Supramolecular Platinum Complexes for Cancer Therapy

Abstract

The rise of supramolecular chemistry offers new tools to design therapeutics and delivery platforms for biomedical applications. This review aims to highlight the recent developments that harness host-guest interactions and self-assembly to design novel supramolecular Pt complexes as anticancer agents and drug delivery systems. These complexes range from small host-guest structures to large metallosupramolecules and nanoparticles. These supramolecular complexes integrate biological properties of Pt compounds and novel supramolecular structures, and that inspires new designs of anticancer approaches that overcome problems in conventional Pt drugs. Based on the differences in Pt cores and supramolecular structures, this review focuses on five different types of supramolecular Pt complexes, and they include host-guest complexes of the FDA-approved Pt(II) drugs, supramolecular complexes of nonclassical Pt(II) metallodrugs, supramolecular complexes of fatty acid-like Pt(IV) prodrugs, self-assembled nanotherapeutics of Pt(IV) prodrugs, and self-assembled Pt-based metallosupramolecules.

Introduction

Platinum complexes play an essential role in cancer therapy. The FDA-approved Pt(II)-based anticancer agents, cisplatin, carboplatin, and oxaliplatin, are widely used in clinics for chemotherapy in the US and worldwide.[1–3] About half of the cancer patients who receive chemotherapy are using these compounds. Their anticancer activity arises from the formation of intra- and interstrand DNA cross-links through coordination bonds of the Pt atoms with the purine nucleobases. These cross-links block transcription, leading to apoptosis of cancer cells.[4] Patients treated with Pt-based chemotherapy usually suffer from a variety of side effects including kidney damage, nerve damage, hearing loss, and suppression of bone marrow activity.[5] Moreover, cancer patients treated with Pt drugs often relapse subsequently and are then deemed incurable due to drug resistance. Thus, there is an urgent need for new therapeutic approaches to overcome these problems in Pt-based cancer therapy.[3]

Supramolecular chemistry has emerged as a promising approach to design new therapeutics and delivery platforms in biomedical research.[6–9] Supramolecular chemistry, also known as “chemistry beyond the molecule”, focuses on reversible non-covalent interactions between molecules, such as hydrogen bonds, metal-ligand interactions, π-π stacking, and hydrophobic effects. With precise control of such interactions, molecular building blocks can assemble into large, sophisticated supramolecular complexes with unique chemical and biological properties. The rise of supramolecular chemistry offers a fresh interface with biological science.[10,11] Harnessing the tools of supramolecular chemistry, such as host-guest complexation and self-assembly, can create novel supramolecular Pt metallodrugs that overcome abovementioned challenges in conventional chemotherapy. This review focuses on the recent developments in this field and aims to demonstrate how synergy between supramolecular chemistry and Pt-based metallodrugs advances cancer research.[6–9] Based on the differences in Pt cores and supramolecular structures, five different types of supramolecular Pt complexes will be discussed in the following sections, and they are (1) host-guest complexes of the FDA-approved Pt(II) drugs, (2) supramolecular complexes of nonclassical Pt(II) metallodrugs, (3) supramolecular complexes of fatty acid-like Pt(IV) prodrugs, (4) self-assembled nanotherapeutics of Pt(IV) prodrugs, and (5) self-assembled Pt-based metallosupramolecules.

Host-guest complexes of the FDA-approved Pt(II) drugs.

Host-guest chemistry allows for encapsulation of small molecular components within a well-defined porous structure in a specific manner. Molecular hosts are macrocyclic chemical structures with interesting host-guest chemistry and potential utility across a vast spectrum of applications. Recent research has shown that molecular hosts can encapsulate the FDA-approved Pt(II) drugs for drug delivery. The metal-organic cage developed by Crowley was able to encapsulate cisplatin in a 1:1 ratio and allowed for on-demand drug release by introducing chloride or 4-dimethylaminopyridine.[12] Calixarene, cucurbiturils, cavitands, pillararenes, and cyclodextrins were able to form host-guest complexes with oxaliplatin and/or carboplatin, and the reported binding constants of such complexes range from 10⁴ to 10⁶ M⁻¹.[11,13–15]. Among these macrocyclic hosts, cucurbit[7]uril exhibits the highest affinity to oxaliplatin with a binding constant of 2.89 × 10⁶ M⁻¹ in phosphate buffers, even though the affinity can be weaken in cell culture media. [16–18] In a recent paper, Zhang used such strong host-guest interactions to develop a new type of nanoformulation of oxaliplatin (Fig 1a) for controlled drug release. Driven by the host-guest interaction, 1 self-assembled with polyethylene glycol (PEG)-based poly-cucurbit[7]uril (PCB) and mitochondria-targeting cytotoxic peptide with an N-terminal phenylalanine (N-Phe-KLAK) to form nanoparticles, which were then protected by a polymeric shell (mPEG-PLL) containing acid-activated competitors for releasing drugs.[19] This “self-motivated” nanoparticle remarkably enhanced the anticancer activity of oxaliplatin against drug-resistant cancer cells.

