Research Progress of Platinum‐Based Anticancer Drugs in Combination with Macrocyclic Drug Delivery System

ABSTRACT

Platinum‐based anticancer drugs represent a cornerstone of clinical cancer chemotherapy, yet their clinical application is severely limited by inherent drug resistance and systemic toxic side effects. Macrocyclic compounds, such as cucurbiturils, cyclodextrins, crown ethers, calixarenes and pillararenes, possess unique cavity structures and excellent molecular recognition capabilities, offering promising strategies for optimizing the chemotherapeutic efficacy of platinum‐based drugs. This review summarizes the latest research progress in supramolecular systems constructed from macrocyclic compounds and platinum‐based drugs via host–guest interactions. It focuses on the roles of such supramolecular complexes in improving drug solubility, stability, tumor targeting, and controlled release performance, as well as their potential to overcome drug resistance and reduce toxicity. Furthermore, the applications of functionalized macrocyclic compounds in intelligent drug delivery and combination therapy are discussed, and future directions, including novel macrocyclic carriers, multifunctional nanoplatforms, and combination with immunotherapy and gene therapy, are prospected. This review aims to provide useful references for the development of precise and personalized applications of platinum‐based drugs in cancer therapy.

This graphical abstract displays three macrocycle‐based platinum delivery strategies built on hostguest chemistry: self‐assembled nanocarriers, direct hostguest combinations and supramolecular hydrogels, which achieve tumor‐targeted cell uptake, sustained drug release and improved antitumor efficacy.

1. Introduction

Approved for clinical use in 1978, cisplatin was the first anticancer drug based on a metal complex, pioneering the use of metal drugs in tumor therapy [1]. Platinum‐based drugs (cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin (Figure 1)remain to this day the first‐line chemotherapeutic agents for a wide range of solid tumors (testicular, ovarian, lung, head and neck), and are indispensable, especially in combination therapies [2]. Platinum‐based anticancer drugs exert unique antitumor mechanisms. They induce tumor cell apoptosis through hydrolysis, generate active intermediates such as [Pt(NH₃)₂Cl(OH₂)]⁺, and crosslink with DNA strands mainly at the N7 site of guanine, thereby blocking DNA replication and transcription and inhibiting tumor proliferation. These agents also possess broad‐spectrum antitumor activity and are effective against a variety of malignancies. Moreover, they exhibit synergistic therapeutic effects in combination with radiotherapy, targeted drugs, and immunotherapy [3]. However, the clinical application of platinum‐based drugs is also facing serious challenges, the most prominent of which is the problem of drug resistance, in which cancer cells gradually become resistant to platinum‐based drugs through various mechanisms, such as enhanced DNA repair ability and increased activity of drug efflux pumps, leading to decreased therapeutic effect or even failure [4]. In addition, the toxic side effects of platinum‐based anticancer drugs should not be ignored, including nephrotoxicity, neurotoxicity, ototoxicity, and myelosuppression, which not only limit the dosage and duration of the drug but may also seriously affect the patient's quality of life [5]. Therefore, researchers are actively exploring strategies to overcome drug resistance and mitigate toxic side effects, such as the development of new platinum‐based drugs, drug combinations, nano‐carrier systems, and individualized treatments, with a view to better exploiting the potential of platinum‐based drugs in future cancer treatments.

FIGURE 1.

Chemical structures of common platinum‐based drugs.

Macrocyclic compounds possess unique cavity structures and superior molecular recognition capabilities, thereby exhibiting great application potential in the fields of drug delivery and supramolecular chemistry. In the field of drug delivery, benefiting from precisely tunable cavity sizes, diverse noncovalent interactions, and excellent structural modifiability, macrocyclic compounds have become essential functional carriers for supramolecular drug delivery [6]. In the field of supramolecular chemistry, macrocyclic compounds act as essential building blocks. They can self‐assemble into functionally diversified supramolecular architectures through non‐covalent interactions, including hydrogen bonding, π‐π stacking, and hydrophobic interactions. A series of functional supramolecular systems, such as molecular machines, sensors, and nanoreactors, can be efficiently formed. These advanced supramolecular platforms offer broad research prospects for materials science, catalytic chemistry, and biomedicine [7]. In addition, the modifiability and multifunctionality of macrocyclic compounds enable them to be combined with other functional molecules, further expanding their application prospects in smart drug delivery systems and complex supramolecular systems. Thus, macrocyclic compounds are driving innovation in drug delivery and supramolecular chemistry as a class of highly promising functional molecules [8].

In drug delivery research, the combination of platinum‐based antitumor drugs and macrocyclic compounds offers an innovative strategy for tumor therapy. Mechanistically, macrocyclic molecules with distinctive cavity structures can encapsulate platinum drugs via host‐guest interactions to assemble stable supramolecular complexes. Such a design effectively improves the water solubility, structural stability, and tumor targeting capacity of therapeutic agents, while distinctly alleviating the systemic toxic and side effects induced by platinum‐based chemotherapy [9]. Furthermore, macrocyclic compound–platinum drug complexes exhibit stimuli‐responsive drug release under the tumor microenvironment (e.g., low pH, high glutathione concentration), thereby further enhancing anticancer efficacy and reducing systemic toxicity. Cyclodextrins and cucurbiturils can protect the stability of platinum‐based anticancer drugs in the in vivo circulation through encapsulation, whereas calixarenes and pillararenes can be functionalized and modified for tumor microenvironment‐responsive drug release. The advantage of this combination is that macrocyclic compounds not only improve the pharmacokinetic properties of platinum‐based anticancer drugs, but also enhance their antitumor effects and reduce their toxicity to normal tissues through targeted delivery and controlled release mechanisms. In addition, the versatility of macrocyclic compounds opens up the possibility of constructing smart nanodelivery systems and combination therapies. Future research directions include designing more efficient and selective carriers for macrocyclic compounds and exploring their application in multidrug‐resistant tumor therapy, as well as developing multifunctional nanoplatforms based on macrocyclic compounds and combining them with emerging technologies, such as immunotherapy and gene therapy, to achieve precision and individualization of cancer treatment. The core strategies of macrocycle‐based delivery systems for platinum drugs are summarized as follows: amphiphilic macrocycle self‐assembled nanocarriers that encapsulate drugs via host–guest interactions to achieve tumor‐targeted delivery; direct host–guest complexation modes, including molecular bonding, molecular inclusion, and pre‐functionalized conjugation; and macrocycle‐crosslinked supramolecular hydrogels for local delivery, which accumulate at tumor lesion sites and realize sustained controlled drug release. All these systems are internalized into tumor cells via endocytosis (Figure 2). This review summarizes the research progress on novel drug delivery systems fabricated via the integration of three generations of classic supramolecular macrocyclic compounds (crown ethers, cyclodextrins, cucurbiturils, calixarenes, and pillararenes) with platinum‐based antitumor drugs.

FIGURE 2.

Schematic illustration of core macrocyclic delivery strategies for platinum‐based anticancer drugs.

2. Crown Ethers and Platinum‐Based Anticancer Drugs

Crown ethers are macrocyclic polyethers that contain multiple ‐oxygen‐methylene‐ structural units in the molecule; common crown ethers are 15‐crown‐5 and 18‐crown‐6 (Figure 3). The cavity structure of crown ether is selective for ions and is a compound with a cyclic polyether structure whose cavity size selectivity confers the ability to complex with specific cations, which can play a role in drug delivery by improving drug solubility, enhancing membrane permeability, and serving as a platform for target modification [10]. When used in combination with platinum‐based anticancer drugs, coronary ether enhances the delivery efficiency of platinum‐based anticancer drugs through membrane transporter facilitation, lysosomal escape effect and intracellular release regulation, and at the same time overcomes drug resistance by bypassing the efflux of transporter proteins, protecting platinum‐based anticancer drugs from glutathione inactivation, and synergistically enhancing DNA damage, thus significantly enhancing the therapeutic effect of platinum‐based anticancer drugs and expanding their clinical potential [9].

FIGURE 3.

Chemical structures of common crown ether.

2.1. Research Examples of Crown Ether‐Platinum Complexes

Li Yao et al. [11] assembled liposomes (cisPt(IV)‐Lip) constructed from cisplatin prodrugs with perfluoro‐15‐crown‐5‐ether, and successfully synthesized oxygen‐carrying perfluorocarbon nanoemulsions, PFCE@cisPt(IV)‐Lip (Figure 4), which were used to enhance tumor oxygenation and achieve synergistic treatment with radiotherapy. This nano‐system significantly improves the tumor hypoxic microenvironment through the oxygen carrier function of perfluorocarbon, which can continuously release oxygen and increase the concentration of dissolved oxygen by 3 times, significantly enhancing the sensitivity of radiotherapy. Meanwhile, cisplatin prodrugs released responsively at the tumor site, combined with a significant reduction in clonogenic survival of 4T1 cells after X‐ray radiotherapy, were efficiently taken up by tumor cells and exhibited cytotoxicity superior to that of free cisplatin. Animal experiments have shown its dual functions of chemo‐sensitization and tumor oxygenation, providing a novel multifunctional nanoplatform to address radiotherapy resistance in solid tumors.

FIGURE 4.

Chemical structures of PFCE@cisPt(IV)‐Lip.

Antonino et al. [12] successfully synthesized a series of dinuclear metal crown ether complexes (1–5) by reacting the azacrown ether dithiocarbamate ligand (K₂L) with [Pd(PPh₃)₂Cl₂], the in situ‐prepared [Pt(PPh₃)₂Cl₂], and [NiCl₂(PPh₃)₂], respectively, in a chloroform/methanol system (Figure 5). The platinum complexes 2 ([LPt₂(PPh₃)₄]Cl₂) and 4 (LPt₂(PPh₃)₄₂) were the focus of the study. The crystal structure of the resulting platinum complex showed a unique “metal‐crown ether” hybridization, which exhibited significant activity against A2780 ovarian cancer cells and its cisplatin‐resistant strain A2780cis, and the activity was further enhanced when combined with NaCl/KCl. The study confirms the structural features by multidimensional characterization and reveals the charge separation properties of [LPt₂(PPh₃)₄]^{2 +} cations by electrostatic potential map analysis.

FIGURE 5.

Chemical structures of Complexes 1−5.

