Supramolecular coordination complexes as diagnostic and therapeutic agents

Abstract

The metal-based drugs represented by cisplatin, carboplatin, and oxaliplatin, prevail in cancer treatment, while new therapeutics are extremely slow to step into the clinic. Poor pharmacokinetics, multidrug resistance, and severe side effects greatly limit the development of metal-based anticancer drugs. The robustness and modular composition of supramolecular coordination complexes allow for the incorporation of novel diagnostic and therapeutic modalities, showing promising potentials for precise cancer theranostics. In this mini review, we highlight the recent advances in the development of supramolecular coordination complexes as diagnostic and therapeutic agents. The key focuses of these reports lie in searching sophisticated coordination ligands and nanoformulations that can potentially solve the issues faced by current metal-based drugs including imaging, resistance, toxicity, and pharmacological deficiencies.

INTRODUCTION

Cancer is fast becoming the leading cause of death worldwide, placing a heavy burden on patients, their families and society.[1–4] Sophisticated drugs or nanoformulations that can specifically kill cancer cells yet biocompatible to the normal tissues are urgently needed for cancer patients. However, this goal is currently out of reach because of the considerable variations among tumor subpopulations and individuals.[5,6] Theranostics that integrates therapeutic and diagnostic capabilities into a single platform potentially meets the challenges for the next generation of personalized medicine. In these platforms the diagnostic component reports the presence of tumors, their status, and their response to therapy, providing important information for the subsequent precise treatments.[7–12] However, such advances so far are mostly confined to the academic settings, with the majority of the reported theranostics incorporate the imaging and therapy independently rather than in an integrated platform, mismatching the diagnostic and therapeutic outputs. Additionally, the therapeutic performances of the present drugs or nanomedicines are unsatisfactory in the clinic, prompting researchers to construct smart formulations synergistically combining multiple therapeutic modalities.

Since the serendipitous discovery of the antiproliferative capability of cisplatin by Barnett Rosenberg et al. in 1965, much effort has been devoted to exploring potent drugs on the basis of metal complexes for oncology therapy.[13] A large number of transition metal complexes including platinum (Pt^II and Pt^IV), gold (Au^I and Au^III), titanium (Ti^IV), and ruthenium (Ru^II and Ru^III) have been extensively studied and evaluated, and some of them have entered clinical studies at different stages.[13–16] Still, most of these emerging therapeutic agents have encountered obstacles, such as low water solubility, poor pharmacological behaviors, unsatisfactory efficacy, severe side effects, and drug resistance. Fortunately, some of these drawbacks can be effectively solved by fully exploiting supramolecular coordination chemistry and nanotechnology using these therapeutic metal complexes as building blocks.[17–20] Through the judicious choice of organic ligands and metal ions/clusters, discrete supramolecular coordination complexes (SCCs) with fascinating topologic structure have been fabricated via coordination-driven self-assembly.[21,22] More interestingly, diagnostic capability can be introduced into these SCCs by employing imaging probes as the coordination donors, facilitating non-invasive monitoring of the delivery, release, and excretion of the organometallic drugs with the assistance of fluorescence imaging, magnetic resonance imaging (MRI), positron emission tomography (PET), or photoacoustic imaging (PA).[23,24] By integrating other therapeutic agents into the SCCs, the anticancer properties of the resultant formulations are vastly improved by combining chemotherapy with photodynamic therapy (PDT) and photothermal therapy (PTT). Herein, we highlight the recent developments of SCCs in cancer theranostics aiming to point out some pivotal tendency in potential applications of the reported supramolecular structures.

Incorporation of diagnostic functions into SCCs

The inspiration for the employment of SCCs in biomedical applications arises from their awesome merits of (i) the ease of fine-tuning the topological structures of the coordination complexes, (ii) the plentiful choices of metal ions or clusters with changeable sizes and angles, (iii) the feasible integration of specific agents with fascinating functions via pre- or post-modifications. Imaging probes can be incorporated into SCCs for in vitro and in vivo imaging to trace their delivery and excretion. Various strategies have been exploited to achieve this goal, such as chemical modification, direct coordination self-assembly, physical encapsulation, and host–guest recognition.

