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Review

The Applications of Metallacycles and Metallacages

by
Changfeng Yin
1,
Jiaxing Du
1,
Bogdan Olenyuk
2,
Peter J. Stang
3,* and
Yan Sun
1,*
1
Key Laboratory for Special Functional Materials of Ministry of Education, National & Local Joint Engineering Research Center for High-Efficiency Display and Lighting Technology, School of Materials Science and Engineering, Collaborative Innovation Center of Nano Functional Materials and Applications, Henan University, Kaifeng 475004, China
2
Proteogenomics Research Institute for Systems Medicine, La Jolla, CA 92037, USA
3
Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA
*
Authors to whom correspondence should be addressed.
Inorganics 2023, 11(2), 54; https://doi.org/10.3390/inorganics11020054
Submission received: 21 December 2022 / Revised: 19 January 2023 / Accepted: 20 January 2023 / Published: 22 January 2023
(This article belongs to the Special Issue Metallamacrocycles and Metallacages: Foundations and Applications)
Browse Figures
Versions Notes

Abstract

:
Metallacycles and metallacages constitute a class of coordination compounds composed of metal ions and organic ligands. Because of their precise stoichiometry, the flexibility and viability of design, metallacycles and metallacages have attracted considerable attention as supramolecular assemblies. Various two-dimensional polygons, three-dimensional polyhedra, and other nanoscale materials have been constructed and applied. The highly diverse structures, sizes, and shapes endow metallacycles and metallacages with unique physical and chemical properties and make them suitable for various applications such as encapsulation, separation, catalysis, and biological science. Herein, we review the recent developments in various metallacycles and metallacages in different fields. The text highlights biomedical applications involving molecular recognition and binding, antibacterial activity, and especially cancer diagnosis and treatment, including imaging, chemotherapy, PDT, and PTT.

Graphical Abstract

1. Introduction

Metallacycles and metallacages are members of a class of metal organic complexes (MOCs) that are accessed through coordination-driven self-assembly [1,2,3,4]. The bonding between metal and ligand, which serves as the driving force for assembly, promotes the formation of two-dimensional polygons, three-dimensional polyhedra, and other nanoscale materials [5,6,7]. Different kinds of organic ligands can be used as building blocks to prepare metal organic complexes, such as bis-pyridyl, ter-pyridyl, and heterotopic ligands. Recently, researchers have prepared many types of metallacycles and metallacages with different shapes and sizes, such as triangles [8,9,10], rectangles [11], hexagons [12,13,14], trigonal prisms [15], hexagonal prisms [16,17], and cubes [18,19], in which the overall performance can be designed to achieve interesting properties and functions through the interaction between metal centers and ligands. For example, tetraphenylethylene (TPE), boron-dipyrromethene (BODIPY), and porphyrin have been employed to endow fluorescent and imaging abilities. Significant progress has been made in the development of Pt- and Pd-based metallacycles and metallacages due to the efforts of Stang, Fujita, and other groups. In addition, other metal centers, such as Ru [20,21,22], Fe [23,24], Ir [25,26], Zn [27], Ni [28], and Co [29,30], can also be introduced into various metallacycles and metallacages.
Metallacycles and metallacages have attracted considerable scientific interest because of their advantages of well-organized architectures and tunable sizes and their unique structure and excellent application prospects [13], including guest recognition [31], encapsulation [32], separation [33], catalysis [29], sensing [34], drug delivery [18], etc. With increased structural complexity and novel designs of metal acceptors and ligand donors, biological studies related to metallacycles and metallacages have been widely carried out, with these complexes being used as anticancer agents, drug carriers, and photosensitizers in chemotherapeutic or phototherapeutic treatment. Multiple functional systems involving metallacycles and metallacages can also be constructed to reduce biological toxicity and side effects and enhance enrichment in tumors via active or passive target transport; this strategy is the same as that used for nanodrug delivery systems [35,36].
In this review, a number of metallacycles and metallacages based on different metal centers are introduced. More importantly, we present recent developments in different fields, with a focus on biological applications.