By optimizing the preparation time and stirring rate, Yue et al. [9] successfully facilitated the synthesis of DDP@18‐crown‐6 via the 1:1 stoichiometric binding between cisplatin and 18‐crown‐6 in aqueous solution (Figure 6). The resulting complexes significantly enhance the solubility of cisplatin in water, which may be attributed to the formation of a water‐soluble DDP@18‐crown‐6 complex through a hydrogen‐bonding network between the ‐NH₃ moiety of DDP and the oxygen atom of 18‐crown‐6, a finding that provides new ideas for drug discovery and development. While significantly enhancing the solubility and stability of cisplatin, 18‐crown‐6 can be expanded into a universal optimization platform for drugs containing ‐NH₃ groups or metallic elements such as platinum, silver, lithium, vanadium, and gold.

FIGURE 6.

Self‐assembly of cisplatin and 18‐crown‐6.

2.2. Comprehensive Summary of Crown Ether System Characteristics

Based on the structural characteristics, host–guest interaction mechanisms, and research progress of crown ethers in the delivery of platinum antitumor drugs, the fundamental properties, therapeutic efficacy, application limitations, and future research challenges are systematically summarized, as shown in Table 1.

TABLE 1.

Summary of crown ether‐based platinum drug delivery systems.

Category	Content
Key properties	Cyclic polyether structure; Tunable cavity size (e.g., 18‐crown‐6); Selective complexation of metal ions (e.g., K+, Na+), but weak direct binding affinity toward platinum‐based drugs; Commonly employed as an ionophore or a functional module for supramolecular self‐assembly.
Therapeutic efficacy	Drug loading efficiency: moderate, primarily relying on electrostatic interactions or intercalation for drug encapsulation; Release behavior: sustained release pattern mainly governed by diffusion control; In vivo tumor inhibition rate: overall moderate efficacy; significant enhancement of antitumor effect requires combination with other materials; Toxicity reduction: only mild improvement, primarily through pharmacokinetic optimization to alleviate adverse effects.
Limitations	Weak direct inclusion capability toward platinum‐based drugs; primarily used for constructing nanochannels or as liposome additives; Certain crown ethers exhibit hemolytic and other biological toxicities; Moderate structural stability under physiological conditions.
Challenges	Design of covalent or supramolecular complex systems between crown ethers and platinum‐based drugs to enhance drug loading stability; Mitigation of competitive binding between crown ethers and endogenous metal ions in vivo; Current studies are largely confined to in vitro experiments and ion sensing research, with a notable lack of systematic in vivo antitumor efficacy evaluations;
Relevant literature	[9, 11, 12]

Studies have shown that crown ethers can not only overcome drug resistance by protecting platinum‐based drugs from inactivation by glutathione and bypassing the efflux of transporters, but also synergistically enhance the effect of DNA damage. For example, the PFCE@cisPt(IV)‐Lip nanosystem developed by the team of Li Yao can significantly enhance the radiosensitivity through the synergy of oxygenation and chemotherapy. The binuclear platinum crown ether complex synthesized by Antonino et al. exhibits excellent activity with nearly no drug resistance against drug‐resistant strains. Moreover, the DDP@18‐crown‐6 complex constructed by the research group of Yue can greatly improve the water solubility of cisplatin through a hydrogen bond network. However, with the rapid development of nanodelivery technologies, studies on the combination of crown ethers and platinum‐based drugs have shown a downward trend, which may stem from the following reasons. Emerging technologies such as nanodelivery systems and novel platinum derivatives have been able to optimize drug delivery and reduce side effects more efficiently, making modification strategies for crown ethers redundant. In addition, the focus of research has shifted to more cutting‐edge anticancer approaches such as immunotherapy and targeted drugs, leading to a decline in the attention paid to the study of crown ether‐platinum combinations, coupled with the complexity of synthesis and the high cost of crown ether‐platinum complexes, which further reduces their attractiveness, and hence the gradual decline of research in this area.

3. Cyclodextrins and Platinum‐Based Anticancer Drugs

Cyclodextrin (CD) is a type of cyclic oligosaccharide composed of glucose units linked by α‐1,4‐glycosidic bonds. Commonly encountered ones include α‐, β‐, and γ‐cyclodextrins (Figure 7). Its molecular structure is truncated conical, featuring a hydrophobic inner cavity and a hydrophilic outer surface. It is capable of encapsulating a variety of hydrophobic molecules through host‐guest interactions. Due to its unique cavity structure, it has advantages such as solubilization, enhanced stability, and targeted delivery in drug delivery [13]. The unique mechanism underlying the combined application of cyclodextrins and platinum‐based drugs is that functionalized cyclodextrins (e.g., biotin‐modified cyclodextrins) can specifically bind to overexpressed receptors on tumor cell surfaces, thereby achieving targeted delivery of platinum drugs. This strategy reduces toxicity to normal tissues and increases drug accumulation at tumor sites [14]. Cyclodextrins and platinum‐based anticancer drugs may also enhance anticancer effects through synergistic effects, such as cyclodextrin‐encapsulated oxaliplatin showed stronger cytotoxicity and tumor inhibition in both in vitro and in vivo experiments, and these mechanisms work together to make cyclodextrins an important tool for improving the efficacy and safety of platinum‐based anticancer drugs. This paper details relevant research on cyclodextrins and platinum‐based antitumor drugs in terms of enhancing solubility and stability, reducing toxic and side effects, optimizing targeted delivery, overcoming drug resistance, developing diverse dosage forms, and constructing co‐delivery systems.

FIGURE 7.

Chemical structures of α,β,γ‐Cyclodextrin.

3.1. Research Examples of Cyclodextrin‐Platinum Complexes

Cyclodextrins encapsulate the hydrophobic groups of platinum‐based drugs (e.g., the cyclohexyl group of oxaliplatin and the hydrophobic structure of cisplatin) via their hydrophobic inner cavities. Their hydrophilic outer surfaces enhance the water solubility of the drugs. After encapsulation, new crystal forms or composite structures are formed, which reduce the degradation of drugs during storage and in vivo transport, thereby improving their stability and bioavailability.

Zhang et al. [15] successfully fabricated three water‐soluble inclusion complexes (Figure 8) via grinding and mixing oxaliplatin with β‐cyclodextrin (β‐CD), γ‐cyclodextrin (γ‐CD), and hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD), respectively at a molar ratio of 1:1. The 1:1 inclusion mode was validated through the Job's plot method and phase solubility experiments. Nuclear magnetic resonance spectroscopy revealed that the cyclohexane moiety of oxaliplatin was embedded into the cavity of cyclodextrins, while differential scanning calorimetry and scanning electron microscopy analyses demonstrated the formation of a new crystalline form in the inclusion complexes. The most pivotal finding of this study is that the β‐CD inclusion complex not only remarkably enhanced the water solubility of oxaliplatin but also exhibited in vitro cytotoxicity against human colon cancer HCT116 cells and breast cancer MCF‐7 cells, with the activity reaching nearly twice that of the free drug. This research provides a novel strategy for improving the solubility and bioavailability of platinum‐based anticancer agents.

FIGURE 8.

Schematic diagram of host‐guest inclusion between β‐CD and oxaliplatin.

Jian‐Qiang Zhang et al. [16] successfully synthesized a satraplatin/β‐cyclodextrin (β‐CD) inclusion complex (Figure 9) using the platinum‐based anticancer drug satraplatin and β‐CD as raw materials. The formation of this complex was verified through characterizations including Job's continuous variation method, X‐ray diffraction, and Fourier‐transform infrared spectroscopy. Moreover, the complex exhibits a plate‐like structure that is completely distinct from its raw materials, which confirms the successful construction of a novel inclusion system. This study addresses the clinical challenge of low oral bioavailability of satraplatin, providing a new insight into the development of oral formulations for platinum‐based drugs. Additionally, it systematically elucidates the improvement of the physicochemical properties of the drug by cyclodextrin inclusion via multi‐scale characterizations, thereby demonstrating promising prospects for clinical application.

FIGURE 9.

Satraplatin/β‐CD inclusion complex.

May N. Bin Jumah et al. [17] achieved efficient loading and controlled release of cisplatin by constructing a zinc phosphate@hydroxyapatite/β‐cyclodextrin (CD@ZP/HAP) composite carrier system (Figure 10). In the study, natural Egyptian limestone was first used as the raw material. After being pulverized in a ball mill, the limestone was dissolved in nitric acid to obtain a Ca^{2 +}/Mg^{2 +} ion solution. This solution was then reacted with zinc chloride and phosphoric acid to successfully synthesize the ZP/HAP biphasic crystalline structure. Subsequently, β‐cyclodextrin (β‐CD) was combined with ZP/HAP via an ultrasound‐assisted method to form the composite. Drug‐loading experiments demonstrated that the introduction of β‐CD rendered the drug‐loading mechanism conform to the monolayer model of one energy site. The hydrophobic cavity of β‐CD, in synergy with the active sites on the ZP/HAP surface, significantly enhanced the CPN loading capacity. In in vitro experiments against human cervical cancer HeLa cells, the CPN‐loaded CD@ZP/HAP exhibited a remarkable synergistic effect on cytotoxicity. This composite system optimized the solubility and targeting ability of platinum‐based drugs through the macrocyclic inclusion property of β‐CD. It provides a novel strategy for anticancer drug delivery based on natural mineral‐macrocyclic molecule hybrid systems and demonstrates potential application value in the field of tumor therapy.

FIGURE 10.

Schematic decigram for the loading and releasing mechanism of cisplatin (CPN) using b‐cyclodextrin@zinc phosphate/hydroxyapatite (CD@ZP/HAP).

Clifford W. Fong [18] systematically investigated the molecular mechanisms and clinical application potential of cisplatin‐cyclodextrin inclusion complexes as free radical chemoradiosensitizers via quantum mechanical calculation methods. The study focused on three cyclodextrin carriers (β‐CD, γ‐CD, and HPBCD) and revealed that the CisPt@HPBCD complex, formed by cisplatin and 2‐hydroxypropyl‐β‐cyclodextrin, exhibits a dynamic equilibrium in water. The diradical/dianion species formed after electron attachment to this complex can induce significant elongation of Pt‐Cl bonds—a characteristic that facilitates the release of cisplatin free radicals in the tumor microenvironment, thereby exerting a radiosensitizing effect. Molecular orbital analysis of the γ‐cyclodextrin complex, CisPt@[γ]CD, demonstrated that the highest occupied molecular orbital (HOMO) is localized on the platinum atom, suggesting that electron transfer may preferentially occur at the metal center. Compared with cucurbit[7]uril carriers, cyclodextrin complexes release active cisplatin species more readily and may enhance anticancer efficacy through interactions with apoptosis‐related proteins. The study employed the ONIOM multiscale computational method to verify the reliability of the model. Although ultra‐high precision was not pursued, the approach was sufficiently robust to confirm the rationality of the trend in free radical‐induced bond length changes. This work provides a theoretical basis for the development of cyclodextrin carrier‐based targeted delivery strategies for cisplatin and synergistic radiotherapeutic regimens.