Fluorophores with high quantum yield could be conjugated to the coordination building block, thus introducing imaging capability into SCCs. For example, Casini and coworkers conjugated highly emissive boron dipyrromethene (BODIPY) moieties to 3,5-bis(3-ethynylpyridine)phenyl scaffold and obtained luminescent Pd₂L₄ metallacages (1 and 2).[25] The bright fluorescence arising from BODIPY allowed for monitoring the cellular uptake and sub-cellular localization of the metallacages, and found that the internalization was driven by active transportation and the metallacages accumulated in cytoplasmic vesicles (Figure 1a).

Figure 1.

(a) Chemical structures of the BODIPY-modified Pd₂L₄ metallacages (1 and 2) and the CLSM images of the cells culture with 1 and 2. Reproduced with permission from [25], copyright 2019 Elsevier. (b) Chemical structures of the BODIPY-embedded metallacycles (3–6) and the CLSM images of the cells cultured with 5. Reproduced with permission from [26], copyright 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (c) Chemical structure of the TPE-based metallacyclce (7). (d) Illustration of crosslinked polymers constructed from the emissive TPE-based metallacycle. (e) In vivo fluorescence image of the mouse injected with the nanomaterial prepared from the polymer (P2). Reproduced with permission from [35], copyright 2016 National Academy of Sciences. (f) Chemical structure of the porphyrin-based metallacyclce (8). (g) NIR fluorescence, PET, and MRI images of the mice injected with the metallacage-loaded nanoformulations. Reproduced with permission from [37], copyright 2018 Nature Publishing Group.

Fluorescent probes with rigid structures are inherent coordination donors when modified with carboxylate or pyridine groups, such as BODIPY, tetraphenylethane (TPE), and porphyrins. Gupta, Mandal, Lee and coworkers constructed thiophene-based BODIPY Ru(II) rectangles (3–6) using dinuclear arene-ruthenium precursors and a thiophene-functionalized dipyridine BODIPY ligand, and the intracellular distribution of this metallacycle was visualized by the net fluorescence of BODIPY (Figure 1b).[26] Pd(II)- and Pt(II)-cornered square-planar complexes were also employed by Tim and Lee to fabricate BODIPY-based fluorescent triangles and rectangles.[27,28] The characteristic fluorescence of the BODIPY cores allowed intracellular visualization of these metallacycles by using a confocal microscope. Zhang et al. constructed three highly fluorescent metallacycles utilizing a near-infrared (NIR) emissive dipyridyl ligand and Pt(II) precursors with different shapes.[29] Interestingly, the formation of D-π-A structures due to the introduction of two electron donors to the cyanostilbene-based backbone shifted the emission of the ligand to 735 nm. These metallacycles combining both imaging and therapeutic abilities offered a new type of theranostics towards cancer management. Notably, the anticancer ability of the metal-acceptors was greatly maintained by the formation of SCCs, the IC₅₀ values of these SCCs were comparable to or even lower than cisplatin.

Different from traditional fluorophores suffering from aggregation-caused quenching, TPE derivatives exhibit unique aggregation-induced emission (AIE) phenomenon at concentrated states through the restriction of intramolecular rotation.[30,31] Interestingly, the intramolecular rotation could be hindered by the formation of SCCs through coordinations, making the metallacomplexes highly emissive even in diluted states.[32–34] Stang and coworkers prepared a rhomboidal TPE-based metallacylce (7) and further crosslinked the fluorescent metallacycle-cored polymers via bifunctional covalent linkages (Figure 1c and d).[35] Benefiting from the AIE effect, nanoparticles prepared from these supramolecular polymers were used as contrast agents for cell imaging and in vivo fluorescence imaging (Figure 1e). Chen, Huang, Stang and coworkers synthesized a TPE-based metallacage via multiple-component coordination, exhibiting bright emission as a result of AIE effect.[36] The stability of this theranostic SCC was significantly improved by encapsulation into the nanoparticles formed from two lipid-polymer conjugates. The delivery process was detected in real-time by exploiting the AIE feature of this metallacage. Based on both enhanced penetration permeability and retention (EPR) effect and active targeting ability, this nanomedicine highly accumulated in tumor tissue, which enhanced anti-tumor efficacy and reduced systemic toxicity.