2. Applications of Metallacycles and Metallacages

2.1. Encapsulation and Separation

With well-defined shapes and cavities, host-guest inclusion complexes can be formed through weak interactions, which have attracted the attention of scientists in the field of supramolecular chemistry, and numerous systems have been developed to investigate the encapsulation and separation of various guests. To realize the recognition process, it is necessary to maintain a relatively short distance between the guest and the host molecule, which requires matching their size and shape. In this regard, metallacycles and metallacages formed by the self-assembly of metal ions and organic ligands may provide obvious advantages for tunable structures and sizes.
The anion encapsulation and separation ability of metallacages open up future applications in extraction and recovery. Nitschke and coworkers reported a Co12L6 cuboctahedron metallacage M1 (Figure 1a) that is able to cooperatively bind neutral guests and anions [37]. They also prepared an azaphosphatrane-functionalized Fe4L4 tetrahedron metallacage M2 and investigated the hydrogen-bond donating ability of +P-H through anion recognition [38]. Based on the strong electrostatic driving force, the affinity of the hydrogen bond donor, and its good solubility and flexibility, M2 can encapsulate anions within the volume range of 35–219 Å3 inside the cavity. In subsequent work, researchers reported that M2 was able to extract equimolar amounts of ReO4- and TcO4- from water into nitromethane (Figure 1b) [39]. This work demonstrated the feasibility of metallacages for two-phase extraction. Fujita’s group constructed a trinuclear Ir(III)-based metallacage M3 that contained three adaptive binding pockets on its rim and was capable of recognizing anions. Anions were recognized and bound on the rim instead of being encapsulated into the cavity [25].
It is necessary to develop selective confinement technology for rare earth metal ions. Fujita and coworkers reported a cationic octahedral metallacage M4, which consisted of PdII coordination blocks and tridentate electron-deficient ligands. The cavity of M4 can selectively isolate rare earth metal ions (La3+-Eu3+) under the action of tripodal anionic caps in a solution state, in which the hydrates are recognized in the isolated space [40]. Benefiting from the cap-like counteranions in the cage’s portals, early lanthanoid(III) ions could be selectively encapsulated into the metallacages from a mixture of two different metal ions via electrostatic interactions, as confirmed by the visualization of competitive dye inclusion.
The cavities of metallacages have also been used for selective molecular separation. Systems have been established to recognize different kinds of guest molecules, including reactive molecules and intermediates. Due to the quite small windows, rhombic dodecahedral metallacages can enclose small molecules. Li described that the Ni-imidazolate Ni14L24 metallacage M5 was able to selectively encapsulate CO2 molecules among several small gas molecules in both solution and the solid state (Figure 1c) [41]. The CO2 molecules could be encapsulated and imprisoned into the cavities under relatively high pressure or supercritical conditions but could not escape from the cages freely. Yuan generated homochiral Zn3L2 metallacage M6 and explored its application in gas chromatographic separations [33]. The manufactured capillary column coated by M6 showed noteworthy chirality recognition and separation of multiple analytes, including polycyclic aromatic hydrocarbons, n-alkanes, racemates, and positional isomers. By stabilizing twisted amides into the cavity of Pd (II) or Pt (II) octahedral metallacages, the reactivity toward hydrolysis under basic conditions through the noncovalent trapping of reactive guests was enhanced by Fujita [42]. As shown in Figure 1d, the planar conformation of the amine group was distorted from planar to twisted due to spatial constraints. As a result, the hydrolysis of amides was obviously accelerated upon encapsulation. Recently, they fixed a 2-biphenylacetylene moiety into the confined cavity of M4, in which a regioselective spirocyclization was performed in the presence of an electrophile [43]. In addition, a semiflexible metallacage M7 with a double wall was also constructed [44], which was able to recognize and encapsulate tetrachloromethane in CD3CN/D2O solution through the adaptive portal and expansionary cavity.
Larger molecules, such as fullerene [32,45,46,47] and proteins with a smaller size than the inner diameter [48], have also been used to explore the encapsulation capability of metallacages. A cubic metallacage M8 with electron-deficient walls was reported [49]. It can selectively bind C60-indene or C60-anthracene, whereas encapsulation does not occur in unfunctionalized fullerenes or monoadducts. A cuboctahedron metallacage and the encapsulation of a single-molecule protein are shown in Figure 1e [48], which provides a useful platform for protein-based nanobiotechnology in stabilization and drug delivery.
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Figure 1. Encapsulation and separation of metallacycles and metallacages. (a) The structures of M1−M8. (b) Selective liquid-liquid extraction of ReO4- from water into nitromethane in the existence of other anions. (c) Schematic of the encapsulation of CO2 by M5 in solution. (d) Schematic of the inclusion of diaryl amide within cage M4. (e) The encapsulation of a single-molecule protein. Adapted with permission from refs. [25,33,37,38,39,40,41,42,44,49]. Copyright 2017, 2018, 2019 and 2020 American Chemical Society; 2021 Royal Society of Chemistry; 2018 and 2022 Wiley-VCH; 2017, 2020 Nature Publishing Group.
Figure 1. Encapsulation and separation of metallacycles and metallacages. (a) The structures of M1−M8. (b) Selective liquid-liquid extraction of ReO4- from water into nitromethane in the existence of other anions. (c) Schematic of the encapsulation of CO2 by M5 in solution. (d) Schematic of the inclusion of diaryl amide within cage M4. (e) The encapsulation of a single-molecule protein. Adapted with permission from refs. [25,33,37,38,39,40,41,42,44,49]. Copyright 2017, 2018, 2019 and 2020 American Chemical Society; 2021 Royal Society of Chemistry; 2018 and 2022 Wiley-VCH; 2017, 2020 Nature Publishing Group.
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2.2. Catalysis