Martin et al. [19] improved the physicochemical properties and biological activities of platinum(II) complexes by the supramolecular coronation technique and synthesized platinum(II) complexes from cisplatin and amantadine. The obtained products possessed the ability to form inclusion complexes with CB7 and β‐CD, thus forming supramolecular assemblies (Figure 11), and exhibited potential biological activities. Introduced lipophilic groups such as adamantanamine, adamantylethylamine, and icosahedral amine optimize the pharmacophore properties of the platinum(II) complexes. X‐ray diffraction confirms that in the structure of the 1a@CB7 complex, the adamantyl group is embedded in the CB7 cavity through hydrophobic interaction, while the N─H group of the platinum complex interacts electrostatically with the oxygen port of CB7 to form a “supramolecular covalent bond”. Mass spectrometric analysis reveals that ligand substitution occurs in the 1a@CB7complex (where chloride ions are replaced by water molecules), resulting in an increased charge. Furthermore, the embedding depth of the adamantyl group within the CB7 cavity in the hydrolyzed 1a_aq@CB7 complex increases by approximately 0.6 Å.

FIGURE 11.

Chemical structures of complex.

Cyclodextrins can achieve the toxicity reduction while efficacy preservation of platinum‐based drugs through two core pathways. On one hand, relying on their unique hydrophobic cavities to encapsulate platinum‐based drugs, they can significantly reduce the non‐specific distribution and accumulation of drugs in non‐target tissues such as kidneys and normal cells, thereby minimizing damage to normal biological tissues at the source. On the other hand, cyclodextrins can act as carriers to realize the synergistic delivery of drugs‐protective components—for instance, when combined with antioxidant and protective ingredients like resveratrol, they further diminish the toxicity of platinum‐based drugs to normal cells. Meanwhile, by virtue of their ability to regulate drug release, they ensure that the drug concentration at the tumor site and the anticancer efficacy remain unaffected, ultimately achieving the clinical optimization goal of reducing systemic toxicity while maintaining tumor therapeutic effects.

Hădărugă et al. [20] harnessed the synergistic effect of γ‐CD and resveratrol to mitigate the cisplatin ‐induced toxic effects. Via molecular encapsulation technology, they constructed the γ‐CD/CP binary complex and the γ‐CD/Rv/CP ternary complex (Figure 12). Furthermore, principal component analysis was adopted to develop a multivariate statistical model for the 18 hematological parameters and 8 biochemical indicators of Wistar rats. The experimental results demonstrated that the ternary complex significantly reduced cisplatin‐induced nephrotoxicity and validated the mechanism by which resveratrol, in synergy with γ‐CD encapsulation, alleviates CP toxicity. The innovation of this study lies in the integration of multivariate statistics and molecular encapsulation technology, which provides a novel γ‐CD‐Rv‐CP ternary synergy paradigm for the detoxification strategy of platinum‐based drugs.

FIGURE 12.

γ‐Cyclodextrin/ cisplatin ternary complex and γ‐Cyclodextrin/resveratrol/cisplatin ternary complex.

Yu‐Hui et al. [21] investigated the anti‐tumor activity of the supramolecular platinum prodrug, 6,6’‐o‐phenylenediselenium bridged bis‐β‐cyclodextrin potassium tetrachloroplatinate complex (Figure 13), which is based on β‐cyclodextrin. The in vitro cytotoxicity of this prodrug on Hela cervical cancer cells and NIH3T3 mouse embryonic fibroblasts was evaluated by MTT assay, and the results showed that CD‐Pt significantly inhibited the growth of tumor cells and was less toxic to normal cells than cisplatin after 48 h of treatment. In vivo experiments were performed using a BALB/c nude mouse Hela cell transplantation tumor model, and CD‐Pt was injected intravenously every 3 days, which was confirmed to be superior to the PBS control group in terms of tumor suppression by tumor volume measurements. The complexes were characterized by nuclear magnetic resonance, electrospray mass spectrometry, and elemental analysis, and the water solubility was enhanced by using the cyclodextrin double cavity structure.

FIGURE 13.

Chemical structures of CDPt.

Ruhe Zhang et al. [22] synthesized supramolecular nanosystems Pt(IV)‐SSNPs (Figure 14) from platinum(IV) prodrug (Pt(IV)‐ADA2) and poly(β‐cyclodextrin) (poly(β‐CD)), and the results were characterized by enhanced anticancer activity and good biocompatibility. In vitro cellular experiments and in vivo animal models verified the anticancer effect of the nanosystems, which significantly induced apoptosis and blocked the cell cycle at S and G2/M phases. The cellular uptake ability and targeting of the nanosystems were verified by in vitro experiments, which demonstrated that Pt(IV)‐SSNPs can be effectively taken up by tumor cells and release drugs intracellularly, induce apoptosis, and at the same time, exhibit responsiveness in the tumor microenvironment, which enables targeted release of the drugs, thus enhancing the therapeutic efficacy. In this study, a poly(β‐cyclodextrin)‐platinum prodrug supramolecular nanosystem was constructed by optimizing the structural design and surface modification of the nanosystem. This approach ensures its in vivo biocompatibility, thereby providing a crucial foundation for its clinical application.

FIGURE 14.

Chemical structures of Pt(IV)‐SSNPs.

Manuela et al. [23] synthesized an amphiphilic block copolymer (hydrophilic segment POEGMEMA₄₀ with hydrophobic segment TMSPMA) with β‐cyclodextrin side chains by RAFT polymerization with click chemistry (Figure 15). The polymer utilizes the host‐guest interaction of β‐cyclodextrin with a platinum(IV) prodrug (CA‐Pt) modified by a bile acid coupling reaction to self‐assemble to form nanomicelles with a particle size of 266 nm, with a release rate of 70% over 24 h in a reduced environment simulated by ascorbic acid. The system has a dual function, acting as an active drug, the Pt(IV) complex is reduced to Pt(II) in the cell, forming DNA adducts and inhibiting cancer cell proliferation; acting as a cross‐linking agent, the Pt(IV) complex enhances the stability of the micelles through cross‐linking and improves the efficiency of the drug accumulation and release at the tumor site. Cellular experiments showed that drug‐loaded micelles were significantly more toxic to ovarian cancer cells A2780 compared to free drug‐loaded micelles, due to a sixfold increase in cellular uptake by the micelles. The micellar system can reduce the damage of Pt(IV) complexes on normal cells and lower the toxic side effects, and the micellar system is simple and environmentally friendly, suitable for large‐scale production with high potential for clinical application, which provides a new idea for the development of anticancer drugs.

FIGURE 15.

Synthesis of block copolymer and Pt‐drug cross‐linker.

In the research on enhancing the targeted delivery of platinum‐based drugs, the core optimization objective is to strengthen their targeting capability toward specific tumor tissues (such as colorectal cancer, breast cancer, and glioblastoma), as well as tumor subcellular organelles (including the endoplasmic reticulum and mitochondria), while decreasing off‐target drug distribution in normal tissues. Cyclodextrins achieve this objective mainly through three mechanisms: first, modifying cyclodextrins with folic acid or receptor ligands to enable their binding to specific receptors on the surface of tumor cells; second, constructing targeted carriers responsive to the tumor microenvironment by compounding cyclodextrins with materials like phillipsite and polymers; and third, realizing the delivery of drugs to tumor subcellular organelles by optimizing the size and surface charge of the carriers.

Naif Altoomd et al. [24] developed a high‐efficiency delivery system for oxaliplatin (OXP)—a therapeutic drug for colorectal cancer—by constructing a β‐cyclodextrin/phillipsite (β‐CD/Ph) organic–inorganic hybrid composite (Figure 16). This system exhibits remarkable drug‐loading capacity and promising potential for antitumor applications. X‐ray diffraction analysis confirmed that phillipsite and β‐CD in the composite form a structurally reconstructed hybrid carrier through chemical complexation or polymer chain grafting. Fourier transform infrared spectroscopy validated the intermolecular interactions between the organic and inorganic components. Studies on the drug‐loading mechanism revealed that the adsorption of OXP onto the carrier follows multi‐stage kinetics: the initial stage is controlled by surface active sites, the second stage transitions to layered adsorption, and the final stage involves processes of interionic attraction and molecular association. By achieving structural design at the molecular level and elucidating the drug‐loading mechanism, this study provides a theoretical basis for the development of platinum‐based drug delivery systems with both high loading efficiency and controlled release properties. It holds significant clinical implications for enhancing the targeting ability and therapeutic efficacy of chemotherapeutic drugs for colorectal cancer.

FIGURE 16.

Schematic decigram of the synthesis of β‐CD/Ph composite, the loading of OXPL drug, and its release process.

Gregory Thiabaud et al. [25] designed a new class of platinum(IV)‐ferrocene conjugates and their cyclodextrin host‐guest complexes. Platinum(IV)‐ferrocene derivatives were synthesized via multi‐step organic synthesis, and the inclusion complex 2@β‐CD was constructed by leveraging the hydrophobic cavity of β‐CD (Figure 17). Single‐crystal X‐ray diffraction analysis revealed that this complex forms a dynamically equilibrated structure in a methanol/water mixed solvent system. Electrochemical studies demonstrated that with the gradual addition of β‐CD, the cyclic voltammogram of the platinum(IV)‐ferrocene compound 2 undergoes significant changes, with the redox potential shifting toward the negative direction. This confirms that host‐guest interactions alter the electronic environment around the platinum center. Cellular experiments showed that the 2@β‐CD complex effectively enhances intracellular platinum accumulation. Confocal fluorescence microscopy observations revealed that the β‐CD labeled with silicon‐rhodamine B co‐localizes with the drug complex in the perinuclear region. Subcellular organelle tracing experiments further confirmed that the complex can target the endoplasmic reticulum and mitochondria. This study provides a crucial theoretical basis and practical strategies for the development of targeted anticancer drugs based on organometallic compound‐cyclodextrin hybrid systems.

FIGURE 17.

