, the drug loading system is relatively easy to passively target to cancerous tissues. This phenomenon will be described in detail later.

In order to achieve active or multi-functional targeting, the particle size of metal organic frameworks should preferably be within 100 nm to avoid clearance by macrophages of the reticuloendothelial system and liver.

Therefore, it is necessary to control the particle size of MOFs. In a typical example, Duan et al. devoted research to controlling the particle size of AZIF-8 (amorphous zeolitic imidazolate framework-8) by a simple method and studying the effects of its particle size on the treatment of tumors [37].

They used nontoxic poly-allylamine hydrochloride (PAH) to precisely control the size of the AZIF-8 by one-pot synthesis method, which broke the tradition of being unable to control the MOFs’ particle size precisely and the need for toxic solvents for synthesis and modification.

The addition of PAH could change the nucleation rate of AZIF-8, which affected the particle size of AZIF-8. The more PAH, the larger the particle size of AZIF-8, but the other physical and chemical properties were not covered.

Through a series of in vitro and in vivo studies, AZIF-8 at 60 nanometers had the best curative effects with excellent biocompatibility and high tumor uptake capacity.

Gao needed to perform magnetic sensitization, light sensitivity, active targeting, and load chemotherapeutic drugs at the same time [31]. Thus, they studied the factors influencing the particle size.

They concluded that the lower the concentration of the reactants, the larger the particle size of Fe-MIL-53-NH2. Additionally, Gao et al. studied the effects of benzoic acid on the particle size of UIO-66-NH2 and synthesized it by a hydrothermal method [38].

Unlike the above, the lower the benzoic acid, the smaller the particle size. Therefore, these experiments also reflected the effect of reactant concentration on the particle size of MOFs. However, these studies only proved the factors affecting particle size, and there lacked the study of particle size for effectiveness and safety.

Some studies only considered the drug-loading capacity, but ignored the effects of particle size on the circulation in the body. Even with the highest drug-loading, the drug loading system is rapidly metabolized and even causes death of model animals after entering the systemic circulation.

Therefore, the therapeutic effects cannot be achieved. Such researches are obviously lacking in value. In recent years, MOFs-based nanocarriers used for cancer treatment have a large difference in particle size, and there is a lack of comprehensive evaluation of the particle size in their application. This also provides direction for our future researches.

Stability of MOFs: Another Property to Consider

Stability is the most basic requirement for the drug-loading systems. In order to improve the efficacy and reduce the toxicity of anticancer drugs, some intelligent drug-loaded nanosystems have begun to attract people’s attention.

First, these nanoparticles should be stable when stored in vitro to ensure efficacy and safety. Then these drug-loaded nanosystems in vivo are preferably stable prior to reaching the target site and responsive to release of the drug at the tumor site.

Rachel obtained Zn-MTX NCP (MTX = methotrexate, NCP = nanoscale coordination polymers) and Zr-MTX NCP materials using Zn2+ and Zr4+ as metal ions, respectively, using the high-temperature surfactant-assisted method and the microwave heating method, and found that both were unstable [30].

The reason might be that the particles would polymerize in the water to break the surface liposome. Finally, they employed microwave heating method to obtain Gd-MTX NCP. Then the phospholipid bilayer was utilized to wrap the metal organic framework. It was noted that the drug-loading system was stable.

Therefore, the establishment of any drug-loading system should take into full consideration the influence of each element on its stability. However, more research is needed on the effects of stability on the body’s efficacy and toxicology.

Applications of Metal Organic Frameworks in Targeting Cancer

Normal cells rely on the integrity of regulatory circuits that control cell proliferation and maintenance. The regulatory circuits are disrupted in cancer cells, and the type and behavior of the cancer cell vary depending on the type of damage caused to the regulatory circuits [39].

This particularity can be exploited against tumor cells in attempts to treat the disease, using passive targeting, active targeting, physicochemical targeting, or a combination of the three [40].

The use of targeted MOFs can also solve the lack of selectivity of some drugs, since they can host, transport and direct the therapeutic agents to the tumor selectively. This strategy permits to allow for a reduction in the dose required for conventional chemotherapy, increasing therapeutic efficacy and diminishing undesired side effects.

Specific cells and organs within the body can also be targeted by modifying the nanomaterials’ surface with antibodies or appropriate ligands. For example, Chen et al. reported the Zr-UiO-66 was further functionalized with pyrene-derived polyethylene glycol (Py−PGA-PEG) and conjugated with a peptide ligand (F3) to nucleolin for targeting of triple-negative breast tumors [41].