Due to their designable structure, nanoscale sizes, and adjustable properties, metallacycles and metallacages have excellent potential for application in catalysis and have exhibited catalytic activities for multiple chemical reactions. Hydrogen evolution from the catalysis of metallacages has been studied by different groups. Boomishankar and coworkers used M9 (Figure 2a) as an efficient photocatalyst with the assistance of a photosensitizer and sacrificial electron donor [30], in which the incorporated dye molecules were used to construct a photocatalytic system. By combining with the catalytic sites of Pd2+ and two encapsulated fluorescein molecules, heterogenized M10 was designed by Huang and exhibited a high H2 production rate under visible light [50]. Liu developed a dual-function photocatalyst based on hybrid materials [51], which were composed of metallacages M11 and TiO2. After loading ReP, the hybrid materials showed selective activity for the photoreduction of CO2 to CO and produced syngas of CO/H2 in a CO2-saturated aqueous solution of dimethylformamide (Figure 2b).
The water oxidation process based on ruthenium catalysis has attracted much attention over the last few years [52,53]. Würthner reported a series of Ru-based trinuclear metallacycles and investigated the impact of substituents [54], sizes [55,56], photosensitizers, and reaction media [57] on the catalytic activity, which deliver excellent supramolecular catalysts for the development of water oxidation. Li prepared a series of Co-based metallacages that could drive water oxidation under visible light [58]. Based on the relationship between the structure and activity, metallacage M12 containing Co-based active sites displayed high catalytic activity and initial oxygen evolution rate. Other catalytic reactions related to metallacycles and metallacages have also been explored. Stang’s group constructed two chiral Pt-based metallacycles M13a and M13b and successfully used them for the asymmetric addition reaction of various α,β-enones with styrylboronic acids in high yields (40−98%) and with high enantioselectivities (87−96% ee) [9]. Su constructed an Fe4L6 metallacage, M14 [59], which was sufficiently stable under different pH conditions as well as in redox processes. M14 not only acted as a catalyst for the dehydrogenation reaction but also exhibited remarkable continuing and recycling performance. Su prepared metallacage M15 by incorporating the metal complex Ir-6-(4-carboxy-phenyl)-nicotinic acid (Ir-ppyc) into a Zr-based cage [60]. M15 showed a higher selectivity in converting CO2 reduction under visible light irradiation than the classical metal-organic framework counterpart.
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Figure 2. Catalysis of metallacycles and metallacages. (a) The structures of M9−M15. (b) Histogram of CO/H2 generation by ReP/TiO2-M11 in CO2-saturated DMF solutions with different water contents for 5 h under visible light. Adapted with permission from refs. [9,30,50,51,58,59,60]. Copyright 2017, 2020, 2021, and 2022 American Chemical Society.
Figure 2. Catalysis of metallacycles and metallacages. (a) The structures of M9−M15. (b) Histogram of CO/H2 generation by ReP/TiO2-M11 in CO2-saturated DMF solutions with different water contents for 5 h under visible light. Adapted with permission from refs. [9,30,50,51,58,59,60]. Copyright 2017, 2020, 2021, and 2022 American Chemical Society.
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In addition to the above examples, many other metallacycles and metallacages can exhibit excellent catalytic performance regarding different reactions, such as Michael addition reactions [61], the solvolysis of acetal [23], cascade reactions [27], oxygen reduction electrocatalysis [62], and the Strecker reaction [63] among others [62,64,65].

2.3. Biomedical Applications

2.3.1. Drug Encapsulation and Delivery

As host-guest containers, metallacycles and metallacages exhibit fascinating potential in drug delivery applications. Mukherjee and coworkers reported that the hydrophobic cavity of M16 (Figure 3a) with large windows strong candidate for encapsulating and transporting small molecule hydrophobic drugs such as curcumin in an aqueous solution [66]. In addition to enhancing the solubility of curcumin, its inclusion in the cavity prevents it from photodegrading. Mirkin constructed the allosterically regulated metallacage M17 [67]. The asymmetric structure of the receptor was able to transform between a rigid cationic configuration and a flexible neutral configuration using a simple ion, which allowed β–estradiol and dextromethorphan to be selectively bound and reversibly encapsulated into M17. Nanoparticles based on metallacages were also designed for drug encapsulation and delivery. Figure 3b displays the fluorescein-conjugated fluorescein-Pt(IV) prodrug loaded into M4 via host–guest interactions [68]. In addition, Therrien’s group has demonstrated the enormous potential of Ru-based metallacages to transport guest molecules such as photosensitizers to cells [69,70,71]. Research on metallacages as drug carriers was also investigated, in which other small-molecule drugs, including 5-fluoracil and cisplatin, were transported [72,73].
Metallacages that are capable of selectively binding two or more different guests have tremendous advantages in numerous potential applications. In this regard, Crowley designed a Pd2L4 multicavity tube-like metallacage M18 based on pentapyridyl and hexapyridyl ligands [74]. With multiple discrete binding sites, it was exploited to selectively bind two or more guest molecules (Figure 3c). Nitschke prepared triangular-prismatic Ni(II)-based metallacages from two different ligands that were able to bind more than twenty different drugs, natural products, and steroid derivatives within their prolate cavity [75].