Chemical structure of 2@β‐CD.

Valentina et al. [26] developed a novel nanodrug‐carrying system, oCyD, based on β‐cyclodextrin polymer (pCyD) (Figure 18). Using β‐cyclodextrin as the starting material, the polymerization reaction was carried out under alkaline conditions with epichlorohydrin (ECH) as the cross‐linking agent, and the oligomers were ensured to be obtained by controlling a lower ECH/monomer ratio (ECH/CyD = 5), focusing on their delivery properties to the platinum‐based anticancer drug LA‐12. A drug‐carrying system with targeting potential was constructed by synthesizing high and low molecular weight β‐cyclodextrin polymers with folic acid functionalized modifications, but only 15% of the cyclodextrin cavities were modified with folic acid. Experimental results indicate that the high‐molecular‐weight polymer pCyD/LA‐12 (at a 5:1 ratio) significantly reduces the IC₅₀ value of MDA‐MB‐231 cells, whereas the low‐molecular‐weight carrier exhibits no notable effect in this regard. The failure of folate modification to enhance cytotoxicity may be due to a low modification rate or limited folate receptor recognition, but this study confirms that cyclodextrin polymers can effectively enhance the aqueous solubility and antitumor activity of LA‐12 through a noncovalent encapsulation strategy, which provides a new way of thinking about the delivery of difficult‐to‐solubilize anticancer drugs.

FIGURE 18.

Sketched structure of oCyDFA, folic acid, and LA‐12.

Sakira et al. [27] have developed a β‐cyclodextrin (β‐CD)‐encapsulated platinum(II)‐based nanoparticle (Pt‐NPs) composite system (Figure 19), which enables efficient treatment of glioblastoma through multimodal synergistic effects. In the study, a platinum(II) complex Pt(LL’) with a well‐defined structure was first synthesized. Subsequently, the hydrophobic cavity of β‐CD was utilized for molecular encapsulation of Pt(LL’) to form nanoparticles, which exhibited excellent stability for 24 h in PBS buffer. This composite system demonstrated significant photodynamic therapeutic efficacy under irradiation with a 390 nm LED. Fluorescence microscopy revealed a large number of propidium iodide‐stained dead cells among glioblastoma Kr158 cells treated with Pt‐NPs for 24 h. Meanwhile, Western blot analysis confirmed that it could downregulate the expression level of p65, a key protein in the NF‐κB signaling pathway. Mechanistic studies indicated that Pt‐NPs achieve a multi‐targeted attack on tumor cells by simultaneously triggering photodynamic killing effects and inhibiting the expression of cell‐protective proteins such as DJ‐1 and ERp29. This work provides a novel approach to overcome therapeutic resistance in glioma treatment. Through the molecular engineering strategy of combining platinum complexes with macrocyclic compounds, it organically integrates the chemotherapeutic properties of metal drugs with photodynamic therapy and signaling pathway regulation, demonstrating great application potential in the field of neuro‐oncology treatment.

FIGURE 19.

Assembly and Release of Pt(LL’)‐β‐CD.

Cancer cells tend to develop resistance to platinum‐based drugs such as cisplatin and oxaliplatin through mechanisms like activating drug efflux pumps and inducing radiotherapy resistance, which in turn leads to therapeutic failure. Cyclodextrin‐based carriers can also reverse platinum drug resistance via multiple strategies, including evading drug efflux, combining with sensitization therapy, and achieving tumor microenvironment‐responsive drug release. The detailed underlying mechanisms and performance comparisons among different macrocyclic carriers will be elaborated in the subsequent chapter on drug resistance.

Wei et al. [28] synthesized multifunctional nanoparticles (Figure 20) by a supramolecular self‐assembly strategy using a platinum(IV) prodrug‐bridged β‐cyclodextrin dimer, Pt‐CD, and an adamantyl‐modified porphyrin, TPyP‐Ad, as the subject and guest molecules. These nanoparticles can simultaneously exert the chemotherapeutic effect of platinum(IV) prodrugs and the photodynamic therapeutic effect of porphyrins, thus realizing dual chemo‐photodynamic therapy for cisplatin‐resistant cancer cells and effectively overcoming cisplatin resistance by entering cells through endocytosis and avoiding cisplatin's recognition and excretion by drug efflux pumps on the cell membrane. Fluorescent probes were used to detect intracellular ROS levels, and the results showed that the ROS levels of nanoparticle‐treated cells were significantly elevated under light, further demonstrating their photodynamic therapeutic effect.

FIGURE 20.

Chemical structures of (a)Pt‐CD;(b)TPyP‐Ad.

Kuikun Yang et al. [29] synthesized supramolecular polymer nano‐assemblies, PCSNs (Figure 21), using supramolecular polymerization‐induced self‐assembly using cisplatin‐cyclodextrin‐ferrocene (Cis‐CD‐Fc) monomers and poly(ethylene glycol)‐ferrocene (PEG‐Fc). The nano‐assemblies were constructed by the supramolecular polymerization‐induced self‐assembly technique, and their core design consisted of Cis‐CD‐Fc supramolecular monomers formed by covalent attachment of platinum(IV) precursors and ferrocene to cyclodextrins. The monomer undergoes supramolecular polymerization via the host‐guest interaction of ferrocene with cyclodextrins to form linear supramolecular polymers (SPs) and further self‐assembles into nanoparticles, while poly(ethylene glycol) (PEG)‐modified ferrocene (PEG‐Fc) is introduced as an initiator to modulate the length of the supramolecular polymerization and to improve the water solubility and biocompatibility of the nano‐assemblies. Nano‐assemblies have multiple functions in tumor therapy, where ferrocene is oxidized to ferrocene ions by hydrogen peroxide in the tumor microenvironment, releasing highly toxic hydroxyl radicals and inducing tumor cell death through chemodynamic therapy. And the platinum(IV) prodrug was reduced to cisplatin at the tumor site, exerting chemotherapeutic effects while promoting the generation of H₂O₂, which further accelerated the dissociation of the nano‐assemblies and the release of hydroxyl radicals, realizing cascade chemotherapy. In addition, through the synergistic effect of the cascade reaction and chemodynamic therapy, the nano‐assemblies achieved a self‐enhanced tumor‐killing effect, the specific dissociation of nano‐assemblies in the tumor microenvironment reduced the toxicity to normal tissues, and the rapid clearance of residues through the kidneys reduced the long‐term side effects.

FIGURE 21.

Self‐assembly of nanocarriers.

Seiji et al. [30] determined the stability constants of inclusion complexes formed between β‐cyclodextrin (β‐CD) and tetrazole‐bridged complexes 1–3 (Figure 22), which possess bulky hydrophobic substituents (namely, phenyl, n‐nonyl, and adamantyl groups, respectively) at the C5 position of the tetrazole moiety, using ¹H‐NMR spectroscopy. The in vitro cytotoxicity and in vivo antitumor effects of complexes 1–3 were subsequently evaluated against the colon cancer Colon‐26 cell line in the absence or presence of equimolar β‐CD. Compared to the platinum‐based anticancer drug oxaliplatin, the cytotoxicity of complex 2 was similar, complex 3 was moderately cytotoxic, and complex 1 was the least cytotoxic, but the cytotoxicity of all of these complexes was reduced in the presence of β‐CD. In in vivo experiments, the antitumor effects of complexes 1–3 were investigated on colon‐26 colon cancer tumors homografted in male BALB/c mice, and the results showed that they inhibited tumor growth relatively less than oxaliplatin. However, in the presence of β‐CD, the in vivo antitumor effect of complex 3 was superior to that of oxaliplatin, providing a new direction for the study of tetrazole‐bridged complexes with high in vivo antitumor activity.

FIGURE 22.

 e tetrazolato‐bridged complexes 5‐H‐Y and 1–3, and (c) β‐cy.

Traditional platinum‐based drugs are predominantly administered via intravenous injection, featuring a single dosage form. Furthermore, monotherapy with a single drug is prone to inducing drug resistance, and while the combined delivery of platinum‐based drugs and other anticancer agents is essential, there is a lack of compatible carriers. Relying on their intrinsic cavity structure, cyclodextrins can simultaneously encapsulate platinum‐based drugs and other hydrophobic anticancer drugs, thereby achieving the synergistic delivery of multiple drugs via a single carrier. For instance, in the research on β‐cyclodextrin side‐chain block copolymer nanomicelles conducted by the Manuela team, the hydrophobic segment of the nanomicelles could further encapsulate paclitaxel, enabling the combined delivery of CA‐Pt (platinum (IV) prodrug) and paclitaxel. In addition, cyclodextrins can adapt to special dosage forms such as oral formulations and hydrogel‐based local injection by enhancing the oral stability and local retention of drugs. The Jian‐Qiang Zhang team improved the gastrointestinal degradation rate and oral solubility of satraplatin through β‐CD encapsulation; they also constructed an oral inclusion complex formulation of satraplatin, which addresses the clinical challenge of its low oral bioavailability (less than 10% for the original formulation) and provides a new strategy for the oral administration of platinum‐based drugs. Sun et al. [31] reported a local drug delivery system based on hydrogel/nanosized 2‐hydroxypropyl‐beta‐cyclodextrin (HP‐β‐CD) for the in vivo study of delivering doxorubicin‐hydrochloride and cisplatin in osteosarcoma treatment. The injectable visible light‐cured glycol chitosan hydrogel system developed by the research team enables the direct delivery of anticancer drugs to tumor tissues via local injection. Its three‐dimensional matrix structure not only allows the loading of drug combinations but also achieves the controlled and sustained release of drugs, thereby circumventing issues such as multidrug resistance and poor systemic blood circulation associated with traditional chemotherapy. This combined drug‐loading system can not only prevent drugs from being metabolized in the blood circulation but also reduce the risk of MDR through a synergistic chemotherapeutic effect, providing a novel strategy for the local treatment of osteosarcoma.

3.2. Comprehensive Summary of Cyclodextrin System Characteristics

On the basis of summarizing the structural features, modification strategies, and drug delivery applications of cyclodextrins, their core performances, antitumor effects, inherent deficiencies, and research difficulties are further concluded, with the detailed information listed in Table 2.

TABLE 2.

Summary of cyclodextrin‐based platinum drug delivery systems.