Fig 1.

Selected examples supramolecular complexes formed by Pt(II) compounds.

Supramolecular complexes of nonclassical Pt(II) metallodrugs.

Over the past several decades, a large number of nonclassical Pt(II) metallodrugs have been developed with the mechanisms of action that distinct from those of the approved drugs.[3] Synergizing such Pt(II) complexes and supramolecular chemistry will bring new insights to bioinorganic chemistry and cancer therapy. For example, Marek reported novel monofunctional Pt(II) compounds bearing an adamantyl moiety, and they are able to form host-guest complexes with cucurbit[7]uril.[20] Interestingly, formation of the host-guest complex promotes the stability of hydrolyzed Pt(II) species in cis-configuration compared to its trans isomer (Fig 1b). Organoplatinum(II) complexes have recently received significant attention for their use as a new type of metallodrugs for biomedical research.[21–24] As shown in Fig 1c, Che recently demonstrated that a Pt(II) N-heterocyclic carbene complex (3) binds vimentin non-covalently with a dissociation constant of 1 μM.[23] Vimentin is a cytoskeletal intermediate filament protein and plays pivotal roles in tumor initiation, progression, and metastasis. Upon binding to vimentin (Fig 1c), 3 effectively suppressed primary tumor growth and impeded metastasis in mice. In a recent paper, Stang used the Pt(II)-phosphine complexes to synergize chemotherapeutic effects of the Pt(II) moiety and photodynamic therapy of porphyrin via assembly of the supramolecular metallaclip (4 in Fig 1d).[25] Additionally, Che recently harnessed intracellular self-assembly of organoplatinum(II) complexes for cancer therapy.[26] As shown in Fig 1e, Compound 5a with a glucose moiety can self-assembled into about 100-nm nanoparticles, which entered cancer cells via endocytosis. Notably, the glycosidic linkage would be cleaved intracellularly by β-glucosidase, resulting in the formation of 5d with a hydroxyl group. 5d then self-assembled into nanofibrils. Formation of the supramolecular structures led to increases in autophagic vacuole formation, lysosomal membrane permeabilization, and mitochondrial membrane depolarization, as well as in vivo efficacy.

Supramolecular complexes of fatty acid-like Pt(IV) prodrugs.