2.3.2. Biological Recognition and Sensing

The recognition and isolation of metallacycles and metallacages toward complex biomolecules, including amino acids, sucrose, small molecule drugs, etc., make them potential candidates for chemical sensing and biotechnology. Cui et al. synthesized three chiral NH-functionalized fluorescent Zn-based metallacycles, M19a-c (Figure 4a) [31] and demonstrated their high binding affinity and enantioselectivity toward small-molecule pharmaceuticals (L-dopa, D-penicillamine), amino acids, and α-hydroxycarboxylic acids. The strong fluorescence allowed its application in chiral sensing (Figure 4b). Yoshizawa prepared a Pt-based metallacage M20 and reported the efficient and selective encapsulation of D-sucrose from natural disaccharide mixtures in water [76]. Zhang constructed a fluorescent metallacycle-cored supramolecular network by linking metallacycle M21 via a dynamic covalent reaction and showed that it can be used as a chemical sensor to detect picric acid and halogen ions [77]. Stang and coworkers prepared three multicomponent Pt-based metallacages, M22a-c [78]. Figure 4c demonstrates strong fluorescence sensing and has been utilized as a “turn-on” fluorescent sensor for the detection of thiol-containing amino acids, including cysteine and glutathione, in methanol/water, which follows a self-destructive mechanism. Moreover, M22 can also be regenerated by adding Pt(II) acceptors. Then, they designed a triangular metallosalen-based metallacycle M23, constructed a Pt(II) metallacycle-cored supramolecular network [34], and examined the amino acid sensing capability. The limits of detection for cysteine and glutathione were 79.1 and 15.4 μM, respectively.

2.3.3. DNA Binding

Terenzi engineered three Pt-based quadrangular metallacycles with different sizes and evaluated their affinity for G-quadruplex DNA [79]. The findings showed the interaction between metallacycles and ligands with double-stranded DNA. Sleiman generated a series of square metallacycles of platinum and examined their binding to guanine quadruplexes [80], including oncogene, DNA, and RNA guanine quadruplexes associated with telomeres. This work proved that it is feasible to regulate the binding activity between DNA and metallacycles.

2.3.4. Antibacterial Activity

Some efficient antibacterial systems based on metallacycles and metallacages have been established in recent years [24,81,82]. Li designed and synthesized three nest-like metallacycles and two hexagonal metallacages [83,84], and they all showed remarkable antimicrobial activity. Niu et al. prepared Pt(II)-based metallacycle M24 (Figure 5a) that exhibited aggregation-induced emission (AIE) activity and self-assembled it with tobacco mosaic virus coat protein [85]. The assembly displayed strong membrane-intercalating ability and reactive oxygen species (ROS) generation in bacteria under light irradiation, which resulted in excellent antibacterial activity against gram-positive bacteria. Mukherjee presented a Pd-based metallacage, M25 [86], which exhibited oxidase-like enzymatic behavior even at very low concentrations under white light irradiation. As shown in Figure 5b, exogenous ROS generation has been exploited in efficient photocatalytic and antibacterial activity toward S. aureus. Yang’s group synthesized a heterometallic triangular necklace-like metallacycle M26 containing Cu(I) and Pt(II) ions [87]. The existence of two metal centers endowed M26 with superior antibacterial activity and nuclease properties, in which bacterium-binding and bacterium-damaging activities against drug-resistant pathogens were shown.
Some metallacycles and metallacages with unique special structures and compositions have antiseptic effects as well as fluorescence imaging. Zhang prepared supramolecular networks by cross-linking hexagonal metallacycle M27 with poly (N-isopropylacrylamide) (PNIPAAM) [88]. M27 exhibits strong fluorescence signals and antibacterial activity for supramolecular networks. Benefiting from the improved bioavailability, supramolecular networks can act as imaging and killing reagents for bacteria. Sun and coworkers designed a hexagonal Pt(II)-based metallacycle M28 [89] and constructed a supramolecular photosensitizer by functionalizing it with pillar [5] arenes through host-guest interactions. The supramolecular photosensitizer showed enhancement in both fluorescence imaging and ROS production capabilities. The results suggested that it can not only track S. aureus in situ but also guide the treatment of S. aureus-infected mice by fluorescence imaging, and there were no detectable low adverse effects in vitro and in vivo. They also prepared a Ru(II)-based metallacycle M29 with an emissive wavelength beyond ~1000 nm, which showed outstanding optical penetration and excellent antibacterial activity while exhibiting low cytotoxicity to normal mammalian cells [90]. When M29 was prepared in nanoparticles (NPs), accurate bacterial diagnosis and effective phototherapy were performed on S. aureus-infected mouse models by NIR-II fluorescence-guided imaging and photoinduced treatments (Figure 5c).