Category	Content
Key properties	Truncated cone‐shaped cyclic oligosaccharide structure; Possesses a unique architecture featuring a hydrophilic exterior and a hydrophobic interior cavity; Chemically functionalizable via hydroxyl groups; Host–guest inclusion binding constants range from moderate to high; recognized as an FDA‐approved pharmaceutical excipient.
Therapeutic efficacy	Drug loading efficiency: high, particularly suitable for hydrophobic platinum‐based prodrugs; Release behavior: enables dual pH‐ and glutathione‐responsive drug release through the introduction of responsive crosslinkers; In vivo tumor inhibition rate: markedly enhanced antitumor efficacy; Toxicity reduction: significantly alleviates platinum‐induced nephrotoxicity and gastrointestinal toxicity.
Limitations	Inability to accommodate platinum complexes with molecular dimensions exceeding the host cavity diameter; Unmodified β‐cyclodextrin exhibits risks of nephrotoxicity and hemolysis; Short in vivo circulation half‐life, rendering it susceptible to rapid renal filtration and clearance.
Challenges	Conjugation of targeting moieties such as folate and antibodies to construct active tumor‐targeting delivery systems; Precise regulation of drug release kinetics to circumvent systemic toxicities and adverse effects; Resolution of batch‐to‐batch stability and scalability consistency issues during clinical translation.
Relevant literature	[15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30]

The combined application of platinum‐based drugs and cyclodextrins holds great significance in cancer treatment. Cyclodextrin‐modified nanocarriers can achieve targeted drug delivery, reduce damage to normal tissues, and reverse the drug resistance of cancer cells. In the future, research directions in this field center on the development of multifunctional cyclodextrin carriers and the establishment of multimodal combined therapeutic strategies integrated with photodynamic therapy, immunotherapy, and other modalities to further optimize tumor targeting and drug release efficiency. Meanwhile, further investigations will be devoted to enhancing intracellular drug uptake and overcoming drug resistance via cyclodextrin‐based delivery systems. However, challenges remain, such as the long‐term biosafety of cyclodextrins, the optimization of drug‐carrying efficiency, and the feasibility of large‐scale production still need to be further investigated and addressed. By continuously refining the design and functionality of cyclodextrin‐based carriers, the combined application of platinum‐based drugs and cyclodextrin holds significant promise in enhancing therapeutic efficacy for cancer treatment. This approach is poised to offer safer and more effective treatment regimens, thereby improving patient outcomes.

4. Cucurbiturils and Platinum‐Based Anticancer Drugs

Cucurbit[n]urils (CB[n]s) are a class of supramolecular macrocyclic compounds formed by connecting glycoluril units via methylene bridges. Renowned for their unique rigid cavity architectures and highly selective host‐guest recognition capabilities, they are capable of forming stable inclusion complexes with a diverse range of molecules. Among them, cucurbit[6]uril (CB[6]), cucurbit[7]uril (CB[7]), and cucurbit[8]uril (CB[8]) are the most commonly studied (Figure 23) [32]. In the fields of drug delivery and biomedicine, cucurbiturils exhibit prominent application potential [33]. Studies have shown that the combination of cucurbiturils and platinum‐based anticancer drugs may improve drug release behavior through encapsulation, enhance tumor targeting, reduce damage to normal tissues, and possibly overcome drug resistance by regulating drug metabolism and cellular uptake mechanisms, thereby enhancing therapeutic efficacy. Therefore, the synergistic study of cucurbiturils with platinum‐based anticancer drugs has important scientific value and clinical application prospects. Cucurbiturils exhibit distinctive structural features, endowing them with high binding constants and excellent selective molecular recognition capability. These unique characteristics enable the formation of highly specific host–guest interactions with platinum‐based drugs. Benefiting from such unique binding properties, cucurbituril‐based delivery systems possess favorable dilution resistance and stable drug‐loading stability, which can effectively inhibit premature drug leakage and further maintain structural and functional stability during in vivo circulation [34]. The combined applications of various platinum‐based antitumor drugs and cucurbiturils are elaborated below.

FIGURE 23.

Chemical structures of CB[7] and CB[8].

4.1. Research Examples of Cucurbituril‐Platinum Complexes

Clifford W. Fong [35] systematically investigated the mechanism of cucurbit[7]uril (CB[7]) acting as a free radical chemoradiosensitizer in enhancing the anticancer efficacy of cisplatin (CisPt) through quantum mechanical calculation methods. The study demonstrated that CisPt can spontaneously enter the cavity of CB[7] to form the {CisPt@CB[7]} inclusion complex, and this process requires an energy consumption of approximately 1.6 kcal/mol for cavity desolvation. Molecular orbital analysis revealed that the highest occupied molecular orbital (HOMO) of the complex is mainly localized on CB[7], while the lowest unoccupied molecular orbital (LUMO) is concentrated on the Pt atom, indicating that electron addition preferentially acts on the Pt site. When {CisPt@CB[7]} accepts a single electron to form the anionic complex {CB[7]CisPt·}, the Pt─Cl bond undergoes significant elongation and forms a trigonal planar configuration with an angle of 144°; this structural distortion serves as the precursor state leading to bond cleavage. With the successive addition of the second and third electrons, forming the dianionic {CB[7]CisPt·} and trianionic complexes, the Pt─Cl bond further elongates, accompanied by structural deformation of the CB[7] host and a prominent charge transfer effect. Theoretical calculations confirmed that these electron addition processes possess thermodynamic spontaneity, and the complex stabilizes its configuration through the formation of four hydrogen bonds between the N─H groups of CisPt and the C═O groups of CB[7]. This mechanism is consistent with the previously reported behavior of cisplatin, where electron addition induces ligand dissociation in aqueous solutions. However, the confinement effect of CB[7] significantly enhances the degree of electron localization, thereby providing a theoretical basis for the development of targeted radiosensitization strategies based on supramolecular carriers.

Sougata et al. [1] synthesized organoplatinum(II) receptors with TMA side groups using 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide hydrochloride (EDC‐HCl)‐mediated amidation reaction and further prepared water‐soluble organoplatinum(II) metallocyclic hexagons by a self‐assembly method. The resulting metallocyclic hexagons were able to self‐assemble into aggregates with well‐defined nanostructures in water, exhibiting good water solubility and self‐assembly properties. The morphological and structural features of these self‐assembled nanostructures were demonstrated by means of characterization such as transmission electron microscopy (TEM) (Figure 24).

FIGURE 24.

Preparation of Discrete Metallacyclic Hexagon 1 and Cartoon Representation of the Formation of Heteroternary Host−Guest Complex 5 from 1, CB[8], and NG.

Barbero et al. [36] synthesized supramolecular assemblies with “hanging necklace” structures by complexing CB [7] and CB [8] with a cysteine‐containing pentapeptide (FGGGC) and a platinum(II) metal center. The resulting product is characterized by a unique mixed head‐to‐head (HH) and head‐to‐tail (HT) arrangement and is capable of site‐specific functionalization in aqueous solution through selective recognition by CB[7] and CB[8]. The study reveals that CB[8] is capable of forming stable dimers with platinum complexes. This assembly is driven by both metal‐metal bonding interactions and dispersive forces between the ligands. Furthermore, leveraging the high‐affinity binding of CB[7] toward phenylalanine residues, selective encapsulation of oligopeptides and protein recognition are achieved. In addition, the study successfully realized the quantitative switching of CB[7] and CB[8] in the assemblies, which provides a new strategy for protein identification and rational design of oligopeptide constraints (Figure 25).

FIGURE 25.

Chemical structures of CB[8]^Pt.1₂ and CB[8]^Pt.(1.CB[7]^Phe)_2.

Carboplatin is mainly used in the treatment of a variety of cancers, including ovarian, lung, head and neck, testicular, and bladder cancers, and inhibits the growth of cancer cells by binding to DNA, forming cross‐links and preventing DNA replication and transcription [37]. The molecular recognition and encapsulation effects of cucurbiturils can enhance the antitumor efficacy of carboplatin and reduce its side effects. Carboplatin interacts with CB[7] in two main forms, the inclusion complex (carboplatin is located inside the CB[7] cavity) and the exocytosis complex (carboplatin is located outside of CB[7] and interacts only with the oxygen port) (Figure 26). Mirzaeva et al. [38]. synthesized a complex of carboplatin with CB [7] using multinuclear nuclear magnetic resonance spectroscopy and density‐functional theory calculations by mixing carboplatin with CB [7] and studying their interaction. The optimized structures of the inclusion and exclusion complexes, in which the stabilization energy of the exclusion complex (−55.68 kJ/mol) is significantly higher than that of the inclusion complex (−23.36 kJ/mol), indicate that the exclusion complex is energetically more favorable. In the exocyclic complexes, carboplatin interacts more strongly with CB [7], with shorter hydrogen bonding distances and angles closer to the ideal values, whereas the interactions are weaker in the inclusion complexes. The resultant complex exhibits a certain degree of stability in acidic media. NMR spectroscopy and DFT (Density Functional Theory) calculations have provided evidence for the decomposition behavior of carboplatin in the presence of CB[7], yielding 1,1‐cyclobutanedicarboxylic acid and cis‐PtL₂(NH₃)₂ (where L═H₂O or OH⁻). The latter forms a stable complex with CB[7]. Through peak integration analysis of NMR spectra, a molecular ratio of 2:1 between CB[7] and carboplatin has been determined. Comparative experiments have verified that the decomposition of carboplatin is attributable to the presence of CB[7] rather than other influencing factors.

FIGURE 26.

Chemical structures of (a) the exclusion {carboplatin þ CB[7]} complex and (b) the inclusion {carboplatin þ CB[7]} complex.

Carboplatin, a widely used platinum‐based chemotherapeutic agent whose hydration process (the conversion of the drug to its active form in the body) has a significant impact on its efficacy and toxicity. Irina et al. [39] studied the hydration of carboplatin in phosphate buffer solution (PBS) and RPMI‐1640 medium and analyzed the effect of CB [7] on this process. Carboplatin was found to undergo a hydration reaction in the presence of CB[7] to produce a hydrate of 1,1‐cyclobutanedicarboxylic acid (CBDC) and platinum, the complex showed high stability in acidic medium, and the hydration reaction of carboplatin and its dynamic binding and dissociation process with CB[7] were demonstrated by ¹H NMR spectroscopy. The results showed that CB [7] was able to influence the hydration rate of carboplatin, and the corresponding reaction rate constants were obtained by kinetic fitting of the. In D2O, CB[7] increased the rate of hydration by preventing the formation of carboplatin dimers; in PBS, CB[7] similarly increased the rate of hydration, but by a smaller amount, probably due to the partially offsetting effects of increasing the rate of hydration and encapsulating the medium components; whereas, in RPMI‐1640, CB[7] decreased the rate of hydration presumably because it encapsulated certain carboplatin‐activating hydration mediator components. This study reveals the role of CB[7] in modulating the hydration behavior of platinum‐based anticancer drugs, which provides a theoretical basis for the development of cucurbitacin‐based drug delivery systems and may help to overcome the problem of platinum drug resistance.