Functionalized Zr-UiO-66 demonstrated strong radiochemical and material stability in different biological media. Based on the findings from cellular targeting and in vivo positron emission tomography (PET) imaging, the author concludes that Zr-UiO-66/Py−PGA-PEG-F3 can serve as an image-guidable, tumor-selective cargo delivery nanoplatform. Figure 2 summarizes the types of tumor targeted therapies. Table 3 summarizes the strategies for targeted therapy using MOFs in recent years.

Table 3

Targeting strategies for metal organic frameworks.

Targeting Cancer Cell
Drug	Target	Target Cell Line	Targeting Type	Ref.
BSA/SAs@MOF	CA IX	4T1 cancer cells	Light-responsive	[42]
Caspase-FA/TMPyP@MOF	FRs	HeLa cells	Light-responsive	[43]
FA/5-FU @IRMOF-3	FRs	HeLa cells, lung adenocarcinoma A549 cells, KB cells	Active targeting	[9]
PNA@UiO-66	miRNAs	MDA-MB-231, MCF-7	Gene-responsive	[44]
Polymer-Modified Gd MOF	αvβ3-integrins	FITZ-HSA tumor cells	Magnetic-responsive Light-responsive	[45]
CPC@MOF	CaB	HeLa cells	Light-responsive	[46]
mCGP	(4T1) cancer cell membrane	4T1 cancer cell, B16F10 cells, HepG2 cells, COS7 cells	Starvation and Photodynamic Therapy	[29]
MB @THA-NMOF-76 @cRGD	αvβ3-integrins	HeLa cells, A549 cells	Light-responsive, Active targeting	[20]
Gd-MTX NCP	sigma receptors	Jurkat ALL cells	Active targeting	[30]
Zr(IV)-based porphyrinic MOF–UCNP	epidermal growth factor receptor	The MDA-MB-468 cells	Gene-responsive, Light-responsive	[47]
Fe-MIL-53- NH2-FA-5- FAM/5-FU	FRs	MGC-803 and HASMC cells	Light-responsive, Magnetic-responsive Active targeting	[31]
ZIF-8/5-FU @FA-CHI- 5-FAM	FRs	MGC-803 cells	Light-responsive, pH-responsive, Active targeting	[32]
UCNPs@MOF- DOX-AS1411	nucleolin	MCF-7 cells	Light-responsive, pH-responsive, Active targeting	[48]
UCNPs@ZIF-8/FA/5-FU	FRs	HeLa cells, mouse fibroblast (L929) cells	Light-responsive, pH-responsive, Active targeting	[49]
MOF@HA@ICG	CD44	MCF-7 cancer cells	Light-responsive, Active targeting	[50]
Fe-soc-MOF@PPy	/	4T1 cancer cells	Light-responsive	[21]
FA@Ni-hemin metal organic framework	FRs	MCF-7 cancer cells	Active targeting, Redox responsive	[51]
PEG-FA/PEGCG@ZIF-8 NPs	FRs	HeLa cells	pH-responsive, Active targeting	[52]
Streptavidin/GOx@ZIF-8-AuNCs	biotinylated antibody against galectin-4	colorectal cancer, breast hepatocellular carcinoma, gastric cancer, etc.	Active targeting, Light-responsive	[53]
RGD@CPT@ZIF-8	αvβ3 receptor	HeLa cells	Active targeting, pH-responsive	[54]
DOX@MOFs-Glu	glucose-transported protein (GLUT1)	HeLa cells	Active targeting, pH-responsive, the magnetic resonance (MR) imaging	[55]

Passive Targeted Therapy Used Metal Organic Frameworks
Passive targeting refers to the targeting of nano-targeted drug system on specific organs or disease sites according to the physiological mechanism after entering the blood circulation through intravenous injection.

The nanoparticles were widely used in the anti-tumor drugs delivery system, because they have an ability to target tumor tissue passively, which is due to the enhanced permeation and retention effect (EPR effect.). Jihye et al. studied the passive targeting function of PCN-224 with different particle sizes [56]. They verified that MOFs can enhance photodynamic efficacy. Photosensitizers without MOFs get the lowest cytotoxicity.

TCPP@PCN-24 with a particle size of 90 nm has the best photodynamic therapy effect, and TCPP@PCN-24 with a particle size of 190nm has the worst effect. Duan also proved that 60nm AZIF-8 has better anti-tumor effect than other particle sizes, due to the strongest retention effect in the tumor area of this particle size [37].