2.3.5. Tumor Imaging and Treatment

Pt-, Pd-, and Ru-based metallacycles and metallacages are widely used in cancer diagnosis and treatment [18,91,92,93,94]. Das generated two Pt(II)-based irregular hexagonal metallacycles and studied their cytotoxicity using various cell lines, including the A549, KB, MCF-7, and HaCaT cell lines [95]. The results showed that the smaller metallacycle exhibits better cytotoxic effects. They also prepared two other Pt(II)-based metallacycles with hexagonal shapes and confirmed their anticancer efficiency in comparison to cisplatin [96]. Stang and coworkers produced an effective drug delivery system based on the water-soluble hexagonal metallacycle M30 (Figure 6), which transports curcumin into different cancer cells. The encapsulation of curcumin results in the synergistic enhancement of M30 [97]. Yang presented porphyrin-functionalized star polymers through post-assembly polymerization of a hexagonal Pt(II)-based metallacycle M31 cisplatin [98]. The obtained metallacycle-linked star polymer showed an excellent ability to enhance cellular uptake and generate 1O2, and therefore, superior antitumor activity was observed under light irradiation. Combining the fluorescence, anticancer and targeted properties into a single entity, Zhang’s group prepared two biotinylated fluorescent Pt(II)-based metallacages, which were successfully employed for bioimaging, cancer treatment, and targeting [99].
The metallacycles and metallacages incorporated anticancer drugs showed better anticancer activity in vitro than the precursors, such as cisplatin. Casini et al. designed Pd(II)-based metallacage M32 and constructed an integrin-selective drug delivery system by conjugating it to different integrin-binding ligands [18]. After encapsulation of cisplatin, the conjugated metallacages exhibited increased anticancer activity in vitro, overexpressing αvβ3 integrins. Lee prepared four Pd(II)-based metallacycles with triangular or square architectures bearing boron dipyrromethane (BODIPY) ligands [100]. Compared with cisplatin, these metallacycles are highly cytotoxic against U87 glioblastoma cells. In another work, they reported four Pt- or Pd-based octacationic metallacycles from BODIPY ligands [101]. The activities against cell lines showed strong cytotoxicity toward cancer cells compared to cisplatin but exhibited 7.0–15.2 times lower toxicity in normal cells. Mukherjee synthesized four octanuclear Ru(II) metallacages and compared the in vitro antitumor effect with that of cisplatin [102]. The very low micromolar IC50 values indicated that their metallacage that can generate ROS has the greatest anticancer effect against the selected cancer cell lines. Stang synthesized six tetranuclear metallacycles and hexanuclear metallacages by coordination-driven self-assembly and evaluated their cytotoxicity toward human normal and cancer cell lines [103].
To further explore the in vivo biological application of metallacycles and metallacages, much research has been carried out. In this respect, Stang and coworkers have published a series of excellent works. They synthesized a four-armed amphiphilic polymer consisting of an AIE metallacycle M33 (Figure 7a) core and GSH-responsive arms [104]. After self-assembly into NPs and vesicles, the small molecule anticancer drugs doxorubicin or doxorubicin hydrochloride were further encapsulated. The results showed that the drug delivery system has a synergistic anticancer effect both in vitro and in vivo. A suite of Pt(II) drug-loaded metallacycle M34 was designed and synthesized for combination with cancer chemotherapy [105], in which the chemotherapy drugs camptothecin (CPT) and combretastatin A4 (CA4) were loaded in metallacycles. Nanoformulations (NFs) were fabricated by encapsulating M34 into folic acid (FA)-functionalized diblock copolymers, which exhibited high anticancer efficacy as well as few side effects (Figure 7b). In another study, they prepared NPs by self-assembly of an amphiphilic copolymer, which consisted of H2O2-responsive diblock copolymer arms and a hexagonal metallacycle M35 core [106]. The NPs can not only encapsulate doxorubicin and palmitoyl ascorbate but also show excellent antitumor performance with negligible systemic toxicity. The group also prepared a theranostic nanoprobe that incorporated rhomboidal Pt-based metallacycle M36 and NIR-II molecular dye. The applications for cancer diagnosis and treatment are shown in Figure 7c [107]. The nanoprobe provides accurate diagnosis with high resolution and can inhibit tumor growth with fewer adverse reactions than cisplatin via the enhanced permeability and retention (EPR) effect. A dual-emissive Pt-based metallacage M37 was reported [108]. The NPs formed by M37 and amphiphilic diblock copolymers demonstrate hypoxia imaging as well as chemotherapy in vivo. Mao et al. constructed a theranostic NIR metallacage M38 and developed it in MNPs for imaging-guided cancer radiochemotherapy, which revealed better antitumor performance against cisplatin-resistant tumors [109]. Zhang synthesized metallacycles M39a-c cored amphiphilic NPs formed by β-CD [110], which not only acted as contrast agents for cell imaging but also displayed increased anticancer activity.