Oxaliplatin is primarily applied in the clinical treatment of colorectal cancer, gastric cancer, pancreatic cancer, and other malignancies, and exhibits prominent therapeutic efficacy, especially when combined with 5‐fluorouracil and leucovorin. Nevertheless, its rapid in vivo clearance and systemic toxicity severely restrict the overall therapeutic outcomes [40]. Hao Chen et al. [41] synthesized the main‐chain polymer poly‐CB[7] by combining CB[7] with α,ω‐diazido polyethylene glycol (PEG) (Figure 27). The polymer has CB[7] and PEG structural units, and the resulting poly‐CB[7] is able to encapsulate the anticancer drug oxaliplatin through the molecular recognition of CB[7] to form a stable drug carrier complex, and use the PEG chain to improve the solubility and blood circulation properties of the drug. Research demonstrates that poly‐CB[7] can markedly mitigate the cytotoxicity of oxaliplatin toward normal cells while facilitating drug release within cancer cells through competitive displacement (e.g., spermine), thereby reinstating its anticancer efficacy. This study combines the advantages of supramolecular chemotherapy and polymer therapy to develop a novel supramolecular polymer chemotherapeutic strategy that achieves reduced toxicity to normal cells, enhanced toxicity to cancer cells, and improved drug circulation performance in vivo, providing a new way of thinking about the delivery of anticancer drugs.

FIGURE 27.

Schematic illustration of supramolecular polymeric chemotherapy based on poly‐CB[7].

Han Wu et al. [42] synthesized nanocarriers with self‐encapsulated structures by encapsulating an activatable host‐guest conjugate, DCBSS, designed based on the self‐encapsulation mechanism of CB [7] and alkylammonium, with oxaliplatin(OxPt) (Figure 28). The resulting product, DCBSS‐OxPt conjugate, has controlled drug release properties and is capable of achieving efficient drug release under specific conditions. When the DCBSS‐OxPt conjugate is exposed to a reducing agent (e.g., tris(2‐carboxyethyl)phosphine, Tcep), the disulfide bond in the DCBSS is reduced to a thiol, which triggers the self‐encapsulation of the CB[7] with alkylammonium, which in turn releases the encapsulated drug oxaliplatin. The strong binding affinity between DCBSS and OxPt was demonstrated by isothermal titration calorimetry (ITC) and diffusion‐ordered nuclear magnetic resonance spectroscopy (DOSY), etc., and the existence of self‐encapsulated structure was confirmed, and the ability of this nanocarrier to achieve controlled release of the drug in phosphate buffer was further verified by time‐dependent nuclear magnetic resonance (¹H NMR) experiments.

FIGURE 28.

Schematic Illustration of the Disguise and Exposure of the Drug by Using an Activatable Host−Guest Conjugate as a Nanocarrier.

Ekaterina A. Pashkina et al. [43] complexed cucurbit[7]uril (CB[7]) with oxaliplatin and carboplatin, synthesized CB[7]‐oxaliplatin complexes and CB[7]‐carboplatin mixtures, and investigated the effect of their antitumor and immunomodulatory properties (Figure 29). In vitro experiments revealed that the complex formed by CB[7] with oxaliplatin, as well as a CB[7]‐carboplatin (1:1) mixture, significantly enhanced the cytotoxicity and cytostatic effect on B16 and K562 tumor cell lines, which was verified by ¹H NMR and diffusion‐ordered spectroscopy (DOSY). In vivo experiments further showed that the two complexes prolonged the survival of melanoma model mice, and the effect was confirmed to be significant by statistical analysis.

FIGURE 29.

Effects of CB[7] on the properties of platinum(II) compounds.

Nedaplatin suppresses the proliferation of cancer cells by disrupting the DNA replication and repair mechanisms of tumor cells. It is clinically applied for the treatment of a variety of malignancies, including non‐small cell lung cancer, ovarian cancer, as well as head and neck cancers [44]. Chunyan Jia et al. [45] synthesized CB[7] by condensing glyburide with paraformaldehyde, which has a molecular weight of 1162.96 g/mol and a density of 2.69 g/cm³. CB[7] formed the host‐guest inclusion NDP@CB[7] with the cisplatin derivative nedaplatin (NDP) (Figure 30), which possessed improved antitumor activity and resulted in a significant increase in the aqueous solubility of NDP, exhibiting two‐threefold higher cytotoxicity than free NDP against A549 and HCT116 cancer cells. Fluorescence spectroscopic titration demonstrated the strong binding affinity between CB[7] and NDP with a binding constant of (2.89 ± 0.26) × 106M⁻¹ and the formation of the inclusion complexes in accordance with a 1:1 stoichiometric ratio. Powder X‐ray diffraction (XRD) analysis confirmed the formation of the inclusion complexes, whose crystal phases differed from those of CB[7] or NDP alone, exhibiting a unique amorphous structure.

FIGURE 30.

Possible inclusion mode of the NDP@CB[7].

Lobaplatin inhibits the proliferation of cancer cells by forming DNA adducts to interfere with intracellular DNA replication and transcription. It is clinically indicated for the treatment of multiple malignancies, such as small cell lung cancer, ovarian cancer, and breast cancer. Compared with cisplatin, lobaplatin presents lower nephrotoxicity and gastrointestinal toxicity [46]. Yueyue et al. [47] synthesized the LbPt‐CB[7] (Figure 31) host‐guest complex by encapsulating cucurbit[7]uril (CB[7]) with lobaplatin. The resulting product, LbPt‐CB[7], possessed enhanced antitumor activity and was able to significantly inhibit the growth of tumor cells. Isothermal titration calorimetry (ITC) characterization demonstrated the strong binding affinity between CB[7] and LbPt, and the formation of the inclusion complexes conformed to a 1:1 stoichiometric ratio. In vitro experiments showed that the complex could significantly enhance the killing effect on tumor cells such as HCT116, and it was also found that the complex could promote apoptosis of tumor cells by inducing reactive oxygen species (ROS) production and nuclear damage, while changes in the expression level of arginosamine synthetase might be involved in the regulatory process.

FIGURE 31.

Chemical structures of LbPt‐CB[7].

Hang Zhou et al. [48] investigated a supramolecular strategy based on cucurbit[8]uril (CB[8]) for the construction of bisplatinum drug nanocapsules and enhancement of their permeability in the tumor microenvironment of colorectal cancer. Two small‐molecule platinum‐based anticancer drugs, lobaplatin and eplatin (LP and EP), were encapsulated in CB[8] by a self‐assembly method to form a stable ternary supramolecular complex, CLE (Figure 32), with a diameter of about 69 nm. The experimental results showed that the CB[8] nanocapsules significantly enhanced the penetration of platinum‐based anticancer drugs into the tumor microenvironment and altered the nanomechanical properties of the cancer cells, such as reduced adhesion, increased stiffness, and modulus. CLE is characterized by spontaneous formation and exhibits strong stability in aqueous solution at pH 7.0, which has important applications in enhancing the permeability of platinum‐based drugs and improving the nanomechanical properties of colorectal cancer cells.

FIGURE 32.

Chemical structures of the CB[8] complex (CLE).

4.2. Comprehensive Summary of Cucurbituril System Characteristics

Combined with the unique rigid cavity structure, excellent host–guest binding capacity, and research status of cucurbiturils in platinum drug delivery, this section summarizes their essential properties, therapeutic advantages, inherent limitations, and subsequent research challenges, as presented in Table 3.

TABLE 3.

Summary of cucurbituril‐based platinum drug delivery systems.

Category	Content
Key properties	Rigid pumpkin‐shaped structure with exceptionally high host–guest binding affinity toward cationic platinum‐based drugs; Exhibits excellent chemical stability under physiological conditions and favorable biocompatibility.
Therapeutic efficacy	Drug loading efficiency: exceptionally high; Release behavior: enables competitive and pH‐responsive controlled release; In vivo tumor inhibition rate: significantly enhanced in vivo antitumor efficacy; Toxicity reduction: markedly reduces systemic toxicities and adverse effects of platinum‐based drugs.
Limitations	Stringent size requirements of the cavity toward guest molecules, accommodating only specific platinum‐based prodrugs; Unmodified CB[7] at high doses may induce acute pulmonary embolism; Limited in vivo biodegradability; Sparse in vivo biodistribution data and unknown long‐term safety profile; Excessive molecular rigidity hindering chemical functionalization.
Challenges	Development of functionalizable cucurbituril derivatives to construct tumor‐targeted delivery platforms; Enhancement of in vivo blood circulation stability of the system; Design of stimulus‐responsive drug release systems with more precise regulatory mechanisms.
Relevant literature	[1, 36, 38, 41, 42, 43, 45, 47, 48]

The combined application of cucurbiturils and platinum‐based drugs has demonstrated remarkable synergistic therapeutic effects. The combination of platinum(IV) prodrugs with cucurbiturils systems has enabled real‐time monitoring of drug reduction processes in living cells and animal models, which provides a new tool for understanding the mechanism of drug action. In the future, the development of more selective and biocompatible cucurbiturils derivatives, the optimization of stimulus‐responsive delivery system to achieve spatiotemporally controlled drug release, the deepening of the mechanism research by combining with real‐time monitoring technology such as bioluminescence imaging, and the exploration of cucurbiturils and platinum complexes in overcoming tumor drug resistance will promote the development of supramolecular drug delivery system in the direction of precision, intelligence, and visualization.