Porphyrin is a classic fluorophore, while the fluorescence is remarkably quenched by the π-π stacking of the hydrophobic core. Although various modifications have been conducted by introducing water soluble segments aiming to improve their solubility, it remains a challenge to realize single molecular dispersion. Chen et al. inserted 5,10,15,20-tetra(4-pyridyl)porphyrin (TPP) into the metallacage (8) as top and bottom faces through a multicomponent coordination-driven self-assembly (Figure 1f).[37] The distance between the fluorophores was mechanically elongated. In this way, the intermolecular π-π stacking of TPP was remarkably suppressed, significantly enhancing the fluorescence. Metallacage-loaded nanoparticles were obtained, and their in vivo delivery was traced by NIR fluorescence imaging. More intriguingly, the porphyrin cores of the metallacage were suitable hosts for magnetic Mn²⁺ and radioactive ⁶⁴Cu²⁺ ions, which allowed the implementation of MRI and PET imaging with high sensitivity and resolution (Figure 1g). The nanoparticles with trimodality imaging allowed precise diagnosis of tumors and tracing of the delivery, organ distributions, and excretion of the nanoparticles.

NIR-II imaging holds promise to provide information of tumor location and progression attributing to its low interfering signal, deep penetration, and high signal-to-background ratio. Inspired by these superb merits from the NIR-II over the NIR I window for in vivo imaging, Stang and coworkers developed a series of theranostics through physical encapsulation. For example, ternary theranostic nanoparticles comprising of a rhomboidal metallacycle, a NIR-II probe and an amphiphilic copolymer were prepared.[38] This theranostic system possesses excellent photostability for accurate diagnosis of cancer with high resolution and signal-to-noise ratio. Similarly, a nano-cocktail was prepared by loading an organic NIR-II dye and an organoplatinum(II) metallacycle into the polymeric nanoparticles self-assembled from Pluronic F127.[39] This nano-cocktail exhibited high photostability and negligible background in the NIR-II region, showing unparalleled advantages for real-time monitoring the process of therapy. Moreover, the same group also engineered a dual-modal theranostic nano-agent by incorporating discrete Pt(II) metallacycle (9) and NIR-II dye (10) into multifunctional melanin dots (Figure 2a).[40] Both NIR-II imaging and photoacoustic imaging confirmed accumulation of the nano-agent (NP1) in tumor region (Figure 2b), which allowed for image-guided chemo-photothermal therapy (Figure 2c). It should be emphasized that the coordination self-assembly and nanoformulations did not diminish the anticancer activity of the organoplatinum(II) precusors in these cases, and additional PTT arising from the carriers even elevated the therapeutic efficacy.

Figure 2.

(a) Structures of discrete metallacycle 9 and NIR-II molecular dye 10. (b) NIR-II fluorescence and photoacoustic images of the mice bearingU87MG tumors at different times post tail vein injection of NP1. (c) Schematic diagram of nanotheranostic NP1 for chemo-photothermal synergistic therapy. Reproduced with permission from [40], copyright 2019 National Academy of Sciences. (d) Chemical structure of C-2. (e) Single crystal structure of [ReO₄⊂C-2]¹¹⁺. (f) SPECT images of the mice injected with free [^99mTc]TcO₄⁻ and [^99mTc][TcO₄⊂C-2]¹¹⁺. Reproduced with permission from [44], copyright 2018 American Chemical Society.

Metallacages with hollow cavity are able to complex diagnostic guests, making the host–guest recognition an effective mothod to visualize the metallacages. Therrien et al. constructed water-soluble arene ruthenium metallacages and used them as supramolecular hosts to encapsulate hydrophobic porphin.[41,42] The cellular endocytosis of the supramolecular complexes and release of porphin after internalization into the cells were fully investigated by fluorescence imaging. Li, Chen, Stang and coworkers also employed a discrete organoplatinum(II) metallacage with a well-defined cavity as a supramolecular host to load octaethylporphine and further encapsulated the host–guest complex into polymeric nanoparticles for fluorescence image-guided chemo-photodynamic therapy.[43] Lusby, Archibald and coworkers synthsized a tetrahedral Co^III₄L₆ (C-2), which exhibited high binding affinity towards γ-emitting [^99mTc]TcO₄⁻ anion (Figure 2d).[44] The association constant was as high as 61000 M⁻¹ betwen this metallacage host and pertechnetate analogue (perrhenate, ReO₄⁻) (Figure 2e). Subsequent single-photon emission computed tomography (SPECT) imaging indicated that the capsule remained intact during imaging (Figure 2f). Compared with the thyroid accumulating free oxo-anion, in vivo imaging also indicated dramatic variations in the distributions of the complex.