Due to its excellent therapeutic effects, negligible side effects, and noninvasiveness, photodynamic therapy (PDT) has recently gained increasing attention in cancer treatment. Through the ingenious design of structures, Therrien and coworkers incorporated photosensitizers into Ru-based metallacages and widely investigated their applications in PDT, in which the metallacages showed good therapeutic effects in cancer as well as rheumatoid arthritis [111,112,113]. Tang synthesized two amphiphilic Pt(II)-based metallacycles, which can potentially be applied to PDT [114]. Stang designed and synthesized Ru-Pt metallacycles and octahedral metallacage M40 (Figure 8a) via a photosensitizer based on Ru(II) and building blocks based on Pt(II), which demonstrated a large two-photon absorption cross-section as well as high efficiency of ROS generation [115]. After encapsulation into a polymer and the formation of NPs, excellent PDT performance was demonstrated in three-dimensional MCs and in vivo studies. They also described two porphyrin-containing Pt(II) metallacages, M41a and M41b, and examined their potential in PDT [116]. In vivo and in vitro investigations indicate the NPs containing M41a and M41b display enhanced antitumor effects with lower dosage requirements and very few adverse effects compared with the precursors. Dong reported an indocyanine green (ICG)-involved photoactive antitumor hexagonal nanoplate based on Pd(II) metallacage M42, which served as an efficient antitumor photosensitizer via PDT for increased NIR light-induced 1O2 generation, enhanced cellular uptake, and selective targeting ability of lysosomes [117]. Yang designed a dual-stage metallacycle M43 and constructed M43-loaded NPs that realized reversible control of 1O2 generation [118]. As a promising platform for selective PDT, the dual-stage system exhibits promising anticancer applications.
Some metallacycles and metallacages have been used as therapeutic agents for PTT. Stang et al. reported a rhombic Pt(II)-based metallacycle M44 with high photothermal conversion capacity and encapsulated it into NPs via Pluronic F127, which presented excellent hydrophilicity and biocompatibility [119]. The F127/M44 NPs exhibited enhanced photothermal effects and excellent antitumor PTT behavior in vivo. Zhao and coworkers synthesized a series of Pt(II)-based metallacycles with high photoconversion efficiency for synergistic PDT/PTT therapy [120]. Compared with their precursors, the in vitro studies of M45-NPs showed significant photoconversion, which promoted photoinduced cell injury and subsequently realized tumor ablation.
Multifunctional nanocarrier systems based on metallacycles and metallacages for cancer diagnosis and treatment have undergone great development in recent years. Chen et al. integrated a chemotherapy and PDT strategy utilizing a porphyrin- and Pt(II)-based metallacage M46 (Figure 9a) via multicomponent self-assembly, in which M46 served as a multimodality theranostic platform to fabricate NPs [121]. The cooperation of chemotherapy and PDT exhibited remarkable synergistic antitumor efficacy in vitro and in vivo. Kim constructed an NIR-II nanotherapeutic platform through the incorporation of Pt(II)-based metallacycle M47 and NIR-II dye into F127 [122]. The designed NPs showed high tumor uptake with superior photostability and a high signal-to-noise ratio for real-time guiding therapy, increasing the antitumor efficacy as well as reducing the adverse effects in the U87MG glioblastoma model.
Considering the flexibility and compatibility of photoacoustic (PA) imaging and NIR-II fluorescence imaging, Stang et al. described a dual-modal imaging and chemo-photothermal synergistic therapy nanoagent that incorporates metallacycle M48 and NIR-II fluorescent dye into molecular-dye-modified melanin dots [123]. Nanoagents showed both favorable stability and optical properties in vivo, as well as passive targeting ability for tumors, and provided a remarkable multifunctional theranostic platform for biomedicine. In addition, they utilized Pt-based metallacage M49 to encapsulate a photosensitizer and constructed a dual-functionalized system by wrapping it into NPs [16]. The in vivo results revealed that synergistic PDT and chemotherapy displayed excellent anticancer behavior toward drug-resistant tumors.