The Pt(IV) prodrug approach is a widely used strategy to improve the therapeutic index and decrease side effects of Pt-based metallodrugs.[3,27,28] Pt(IV) prodrugs are typically prepared by chemical oxidation of an active square-planar Pt(II) species, and that adds two so-called “axial” ligands. The resulting octahedral Pt(IV) complex is more inert to ligand substitution than the parent Pt(II) complex. Within the reducing environment of cancer cells, the Pt(IV) center is converted to Pt(II) with release of two ligands and regeneration of the active square-planar Pt(II) complex. Fatty acid-like Pt(IV) prodrugs (FALPs) represent a new type of Pt(IV) prodrugs and attracted much attention in recent years. FALPs were developed to mimic the structures of fatty acids, by which, they can harness the host-guest interactions with human serum albumin (HSA) for drug delivery.[29–31] In the pioneer study (Fig 2a), Lippard found that FALP (6) binds to HSA via non-covalent interactions and form a non-covalent complex with a binding constant of 1.04 × 10⁶ M⁻¹.[29] In this complex, 6 is buried below the surface of the protein, and therefore, complexation to HSA is able to reduce the rate of reduction of the prodrug by reducing agents. Consequently, 6 exhibited significant stability in whole human blood, attributed to its interaction with HSA. In a recent study, Zheng demonstrated that FALPs act like a “Trojan horse” exploiting the CD36 to facilitate cell entry in ovarian cancer.[32] CD36 is a transmembrane protein that non-covalently binds to fatty acid and facilitates their cell entry. This protein is an emerging target for cancer therapy, as it has been found to be upregulated in various cancer types. Unlike fatty acids providing energy for lipid metabolism, FALPs accumulate in mitochondria and induce mitochondrial damage. FALPs can be quickly converted to Pt(II) species upon reduction by the reduced form of cytochrome c (Cyt c).[33] Interestingly, the Pt(II) products can subsequently platinate Cyt c and lead to enhanced proapoptotic peroxidase activity along with an elevated level of reactive oxygen species (ROS). Consequently, FALPs exhibit high potency against CD36-upregulated ovarian cancer cells with cisplatin resistance. Additionally, FALPs can be readily modified via chemical synthesis to alter their biological activities and chemical properties.[34] For example, Compound 7 (Fig 2b) conjugated with indoleamine-2,3-dioxygenase (IDO) not only effectively kills hormone-dependent, cisplatin-resistant human ovarian cancer cells, but also promotes T-cell proliferation.[35] Attachment of positively charged groups significantly promoted mitochondrial damaging effects of FALPs (8 and 9), and more importantly, Compound 8 can readily eliminate ovarian cancer stem cells, which are believed to be the root of tumor metastasis, cancer relapse, and development of drug resistance.[36] Adding fluorophores to FALPs (10 and 11) enables imaging of such compounds in vitro and in vivo. Using intravital imaging, Weissleder found that 10 can diffuse from tumor-associated macrophages to neighboring tumor cells in vivo.[37] Furthermore, recent studies showed that such novel Pt(IV) prodrugs can be easily incorporated into nanoparticles via either non-covalent encapsulation or covalent conjugation based on their amphiphilic structures and the FALP scaffold can be expanded to include oxaliplatin and carboxylate hydrocarbon tails (12–18 in Fig 2b).[34,38–41] Most reported FALPs exhibit superior in vitro potency against a wide range of cancer types and promising in vivo efficacy in different mouse models. Overall, FALPs have become a powerful scaffold with unique mechanisms of action, high structural diversity, and promising translational potential.

Fig 2.

Fatty acid-like Pt(IV) prodrugs and non-covalent interactions with proteins: (a). Graphical presentation of the mechanism of action of FALPs via the non-covalent interactions with human serum albumin (HSA), CD36, and cytochrome c (Cyt c). (b) A selection of prominent Pt(IV) prodrugs based on the FALP scaffold.

Self-assembled nanotherapeutics of Pt(IV) prodrugs.

Self-assembled nanotherapeutics have been extensively studied as next-generation cancer treatments. Even though several nanoformulations of chemotherapeutics (e.g. Doxil) have been approved by FDA for their clinical uses, there are still no FDA-approved nanotherapeutics with Pt drugs. Self-assembly of Pt(IV) prodrugs has been emerging as a promising method for creating new nanoformulations of Pt drugs. Careful selection of the axial ligands allows for modification of physical, chemical, and biological properties of the Pt(IV) prodrugs as well as enabling self-assembly to nanotherapeutics.[3] Four different types of axial ligands have been explored in the past, including polymers, lipids, host-guest complexes, and peptides (Fig 3). Polymeric nanoparticles of Pt(IV) prodrugs have been studied extensively, and excellent reviews have been published in the past.[3,42] Lipid-based self-assembly of Pt(IV) prodrugs can be achieved via conjugation with phospholipids, cholesterol, and lipophilic hydrocarbon groups (19–23 in Fig 3a).[43–47] Zheng recently created a cholesterol-tethered Pt(IV) prodrug (19) that self-assembled into liposomal nanoparticles with dioleoylphosphatidylcholine (DOPC).[45] Formation of such nanoparticles promoted solubility, stability, and pharmacokinetics of the prodrug with a prolonged circulation time in vivo. Host–guest complexation is another strategy for generating supramolecular nanotherapeutics (24–27 in Fig 3b).[48] Recently, Tian harnessed the host-guest interactions between pillar[5]arene and cyano groups to construct supramolecular drug self-delivery nanomicelles (SDSDNMs).[49] Briefly, two different building blocks were synthesized as the prodrugs of two different chemotherapeutics, cisplatin and gemcitabine. The Pt(IV) prodrug of cisplatin with two pillar[5]arene host units (27) self-assembled with tri-cyano-methylpropionyl-gemcitabine bearing three cyano guest units to form SDSDNMs in aqueous solution. The SDSDNMs facilitated cell entry of both drugs, promoted their accumulation in tumors, and exhibited superior in vitro/in vivo efficacy than the individual drug. In-situ self-assembly of drug-peptide conjugates has attracted great attention for targeted delivery of therapeutic agents and diagnostic molecules.[50] According to a recent report by Liu, a synergistic Pt(IV) prodrug (28), Npx-p_p-Pt(IV), exhibited in situ self-assembly that formed fibrous nanostructures on the cancer cell surface.[51] As shown in Fig 3c, this process was triggered by phosphatases, which confined the nanotherapeutics in the tumor. Thus, it effectively enhanced the cellular uptake of cisplatin, resulting in a high cancer cell selectivity and an extremely low non-targeted cytotoxicity.