SCCs for cancer therapy

By utilizing Pt, Pd, Rh, Ru, and Ir as the coordination acceptors, Therrien, Stang, Chi, Casini et al. developed a series of 2D metallacycles (e.g. triangles, rectangles, rhomboids, and hexagons) and 3D metallacages for cancer therapy. These SCCs exhibited antiproliferative effects agaist various cancer cell lines. The potency of partial SCCs is similar to and in some cases even better than the commercially used cisplatin, carboplatin and oxaliplatin. The anticancer mechanisms of these SCCs mainly include membrane damage, autophagy, DNA damage, cell apoptosis and and increased p53 expression.

Biological activity of Ru-based complexes prompt analogous studies of Ru(II)-arene SCCs with particular interest in their anticancer performance. Supramolecular Ru(II) metallacycles displayed some exciting advantages, such as relatively high solubility and stability in aqueous solution. Therrien et al. designed Ru(II)-arene metallarectangles (11 and 12) that showed exciting potency to cancer cells rather than normal cells. These metallacycles were highly toxic against human ovarian cancer cells (Figure 3a).[45] Chi and coworkers also prepared several therapeutic Ru(II)-arene rectangles and mixed-metal Ru/Pt complexes (13 and 14). Their anticancer activity was pronouncedly higher than that of cisplatin against colorectal, lung, and breast cancer cell lines (Figure 3b).[46] Various Ru(II)-arene metallabowls, Ru(II)-arene [2]catenane, and 3D Ru(II) metallacages have been constructed, and their antiproliferative capabilities were evaluated against a panel of cancer cells.[47–51] The metallabowl (15) featuring 5,8-dihydroxy-1,4-naphthaquinonato (donq) ligands was twice as potent as doxorubicin and cisplatin against HCT-15 cells (Figure 3c).[51] Stang et al. synthesized a series of Ru(II)-arene rectangles (16 and 17) and trigonal prisms (18) self-assembled from bidentate or tridentate imidazole-based ligands with p-cymene ruthenium (II) acceptors (Figure 3d).[52] In vitro anticancer studies demonstrated that only the SCCs containing donq-based scaffolds exhibited satisfactory effect. The screened SCCs displayed pronounced selectivity for HepG-2 cells over the healthy cells.

Figure 3.

(a) Chemical structures of the Ru-based metallacycles (11 and 12). Reproduced with permission from [45], copyright 2015 Elsevier. (b) Chemical structures and cartoon illustration of the preparation of metallacycle (13 and 14). Reproduced with permission from [46], copyright 2011 American Chemical Society. (c) Chemical and single crystal structure of the metallabowl (15). Reproduced with permission from [51], copyright 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (d) Chemical structures of the metallacycles (16 and 17) and metallacage (18) self-assembled from 0° Ru clip and ditopic/ tritopic imidazole-based ligands. Reproduced with permission from [52], copyright 2019 National Academy of Sciences. (e) Illustration of the self-assembly of the hexagon (21) using 19 and 20 as building blocks. Reproduced with permission from [56], copyright 2018 Royal Society of Chemistry.

Kaushik, Stang, Chi and coworkers prepared two tetracationic Pt(II) and Pd(II) metallacycles from an N,N’-bis(4-(pyridin-4-ylethynyl)phenyl)pyridine-2,6-dicarboxamide and cis-blocked metal-complexes.[53] Both metallacycles exhibited antiproliferative effect, especially for the Pt(II) metallacycle, which was more potent than cisplatin against head and neck, and thyroid cancer cells, while less toxic against normal cells. Lee et al. reported Pd(II)-based supramolecule complexes with triangular/square architectures using BODIPY derivatives as ligands.[27] Notably, these SCCs were more potent against glioblastoma cells than normal lung fibroblasts, and their anticancer efficacy was even higher than that of cisplatin against the glioblastoma cells. Crowley et al. investigated the influence of different ligands on the biological activity of Pd₂L₄ helicates.[54] Their study showed that the antiproliferative results of the SCCs were correlated with the stability in biological media. Among them, Pd₂L₄ (L = 1,3-bis-hexanetriazole phenyl) helicate possessed the highest anticancer effect, e.g. it was 7-fold more potent than cisplatin against resistant MDA-MB-231 cells. The anticancer mechanism of this SCC is also different from that of cisplatin through DNA crosslink, it triggers cell apoptosis by disrupting the cell membrane.