2.4. Other Applications of Metallacycles and Metallacages

Stang’s group described Pt(II)-based metallacycles and metallacages that can be used as artificial light-harvesting systems [15,124]. Inspired by the planar chirality of pillararenes, they also prepared metallacycles with chiral optical activities [8]. Metallacycles with high quantum yields and tunable fluorescence wavelengths have been developed in versatile fluorescent materials [125]. A certain quantity of metallacycles and metallacages with specific stimulus-response properties have been made by designing building blocks incorporating functional moieties, such as metal ions [126], temperature [127,128,129,130], ligands [131], light [132,133], and enzymes [134].

3. Conclusions and Outlook

Metallacycles and metallacages have attracted widespread attention, not only because of their precise stoichiometry but also due to the flexibility and viability of their design. Specific applications of metallacycles and metallacages have been discussed herein. The diversification in sizes, geometries, and properties, metallacycles, and metallacages have been widely applied in the field of encapsulation, separation, catalysis, biomedicine, and so on. In particular, the employment of metallacycles and metallacages as drug delivery systems, imaging and theranostic platforms have received a lot of attention. Because of their well-defined structures, the cavities of metallacycles and metallacages can encapsulate drugs and transport them to tumor cells, which enhances the bioavailability of hydrophobic drugs and shows good anticancer activity. Through rational design and encapsulation in amphiphilic block copolymers, NPs based on metallacycles and metallacages can also provide a multimodal and synergistic therapeutic platform for precise cancer diagnosis and treatment, including imaging, chemotherapy, PDT, and PTT.
A wide variety of metallacycles and metallacages have been constructed and applied in various fields. However, there are still many challenges. On the one hand, metallacycles and metallacages with more complicated structures and other metal centers in addition to the commonly used Pt and Pd need to be further explored. However, there is an urgent need to translate the existing research into clinical practice, which is an indispensable part of biological applications. To conclude, metallacycles and metallacages are expected to remain attractive and hot topics in materials science.

Author Contributions

Conceptualization and writing, Y.S., P.J.S. and C.Y.; writing—original draft preparation, C.Y.; validation, B.O. and J.D.; writing—review and editing, B.O., Y.S. and P.J.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Institute of Health grant number R01-CA215157.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Y. Sun thanks the Henan University Third Level Start-up Fund. P.J. Stang is grateful for support by the NIH (grant R01-CA215157).

Conflicts of Interest

The authors declare no conflict of interest.