Active Targeted Therapy Based on Metal Organic Frameworks

Active targeted therapy is to transport the drug system to a specific part by means of the high affinity between the ligands and the overexpressed receptors on the targeted cell surface. Researchers can generally modify the surface of drug-loaded MOFs so that it is not recognized by macrophages.

In addition, researchers can attach specific ligands (such as folate, RGD peptide, aptamers, etc.) on metal organic frameworks to target receptors (folate receptors, etc.). In addition, MOFs linked by monoclonal antibodies become immune microspheres to avoid macrophage uptake. Furthermore, researchers can modify MOFs into pharmacologically inert physics and activate them when they reach the surrounding cancer cells, so as to exert pharmacodynamic effect.

Modification of MOFs with folic acid is currently the most commonly used for targeted therapy. Since folate receptors are overexpressed on the surface of cancer cells. Folic acid can specifically bind to them, and then the drugs are focused and released in cancerous tissues. For example, Jihye and coworkers used folic acid to modify TCPP@PCN-224 which improved the efficacy of the original nano drug delivery system [56].

Same as above, folic acid was modified by Li et al. on a metal organic framework to get FA/DOX@UiO-68 [57]. They injected different substances into the tail vein of liver cancer mice. Tumors in the FA/DOX@UiO-68 group were smaller than those in the doxorubicin.

Targeted anticancer activity of the nanosystem was confirmed by internal and external stimuli responses. Laha and his companions obtained IRMOF-3@CCM@FA in a one-step process, which also utilized folic acid to deliver curcumin to the triple negative breast cancer cells [58]. A series of in vivo and in vitro experiments demonstrated the superior targeting performance of this strategy.

Of course, there are some other overexpressed receptors on the surface of cancer cells, and researchers can use any of these receptors for active targeted therapy. For example, anisamide (AA) can specifically recognize sigma receptors on the surface of cancer cells. Based on this principle, Rachel used A DOPE-AA (DOPE = dioleoyl l-α-phosphatidyl-ethanolamine) in combination with Gd-MTX NCPs to kill leukemia cancer cells [30].

In addition, Hyaluronic acid specifically recognized overexpressed CD44 on the surface of tumor cells [50]. Therefore, MIL-100 (Fe) nanoparticles could aggregate in tumor tissues by modifying hyaluronic acid on their surfaces. MOF@HA@ICG NPs showed better photothermal effect at the tumor site by comparison with ICG and non-hyaluronic acid-modified drug-loaded MOFs (MOF@ICG NPs).

Similarly, taken into account this strategy, Chen and colleagues have also developed VEGF (vascular endothelial growth factor)-responsive doxorubicin-loaded NMOFs, and the experimental results were also satisfactory [59].

This gating strategy has inspired researchers to find other suitable ligands for targeted therapies. More importantly, this strategy is not confined to the treatment of tumors, and other difficult diseases that have overexpressed receptors are applicable.

Hu and coworkers synthesized Rho-BSA/Cu/NQ nanoparticles (NPs) based on albumin as a reactor for a simple method [35]. In particular, the nanoplatform had good solubility, therefore it may be used for injection administration.

Owing to its ability to actively target, the system can have a high utilization rate at the target site. Based on a large number of previous studies, Hu has conducted a series of in vitro and in vivo experiments to demonstrate the potential for clinical application of the drug delivery system with highly effective utilization, excellent stability, superior biosafety.

The success of these researches suggests that researchers can load any other applicable drug into this system for efficient cancer treatment.

Qi et al. modified anti-EpCAM antibodies to ZnMOFs, which specifically capture tumor cells [60]. Additionally, in Li’s report, a biomimetic theranostic O2-meter was introduced to people [61].

It referred to the modification of tumor cell membrane fragments on the surface of MOFs, so that it could identify tumor tissues efficiently, and could avoid the phagocytosis of macrophages and achieve immune escape. The biomimetic nanosystem will be described in detail later.

There are numerous specific receptors on the surface of cancer cells that can be used as targets for tumor diagnosis and treatment. The active targeting strategy is simple and easy, coupled with the unique affinity for tumor cells, greatly increasing the efficiency of targeted therapy. Therefore, active targeted therapy has become an indispensable part of anti-cancer research based on MOFs in recent years.

Reference : Link

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More information: Yoshie Sakamaki et al, Maltotriose Conjugated Metal–Organic Frameworks for Selective Targeting and Photodynamic Therapy of Triple Negative Breast Cancer Cells and Tumor Associated Macrophages, Advanced Therapeutics (2020). DOI: 10.1002/adtp.202000029