Attributing to their inherent anticancer capability, platinum-based complexes have attracted extensive attentions over the past decades. Stang et al. developed large libraries of mono- and multi-nuclear platinum acceptors with different angles and sizes, and further constructed a large number of metallacycles and metallacages. In vitro and in vivo evaluations confirmed excellent anticancer output of these SCCs against various cancer cell lines. For example, Stang, Olenyuk and coworkers designed a endohedral amine-functionalized rhomboid using 2,6-bis(pyrid-4-ylethynyl) aniline and 2,9-bis[trans-Pt(PEt₃)₂NO₃] phenanthrene as building blocks.[55] In vivo anti-tumor evaluations indicated that the mice treated with this metalla-rhomboid resulted in a substantial 64% reduction of the tumor burden. Recently, Zheng and coworker reported a Pt₃L₃ hexagon (21) through the coordination between a Pt(IV) prodrug-conjugated dipyridyl ligand (19) and a bidentate ligand (20) (Figure 3e).[56] Through this supramolecular method, three equivalents of cisplatin could be delivered into the cancer cells by the reduction of the Pt(IV) prodrug. Compared with free cisplatin, higher cellular uptake was realized for the metallcylce, effectively improving the anticancer efficacy against a range of cancer cells. In order to improve the anticancer results and overcome drug resistance, other therapeutic modalities were introduced into the SCCs through covalent and non-covalent ways. For example, Yao, Stang, Tim et al. reported the preparation of metallacycles containing porphyrin-based, Ru complex-based, or BODIPY-based photosensitizer.[28,57–59] The combination of chemotherapy and PDT greatly enhanced the anticancer performance of these metallacycles. Aparted from metallacycles and metallacages, metallohelices with different topological structures and mechanisms of action were developed and applied as anticancer agents. For example, Scott and coworkers used Fe as the coordination acceptor to prepare a series of M₂L₃ helicates, which exhibited higher potency than cisplatin against HCT116 p53^+/+ cell line in nM range.[60] They pointed out the binding strength and number of binding sites of metallohelices played important roles in the interaction with oligonucleotide duplexes with bulges, and these interactions were dependent on the size of the bulge that finally determine their efficacy. Scott et al. further reported the preparation of the stereoselective asymmetric metallohelices possessing anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement.[61] Interestingly, these self-assemblies exhibited structure-dependent anticancer activity against the HCT116 p53⁺⁺ cell line, remarkably changing the cell cycle while merely damaging the DNA structures.

Nanoformulations fabricated from SCCs

For in vivo anti-tumor applications, the stability in physiological environment and pharmacokinetic behaviors of the SCCs should be optimized to improve efficacy while reducing side effects. Nanotechnology was employed to overcome the barriers faced by SCCs during their delivery and action processes. Chen, Huang, Stang et al. encapsulated an AIE metallacage into nanoparticles as cancer theranostics.[62] Attributing to the EPR effect and targeting ability, the circulation time of the nanomedicine was greatly prolonged and its tumor accumulation was significantly increased. This nanomedicine exhibited better anti-tumor results than those of the commercial platinum-based drugs including oxaliplatin, carboplatin, and cisplatin. The administration of nanomedicine achieved more durable tumor suppression and apoptosis of tumor cells, while the side effects of the chemotherapeutic agents towards normal tissues were much reduced. Stang and coworkers conjugated glutathione (GSH)-responsive copolymers to an AIE metallacycle to afford an amphiphilic drug carrier. Nanoparticles self-assembled from this material was able to load neutral doxorubicin (DOX) in the hydrophobic cores. Dual-responsive drug release was achieved due to the degradation of the carrier triggered by the high GSH and the protonation of the DOX by the low pH inside cancer cells. In vivo studies confirmed that the NPs 50 nm in diameter were capable of co-delivering platinum-based anticancer drug and DOX in a synergistic pattern, which effectively suppressed tumor growth. Stang, Sun et al. co-loaded metallacages and NIR probes into the polymeric nanoparticles and melanin dots for tumor diagnosis and NIR II image-guided therapy.[38–40] Attributing to the sophisticated design and advantages from nanotechnology, the therapeutic efficacy of these theranostic systems was greatly improved, the tumors were completely ablated by the chemo-photothermal synergistic therapy.