References

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Figure 3. Drug encapsulation and delivery of metallacycles and metallacages. (a) The structures of M16−M18. (b) The nanoformulation of M4 for Pt drug delivery. (c) Selective binding of cisplatin and triflation in cavities. Adapted with permission from refs. [66,67,68,74]. Copyright 2017 American Chemical Society; 2018 Royal Society of Chemistry.
Figure 3. Drug encapsulation and delivery of metallacycles and metallacages. (a) The structures of M16−M18. (b) The nanoformulation of M4 for Pt drug delivery. (c) Selective binding of cisplatin and triflation in cavities. Adapted with permission from refs. [66,67,68,74]. Copyright 2017 American Chemical Society; 2018 Royal Society of Chemistry.
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Figure 4. Biological recognition and sensing of metallacycles and metallacages. (a) The structures of M19−M23. (b) Fluorescence emission spectra of (R)- and (S)-M19a (2.0 × 10-6 M in THF) upon titration with L-dopa. (c) Fluorescence spectra of M22 with increasing amounts of thiol-containing amino acids. Adapted with permission from refs. [31,34,76,77,78]. Copyright 2017 and 2021 American Chemical Society; 2020 Royal Society of Chemistry; 2017 American Association for the Advancement of Science.
Figure 4. Biological recognition and sensing of metallacycles and metallacages. (a) The structures of M19−M23. (b) Fluorescence emission spectra of (R)- and (S)-M19a (2.0 × 10-6 M in THF) upon titration with L-dopa. (c) Fluorescence spectra of M22 with increasing amounts of thiol-containing amino acids. Adapted with permission from refs. [31,34,76,77,78]. Copyright 2017 and 2021 American Chemical Society; 2020 Royal Society of Chemistry; 2017 American Association for the Advancement of Science.
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Figure 5. The antibacterial performance of metallacycles and metallacages. (a) The structures of M24−M29. (b) Pictures of the bacterial colonies of S. bacteria after exposure to M25 in 0.1 M acetate buffer with white light irradiation. (c) Photographs showing the infected wound after different treatments. Adapted with permission from refs. [85,86,87,88,89,90]. Copyright 2019 and 2022 National Academy of Sciences (USA); 2020 and 2022 Wiley-VCH; 2020 Nature Publishing Group; 2020 American Chemical Society.
Figure 5. The antibacterial performance of metallacycles and metallacages. (a) The structures of M24−M29. (b) Pictures of the bacterial colonies of S. bacteria after exposure to M25 in 0.1 M acetate buffer with white light irradiation. (c) Photographs showing the infected wound after different treatments. Adapted with permission from refs. [85,86,87,88,89,90]. Copyright 2019 and 2022 National Academy of Sciences (USA); 2020 and 2022 Wiley-VCH; 2020 Nature Publishing Group; 2020 American Chemical Society.
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Figure 6. The structures of M30−M32. Adapted with permission from references [18,97,98]. Copyright 2018 National Academy of Sciences (USA); 2018 American Chemical Society; 2019 Royal Society of Chemistry.
Figure 6. The structures of M30−M32. Adapted with permission from references [18,97,98]. Copyright 2018 National Academy of Sciences (USA); 2018 American Chemical Society; 2019 Royal Society of Chemistry.
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Figure 7. (a) The structures of M33−M39. (b) The cellular uptake of M34-NF-FA and the intracellular release of drugs in response to GSH. (c) NIR-II fluorescence images detecting M36 in tumors. Adapted with permission from refs. [104,105,106,107,108,109,110]. Copyright 2017 and 2020 American Chemical Society; 2019 and 2022 National Academy of Sciences (USA); 2020 and 2022 Wiley-VCH.
Figure 7. (a) The structures of M33−M39. (b) The cellular uptake of M34-NF-FA and the intracellular release of drugs in response to GSH. (c) NIR-II fluorescence images detecting M36 in tumors. Adapted with permission from refs. [104,105,106,107,108,109,110]. Copyright 2017 and 2020 American Chemical Society; 2019 and 2022 National Academy of Sciences (USA); 2020 and 2022 Wiley-VCH.
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Figure 8. (a) The structures of M40−M45. (b) Schematic illustration of the fabrication, uptake, and accumulation of M40NPs, and their applications in PDT. (c) A schematic illustration of the application of F127/M43 NPs in imaging-guided photothermal therapy. Adapted with permission from refs. [115,116,117,118,119,120]. Copyright 2019 and 2020 American Chemical Society; 2019 National Academy of Sciences (USA); 2021 Royal Society of Chemistry; 2022 MDPI.
Figure 8. (a) The structures of M40−M45. (b) Schematic illustration of the fabrication, uptake, and accumulation of M40NPs, and their applications in PDT. (c) A schematic illustration of the application of F127/M43 NPs in imaging-guided photothermal therapy. Adapted with permission from refs. [115,116,117,118,119,120]. Copyright 2019 and 2020 American Chemical Society; 2019 National Academy of Sciences (USA); 2021 Royal Society of Chemistry; 2022 MDPI.
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Figure 9. (a) The structures of M46−M49. (b) NIR-II fluorescence images of the M47-based nanotheranostic agent therapeutic response in U87MG tumors. (c) NIR-II fluorescence and PA images of M48-NPs at different times. Adapted with permission from refs. [16,121,122,123]. Copyright 2019 National Academy of Sciences (USA); 2019 Royal Society of Chemistry; 2018 Nature Publishing Group.
Figure 9. (a) The structures of M46−M49. (b) NIR-II fluorescence images of the M47-based nanotheranostic agent therapeutic response in U87MG tumors. (c) NIR-II fluorescence and PA images of M48-NPs at different times. Adapted with permission from refs. [16,121,122,123]. Copyright 2019 National Academy of Sciences (USA); 2019 Royal Society of Chemistry; 2018 Nature Publishing Group.
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Yin, C.; Du, J.; Olenyuk, B.; Stang, P.J.; Sun, Y. The Applications of Metallacycles and Metallacages. Inorganics 2023, 11, 54. https://doi.org/10.3390/inorganics11020054

AMA Style

Yin C, Du J, Olenyuk B, Stang PJ, Sun Y. The Applications of Metallacycles and Metallacages. Inorganics. 2023; 11(2):54. https://doi.org/10.3390/inorganics11020054

Chicago/Turabian Style

Yin, Changfeng, Jiaxing Du, Bogdan Olenyuk, Peter J. Stang, and Yan Sun. 2023. "The Applications of Metallacycles and Metallacages" Inorganics 11, no. 2: 54. https://doi.org/10.3390/inorganics11020054

APA Style

Yin, C., Du, J., Olenyuk, B., Stang, P. J., & Sun, Y. (2023). The Applications of Metallacycles and Metallacages. Inorganics, 11(2), 54. https://doi.org/10.3390/inorganics11020054

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