Fig 3.

Selected examples of Pt(IV) prodrugs that self-assemble into supramolecular nanotherapeutics.

Self-assembled Pt-based metallosupramolecules

Coordination-driven self-assembly is a well-established method for constructing metallosupramolecules with well-defined size and geometry.[7,28,52] Unlike abovementioned macromolecular/supramolecular species, e.g. polymers or liposomes, their structural features can be determined by NMR spectroscopy, mass spectrometry, and X-ray crystallography.[53] By virtue of their unique structural features, these self-assembled structures have attracted increasing attention in biomedical research in recent years.[7,28,52] A number of novel Pt-based metallosupramolecules have been constructed toward effective delivery of anticancer agents.[54–57] Successes of such self-assembly rely on the geometric information encoded within the molecular building blocks of organoplatinum(II) acceptors and organic donors. For example (Fig 4a), 120° pyridyl donors (30 or 33) self-assemble with 120° Pt acceptors (31) to form supramolecular hexagons (32). Zheng presented the first example of using covalent conjugation and coordination-driven self-assembly to develop a delivery platform with well-defined size, geometry, and Pt drug loading.[56] As shown in Fig 4a, each of the metallosupramolecular hexagon (32) carries a payload of three Pt(IV) prodrug molecules. Notably, the self-assembled supramolecular hexagon displays superior therapeutic index as compared to cisplatin against a panel of human cancer cell lines due to high cellular uptake. Coordination-driven self-assembly generates discrete metallosupramolecules with precise compositions and such features have been recently applied to achieve combination chemotherapy.[58] As shown in Fig 4b, camptothecin (CPT) and combretastatin A4 (CA4) are two different chemotherapeutic agents with distinct mechanisms of action, and they were conjugated to the 90° pyridyl donor (34) and Pt(II) acceptor (35), respectively. Upon self-assembly, they form a discrete supramolecular square (36), in which, there are two molecules of CPT and CA4. Nanoformulation (36-NF-FA) of the metallacycle with folate-conjugated polymers (PLGA-b-PEG-FA) enables tumor-targeted delivery of both agents in a precise ratio (1:1).

Fig 4.

Selected examples of coordination-driven self-assembly of Pt-based metallosupramolecules designed for cancer therapy.

Conclusions and Outlook

There has been a surge in research that focuses on applying supramolecular chemistry to address challenging problems in biological science. This review provides an overview of the recent developments of supramolecular Pt complexes, which integrate supramolecular chemistry and bioinorganic chemistry of Pt compounds for the applications of cancer therapy. This review illustrates that non-covalent interactions can be used to generate novel supramolecular Pt complexes ranging from small host-guest complexes to large metallosupramolecules and nanoparticles. By virtue of their unique structural features, supramolecular chemistry alters biological properties of Pt metallodrugs in various ways, such as enhanced pharmacokinetics, increased cell entry, tumor targetability, on-demand drug release, and new subcellular targets, etc. Such improvements and innovations pave new ways toward resolving challenges in conventional cancer treatments, such as systemic toxicity, drug resistance and cancer relapse. Yet, this field is relatively new, and future in-depth investigations are greatly needed. Next generation advances may include but not limited to precise control of intracellular self-assembly, manipulation of non-covalent interactions between abiological supramolecules and biomacromolecules, precision medicine and cancer immunotherapy with tumor-specific stimuli-response drug release, and the applications of supramolecular Pt nanoparticles to include macromolecular therapeutics such as proteins, DNA, siRNA and miRNA.