Yang and corworkers controlled the generation of singlet oxygen (¹O₂) by light through the conjugation of porphyrin (22) and diarylethene moieties (23) to a metallacycle (M) (Figure 4a).[63] In this light-responsive dual-stage metallacycle, the production of ¹O₂ was completely inhibited while the diarylethene groups were in the ring-closed form (C-M), while efficient generation of ¹O₂ was realized when these units were converted to ring-open form (O-M) (Figure 4b). The metallacycle was further encapsulated by mPEG-DSPE to obtain a nanomedicine, which allowed for efficient delivery to cancer cells through EPR effect (Figure 4c). The switchable dual-stage nanomedicine was able to ablate the tumors through controllable light irradiation.

Figure 4.

(a) Self-assembly of the metallacycle (M). (b) Illustration of the controllable ¹O₂ generation M and nanoparticles. (c) Illustration of nanomedicine delivery followed by the EPR effect and PDT effect. Reproduced with permission from [63], copyright 2019 American Chemical Society. (d) Chemical structures of the building blocks (HPPB, DSTP, cPt, OEP, N₃-PEG-b-PLBG, and cRGDfK-DBCO) and cartoon illustration of the nanomedicine preparation. Reproduced with permission from [43], copyright 2019 National Academy of Sciences.

It remains a challenge to develop photosensitizers with high quantum yield (QY) for the generation of ¹O₂ due to the severe π-π stacking. As discussed above, the TPP-based metallacage developed by Chen et al. overcame this obstacle, greatly improving the ¹O₂ generation QY by increasing the intersystem crossing efficiency of the photosensitizer.[37] PEGylation of the metallacage by mPEG-b-PEBP and RGD-PEG-b-PEBP endowed the nanomedicine with prolonged blood circulation time and less nonspecific tissue uptake. This nanoformula had a phototoxicity index as high as 246, indicating that the phototherapy could be spatiotemporally controlled by laser. In vivo studies demonstrated the combination of chemotherapy and PDT possessed outstanding anticancer performances in fighting against U87MG, drug-resistant A2780CIS, and orthotopic tumors, effectively preventing tumor recurrence and metastasis after a single treatment. Stang et al. employed a discrete metallacage (24) as a supramolecular host to complex a photosensitizer (OEP) through host–guest chemistry to form a dual functionalized system, which was further encapsulated into the the nanoparticles to afford a nanomedicine (Figure 4d).[43] This nanoformulation specifically delivered the chemotherapeutic drug and photosensitizer to cancer cells, realizing synergistic effect against the drug-resistant cancer cells. In vivo anti-tumor studies confirmed that the combination of chemotherapy and PDT eradicated the drug-resistant tumors, confirming the superior anti-tumor ability of this nanomedicine. Compared with other delivery vehicles, the excellent compatibility and biodegradability of the polymeric carriers used in these supramolecular systems make these nanomedicine more likely to be clinically translatable.