5. Calixarenes 、 Pillararenes and Platinum‐Based Anticancer Drugs

Calixarenes are macrocyclic compounds formed by the ortho‐condensation of phenolic units via methylene bridges (─CH₂‐) into a cup‐shaped architecture, from which their nomenclature derives. The upper rim (wider aperture) and lower rim (narrower aperture) of calixarenes can be functionalized through chemical modification with diverse substituents, enabling tailored tuning of their physicochemical properties and binding capabilities. Based on the number of phenolic units (n), calixarenes are classified as calix[4]arene, calix[6]arene, calix[8]arene, etc. (Figure 33). Among these, calix[4]arene—comprising four phenolic units linked by methylene bridges to form a characteristic cup‐shaped cavity—is the most extensively studied variant [49]. As a typical category of supramolecular hosts, calixarenes readily form inclusion complexes with platinum‐based drugs via their unique cavity architectures and diverse noncovalent interactions, such as hydrogen bonding and π‐π stacking. Furthermore, calixarenes efficiently regulate cell membrane permeability and promote the intracellular accumulation of platinum‐based drugs. These superior properties effectively inhibit the DNA repair mechanism of tumor cells and enhance the cytotoxicity of chemotherapeutic agents, thereby improving overall antitumor efficacy [50]. Pillararenes are macrocyclic compounds synthesized by the 2,5‐ortho‐condensation of hydroquinone units via methylene bridges (─CH₂‐), forming a rigid tubular architecture that inspires their nomenclature. Characterized by high structural symmetry and a moderately sized cavity, pillararenes exhibit exceptional aptitude for recognizing and binding specific molecules through host‐guest interactions. Based on the number of hydroquinone subunits (n), pillararenes are classified as pillar[5]arene, pillar[6]arene, etc. (Figure 33), with pillar[5]arene—comprising five hydroquinone units in a cyclopentameric arrangement—being the most prevalent variant [51]. Pillararenes can improve the water solubility and structural stability of platinum‐based drugs through multiple strategies, including encapsulation of therapeutic molecules, modification with targeting moieties such as folic acid and antibodies, and the construction of stimuli‐responsive structures for controlled and site‐specific drug release at lesion sites. These approaches reduce in vivo degradation, prolong blood circulation time, and ultimately enhance drug accumulation in tumor tissues [52]. Calixarenes and pillararenes exhibit immense potential in the field of drug delivery systems due to their unique structural architectures and exceptional physicochemical properties. Their inherent advantages, including high drug loading capacity, stimuli‐responsive controlled release, precise tumor targeting and excellent biocompatibility, render them ideal candidates for next‐generation drug delivery platforms. Through continued research and optimization, these macrocyclic hosts are poised to play a pivotal role in advancing future therapeutic strategies by enabling precision medicine, reducing systemic toxicities, and improving patient outcomes.

FIGURE 33.

Chemical structures of (a) calix[4]arene, calix[6]arene, calix[8]arene; (b) pillar[5]arene, pillar[6]arene.

5.1. Research Examples of Calixarene‐Pillararene Platinum Complexes

Natalie Kahwajy et al. [53] synthesized supramolecular complexes featuring a capsule‐like architecture by employing the anticancer drug phenanthriplatin, along with cucurbit[n]uril (CB[n]), β‐cyclodextrin (β‐CD), and p‐sulfonatocalix[4]arene (sCX[4]) as building blocks (Figure 34). The synthesized supramolecular complex, featuring a capsule‐like architecture, was characterized by ¹H NMR spectroscopy and molecular modeling, confirming a 2:1 host‐guest stoichiometry between phenanthriplatin and p‐sulfonatocalix[4]arene (sCX[4]). Specifically, each sCX[4] molecule encapsulates the terminal regions of the phenanthriplatin prodrug, forming a dual‐capped capsular assembly. This binding mode significantly enhances the thermodynamic stability and targeting selectivity of the platinum agent during delivery. Molecular dynamics simulations further revealed the pivotal role of four cooperative hydrogen bonds in stabilizing the host‐guest complex, with the sulfonate groups of sCX[4] engaging in electrostatic and hydrogen‐bonding interactions with the platinum(IV) core and coordinated ligands of phenanthriplatin. Through diffusion‐ordered spectroscopy (DOSY) and density functional theory (DFT) calculations, we elucidated the binding mechanism of phenanthriplatin with macrocyclic hosts, providing detailed insights into the geometric structures and NMR shielding parameters of the resulting complexes. This study employs innovative experimental methodologies and systematic investigations to reveal the binding characteristics of phenanthriplatin with diverse macrocyclic molecules, identifying p‐sulfonatocalix[4]arene (sCX[4]) as a particularly advantageous host for drug delivery applications. The findings introduce novel paradigms and experimental validation for advancing platinum‐based drug delivery systems, offering critical insights for optimizing therapeutic efficacy and reducing off‐target toxicities.

FIGURE 34.

The chemical structures and molecular models of the three types of macrocycles used in this study: A cucurbit[n]urils (n = 7 or 8); B β‐cyclodextrins and C para‐sulfonatocalix[4] arene; D Schematic diagram showing the single intermolecular interaction between the drug's HE/F protons and the β‐cyclodextrin portal H3 resonance.

Xin Dai et al. [54] synthesized a nanomedicine, Pt‐cCAV5‐FU, by complexing p‐sulfonatocalix[4]arene with cisplatin and co‐loading 5‐fluorouracil (5‐FU) (Figure 35). This formulation effectively circumvents cisplatin resistance, protects cisplatin from degradation, and modulates glutathione S‐transferase (GST) activity. Through isothermal titration calorimetry (ITC) and in vitro cytotoxicity assays, the study demonstrated that Pt‐cCAV5‐FU significantly mitigates drug resistance in A549/CDDP‐resistant cells compared to cisplatin alone, reducing the resistance fold from 4.98 to 0.75 and exhibiting enhanced antitumor efficacy.

FIGURE 35.

Vesicle structure verification with fluorescence leakage tests by encapsulating Phloxine B.

Meiying et al. [55] synthesized an amphiphilic phosphorylated calix[4]arene‐based nanocarrier, P4C6, by functionalizing the lower rim of calix[4]arene with n‐hexyl groups, followed by Duff reaction‐mediated formylation, reduction of the aldehyde moiety to an alcohol using sodium borohydride (NaBH₄), and subsequent chlorination/phosphorylation via thionyl chloride (SOCl₂) and triethyl phosphite. The resulting amphiphilic P4C6 exhibited dual drug‐loading capacity, encapsulating both carboplatin and paclitaxel to form stable nanoparticles (Figure 36). In vitro studies demonstrated significant cytotoxicity against colorectal cancer cell lines (e.g., Caco‐2 and HT‐29), with dose‐dependent responses evaluated by half‐maximal inhibitory concentration (IC₅₀) measurements. This study pioneers the use of P4C6 as a nanocarrier for co‐delivering carboplatin and paclitaxel, leveraging a synergistic dual‐drug delivery strategy to enhance therapeutic efficacy against colorectal cancer.

FIGURE 36.

Formation of host‐guest complexes.

Sherif et al. [56] synthesized supramolecular complexes through the non‐covalent assembly of oxaliplatin with p‐sulfonatocalix[n]arenes (specifically p‐SC4 and p‐SC6) in aqueous solution, yielding host‐guest adducts stabilized by intermolecular interactions such as hydrogen bonding, electrostatic attractions, and van der Waals forces. The resulting supramolecular complexes exhibit exceptional thermodynamic stability and specific host‐guest recognition, evidenced by a 1:1 stoichiometric ratio confirmed via Job's plot analysis. Computational modeling further identified the thermodynamically most stable binding conformations as 1U(b) and 2L(a) (Figure 37), characterized by distinct spatial arrangements of oxaliplatin within the calixarene cavity. The ADMET study predicted the biological properties of the complex, which has improved over free oxaliplatin, with enhanced uptake to help cancer cell uptake to improve efficacy, reduced blood‐brain barrier permeability to reduce toxicity to brain cells, and greater binding to plasma proteins, which is expected to prolong the duration of the drug's action.

FIGURE 37.

Four possible inclusion modes of oxaliplatin.

Sherif et al. [57] conducted a comprehensive investigation into the supramolecular complexation of the anticancer agent carboplatin with two calixarene derivatives, PS4 and PS6, via aqueous co‐assembly. By mixing carboplatin with the macrocyclic hosts (PS4 and PS6) in solution, they successfully synthesized 1:1 carboplatin‐calixarene host‐guest complexes with high fidelity, as corroborated by stoichiometric analysis and structural validation (Figure 38). The resulting complexes are highly stable, with hydrogen bonding being the major stabilizing factor, and carboplatin interacts with calixarene in a variety of configurations (upper/lower edge insertion). Notably, these complexes exhibit significantly enhanced anticancer activity compared to free carboplatin. This research provides a theoretical foundation for the development of calixarene‐based drug delivery systems and underscores the immense potential of supramolecular chemistry in the realm of drug design and optimization.

FIGURE 38.

Multiple interaction modes between carboplatin and calixarenes(PS4andPS6).

Sherif et al. [58] synthesized Asplatin (Figure 39) by reacting oxaliplatin with acetylsalicylic anhydride in dimethyl sulfoxide (DMSO). The resulting product exhibited high purity and stability, with a yield of 78%. The structural accuracy of Asplatin was validated through proton nuclear magnetic resonance spectroscopy (¹H NMR) and mass spectrometry (MS). By employing supramolecular chemical approaches, the Asplatin/PSC4 complex was synthesized through the association of Asplatin with p‐sulfonatocalix[4]arene (PSC4) in an aqueous solution. The resultant complex exhibited characteristics of specific binding and high stability. Computational analyses revealed that hydrogen bonding played a pivotal role in stabilizing the complex. In vitro cell viability assays demonstrated that the Asplatin/PSC4 complex displayed significantly enhanced cytotoxicity toward various cancer cell lines, including MCF‐7, HeLa, and A‐549 cells, while exhibiting superior biocompatibility compared to cisplatin when evaluated against normal cells (such as human skin fibroblasts).

FIGURE 39.

Asplatin/PSC4 inclusion complex configurations.

Xin‐Yue et al. [59] reported a calixarene‐based supramolecular drug delivery nanosystem that achieves efficient anticancer drug delivery through a host‐guest chemistry strategy (Figure 40). The research team designed and synthesized a polyethylene glycolated GC5A‐12C nanocarrier, which significantly enhances the cellular uptake efficiency of three anticancer drugs: chlorambucil, oxaliplatin (OX), and methotrexate (MTX). This nanocarrier reduced the half‐maximal inhibitory concentration (IC₅₀) values of these drugs by up to 51‐fold against Hela, HepG2, and MCF‐7 cancer cells. Flow cytometry and fluorescence imaging confirmed that the system enhances the intracellular internalization of the photosensitizer AlPcS₄ in tumor cells via an energy‐dependent endocytic pathway, with fluorescence intensity markedly higher than that of the free drug and liposome control groups. Mechanistic studies revealed that this nanosystem can overcome multiple intracellular barriers, offering a novel perspective for targeted chemotherapy based on supramolecular chemistry.