Host–guest recognition for drug delivery

Chemotherapy often results in tumor relapse and drug resistance, which are the main obstacles to improving life quality and prolonging survival of the patients. Cocktail strategy combining different drugs with distinct anticancer mechanisms is an attractive chioce to boost anticancer results. 3D SCCs with unique cavities are interesting supramolecular hosts, which are able to complex with diagnostic or therapeutic guests through host–guest recognitions, thus realizing synergistic therapeutic efficacy. Lippard et al. developed a well-defined M₆L₄ metallacage (25) and used it as a drug delivery system (Figure 5a).[64] Host–guest complexation between the cage and adamantyl groups drived association of four Pt(IV) prodrugs (26) within each cage. The highly positive charge of the host–guest complex facilitated cellular internalization. Active cisplatin was efficiently released inside the cancer cells through a reduction reaction by biological reductants such as ascorbic acid, thus activating the anti-cancer ability. Zheng and coworkers constructed another host–guest complex using this cage as the host and a Pt(IV) prodrug (27) with a fluorescein tail as the guest in a 1:1 ratio with μM dissociation constants (Figure 5c).[65] The inclusion complex was loaded into the nanoparticles using an anionic block copolymer (28) via electrostatic interactions (Figure 5b). Active anticancer drug released slowly from the nanoparticles, and the efficacy of this nanoformulation (IC₅₀ = 5.02 ± 0.67 μM) was comparable with cisplatin (IC₅₀ = 2.95 ± 0.42 μM) against HeLa cells. The introduction of targeting ligands on the SCCs was a direct chioce to elevate their therapeutic efficacy while alleviate the systemic toxicity by optimizing the biodistributions. Casini and coworkers modified the organic ligands by targeting groups for ntegrin α_vβ₃ or α₅β₁ without affecting their coordination self-assembly.[66] The IC₅₀ value of cisplatin decreased to half of the pristine drug by the formation of host-guest complex with the resultant Pd₂L₄ metallacage with the ability to deliver chemotherapeutics to A375 cells overexpressing α_vβ₃ integrins. Ex vivo measurements further the hepatotoxicity and nephrotoxicity of cisplatin were attenuated on the basis of supramolecular chemistry and active targeting strategy.

Figure 5.

(a) Illustration of the host–guest complexation between Pt(IV) prodrug (26) and the metallacage (25). Reproduced with permission from [64], copyright 2015 Royal Society of Chemistry. (b) Illustration of the nanoformulation strategy (c) Illustration of the host-guest complexation between 25 and fluorescein, and chromatic change of fluorescein upon binding to the metallacage. Reproduced with permission from [65], copyright 2018 Royal Society of Chemistry.

Therrien and Stang developed 3D Ru(II) and Pt(II) metallacages and respectively employed them as host to complex porphyrin-based photosensitizers.[43,67] The metallacages not only protected the photosensitizers from light during the transport, but also facilitated their delivery to cancer cells. The host–guest recognition improved the dispersion of photosensitizer in physiologic environment, thus realizing synergistic anticancer effect to overcome drug resistance encountered by the platinum-based drugs. Stang and Isaacs conjugated 4,4’-bipyridinium to the metallacages and used these platforms as supramolecular guests (Figure 6).[68,69] Prodrug or active drug could be loaded through host–guest chemistry using cucurbit[8]uril as the host by forming 1:1:1 ternary complexes (Figure 6b and c). In vitro studies demonstrated these supramolecular system displayed exciting anticancer results. For example, the inclusion complex displayed ~100-fold anticancer efficacy relative to free curcumin against various cancer cell lines, including C32, B16F10, MCF-7, and MDA-MB231.[69]

Figure 6.

(a) Chemical structure of Pd₁₂L₂₄ metallacage 30 and the prodrug 31. (b) Cartoon illustration of the host–guest complexation. Reproduced with permission from [68], copyright 2016 American Chemical Society. (c) Chemical structure of the building blocks and cartoon illustration of the host–guest complexation. Reproduced with permission from [69], copyright 2018 National Academy of Sciences.

Conclusion

The past decades have witnessed the progress of SCCs in biomedical applications, especially in cancer theranostics. By regulating the functions of the individual building blocks and the geometry of their linkages, diverse nanomaterials with unique and enhanced properties can be prepared. The bioactive nature of the metals or metal complexes also determine the final functions of the SCCs, for example, the widely used Pt and Ru precusors hold excellent anticancer ability. Imaging probes can be incorporated into the SCCs, making the delivery and distribution of the SCCs visible. The therapeutic performance of the SCCs is substantially improved by introducing other modalities through covalent and non-covalent methods, which provide potential ways to overcome drug resistance. The solubility and stability of the SCCs in physiological media are the main obstacles for their in vivo uses, which can be effectively solved by the introduction of organometallic units into the supramolecular scaffolds and nanotechnology. The pharmacokinetic behaviors including circulation halftime and tissue distributions are optimized by the formation of nanoformulations, greatly improving their anti-tumor performances and avoiding systemic toxicity, which paves the way for their clinic translation.