FIGURE 40.

Schematic illustration of the host‐guest nanosystem.

Qi Hao et al. [60] synthesized an oxaliplatin‐carboxylated pillar[6]arene (CP[6]A) complex, designated as OxPt‐CP[6]A, by combining oxaliplatin with carboxylated pillar[6]arene (CP[6]A) in a phosphate‐buffered saline solution (pH 7.4) (Figure 41). The resulting OxPt‐CP[6]A complex exhibited high stability and specific binding, with a 1:1 stoichiometric ratio of binding, as characterized through Job's plot analysis and isothermal titration calorimetry. The results revealed a binding constant of 1.66 × 10⁴ M^{− 1} between OxPt and CP[6]A, indicating a strong binding affinity between the two components. Furthermore, the structural characteristics of the complex were further validated by proton nuclear magnetic resonance spectroscopy (¹H NMR). In the ¹H NMR spectra of both OxPt and CP[6]A, all proton peaks (a−e) of OxPt displayed significant upfield shifts, attributed to the shielding effect induced by the electron‐rich cavity of CP[6]A, confirming the formation of the OxPt−CP[6]A complex. In vitro experiments demonstrated that this complex significantly reduced the cytotoxicity of oxaliplatin against normal cells while enhancing its anticancer activity against colorectal cancer cells.

FIGURE 41.

Chemical structures of CP[6]A and OxPt‐CP[6]A.

Yang et al. [61] synthesized supramolecular drug self‐assemblies based on host‐guest interactions by combining water‐soluble pillar[6]arene (WP[6]) with a drug‐drug conjugate, Cb‐Pt (Figure 42), in an aqueous solution. The drug‐drug conjugate Cb‐Pt was synthesized via an esterification reaction between chlorambucil and oxaliplatin (Oxo‐Pt), wherein the carboxyl group of Cb reacted with the hydroxyl group of Oxo‐Pt to form an ester bond. The resulting SDSAs exhibited stimulus‐responsive drug release behavior. They were characterized using electrospray ionization mass spectrometry, which confirmed the successful synthesis of the drug‐drug conjugate. Furthermore, in vitro cellular experiments and in vivo antitumor efficacy studies were conducted to validate the effectiveness of SDSAs in cancer therapy.

FIGURE 42.

Construction of WP[6]‐based supramolecular drug self‐assemblies.

Cui‐Ting et al. [62] conducted host‐guest self‐assembly by combining a supramolecular host compound, D‐biotin‐modified pillar[5]arene (D‐biotin‐P5), which possesses both targeting capability and chiral recognition functionality, with an electron‐deficient guest molecule containing a quaternary ammonium group, myristoylcholine chloride (MCC). The quaternary ammonium moiety of MCC was embedded within the hydrophobic cavity of D‐biotin‐P5, forming spherical vesicles with a diameter of approximately 80–93 nm at a 1:2 molar ratio (Figure 43). The resulting nanocarrier was capable of selectively capturing and targeting the delivery of oxaliplatin (OXA) enantiomers. This nanocapturing agent could selectively sequester the (R,R)‐OXA enantiomer and, through an enzyme‐induced disassembly process, release the drug in a targeted manner into tumor cells. Chiral separation experiments demonstrated that D‐biotin‐P5⊃MCC nanocomplexes (NCs) were highly efficient in separating the enantiomers of OXA, significantly enhancing the capture efficiency of (R,R)‐OXA. Furthermore, targeted delivery experiments revealed that the nanocapturing agent markedly augmented the intracellular uptake of OXA in MCF‐7 breast cancer cells, achieving efficient drug release. Consequently, it exhibited superior inhibitory effects on MCF‐7 cells compared to free OXA, while concurrently reducing the cytotoxicity of the drug in HEK 293 human embryonic kidney cells.

FIGURE 43.

Self‐assembly of chiral nanocarriers.

5.2. Comprehensive Summary of Calixarene‐Pillararene System Characteristics

After reviewing the structural modifiability, stimulus‐responsive release behavior, and antitumor delivery applications of calixarenes and pillararenes, their fundamental performances, therapeutic efficacy, application drawbacks, and future research prospects are generalized systematically, as illustrated in Table 4.

TABLE 4.

Summary of calixarene‐and pillararene‐based platinum drug delivery systems.

Category	Content
Key properties	Calixarenes: cup‐shaped molecular architecture with functionalizable upper and lower rims; sulfonated water‐soluble calixarenes are widely applied; Pillararenes: rigid pillar‐shaped skeleton featuring an electron‐rich cavity; Both classes allow tunable cavity sizes, with host–guest binding constants ranging from moderate to high;
Therapeutic efficacy	Drug loading efficiency: excellent, compatible with platinum‐based drugs bearing hydrophobic aromatic ligands such as oxaliplatin; Release behavior: calixarenes primarily enable pH‐responsive release, whereas pillararenes facilitate redox‐ and enzyme‐responsive release; In vivo tumor inhibition rate: calixarenes exhibit significant antitumor efficacy, with pillararenes showing even more pronounced effects; Toxicity reduction: moderate to pronounced alleviation of platinum‐induced toxicities and adverse effects.
Limitations	The synthesis and purification processes of calixarenes are cumbersome, and the preparation cost of water‐soluble derivatives is relatively high; Research on pillararenes started at a later stage, and there is a paucity of in vivo toxicity data; The long‐term structural stability of both classes of macrocyclic compounds under physiological conditions remains to be validated.
Challenges	Simplification of synthetic routes to facilitate clinical translation. Precise construction of multi‐stimuli (pH, enzyme) synergistic responsive drug release systems. Refinement of in vivo pharmacokinetic and biodistribution studies of pillararene–platinum drug complexes.
Relevant literature	[53, 54, 55, 56, 57, 58, 59, 60, 61, 62]

Supramolecular assembly systems involving calixarenes and pillararenes with platinum‐based drugs have emerged as a significant research avenue in the field of antitumor drug delivery. The readily functionalizable surfaces of these host molecules further enable the conjugation of targeting ligands or stimulus‐responsive moieties, facilitating the construction of intelligent drug delivery platforms. Existing research has demonstrated that employing amphiphilic phosphorylated calixarenes as nanocarriers for the co‐loading of carboplatin and paclitaxel offers a novel paradigm in drug development, transcending the conventional confinement of drug encapsulation to a single therapeutic agent. In the future, the design of innovative functionalized aromatic derivatives to enhance targeting efficacy, the development of multi‐stimuli‐responsive systems for achieving spatiotemporally precise controlled drug release, and the elucidation of the molecular mechanisms underlying the reversal of platinum drug resistance by supramolecular assemblies will propel the evolution of supramolecular platinum‐based drug systems toward intelligent, visualizable, and multifunctional platforms. This progression will pave the way for a new paradigm in combinatorial cancer therapy.

6. Mechanisms of Macrocyclic Compounds in Reversing Platinum‐Based Tumor Drug Resistance

Tumor drug resistance is the core bottleneck that limits the clinical performance of platinum‐based chemotherapeutic agents [63]. The underlying mechanisms cover multiple biological events, including reduced cellular drug uptake, overexpression of cell membrane drug efflux proteins, intensified intracellular glutathione‐mediated drug detoxification, and aberrant activation of DNA damage repair pathways [64]. By virtue of their distinctive cavity architectures and noncovalent host–guest recognition characteristics, macrocyclic supramolecular compounds have been shown to precisely assemble with platinum‐based drugs to fabricate functional composite systems, and numerous reports indicate that they interfere with and block the core signaling pathways of tumor drug resistance in multiple dimensions [65]. To date, representative macrocyclic host molecules, including crown ethers, cyclodextrins, cucurbiturils, calixarenes, and pillararenes have been validated to reverse platinum drug resistance at the cellular level, while their long‐term in vivo anti‐resistance efficacy remains to be verified.

Host–guest encapsulation of macrocyclic molecules ameliorates the intrinsic deficiencies of platinum‐based drugs in physicochemical properties and in vivo behaviors, thereby weakening the preconditions for drug resistance development [66]. By virtue of the cavity confinement effect, most macrocycles have been demonstrated to stabilize the molecular conformation of platinum agents, effectively enhance their aqueous solubility, and shield active centers from external environmental interference to avoid the hydrolytic inactivation of platinum active sites [67]. Classic cyclic structures, such as 18‐crown‐6 and β‐cyclodextrin, can markedly improve the solubility of platinum‐based therapeutics [9]. Cucurbiturils further strengthen the protection of platinum centers through ion‐dipole interactions and significantly extend the systemic circulation time of drugs [39]. Meanwhile, macrocycles represented by cucurbiturils can inhibit nonspecific binding between platinum drugs and serum proteins via steric hindrance, reducing premature drug inactivation during circulation [21]. The above experimentally verified advantages are widely recognized to facilitate sustained effective drug accumulation within tumor tissues and alleviate therapeutic tolerance triggered by rapid drug metabolism and insufficient in vivo drug exposure.

The specific responsiveness to tumor microenvironment cues is a core design strategy of macrocyclic delivery systems for realizing targeted drug delivery and lowering the risk of tumor drug resistance [68]. Tumor sites commonly possess typical biological features, such as weak acidity, high glutathione levels, and abnormal enrichment of specific metabolites, which provide natural stimulus signals for the controlled drug release of macrocyclic vectors [69]. Calixarenes realize site‐specific drug release in response to the acidic tumor microenvironment. Pillararenes and cucurbiturils can facilitate the targeted liberation of platinum‐based drugs via competitive displacement induced by tumor‐overexpressed spermine [62]. In the process of releasing active pharmaceutical molecules, these macrocycles deplete key substances required for tumor growth, thus endowing the delivery system with synergistic antitumor effects. Disulfide‐modified cucurbituril prodrugs can sensitively respond to the highly reductive tumor microenvironment to achieve stimuli‐responsive drug release [70]. The above stimulus‐responsive release and synergistic antitumor effects have been verified in cell and short‐term xenograft models, which reduce off‐target drug leakage and alleviate resistance arising from insufficient intratumoral platinum exposure. Nevertheless, long‐term multi‐cycle animal studies are still needed to confirm their durable anti‐resistance activity [71].

Disruption of intracellular redox homeostasis is a critical intrinsic factor contributing to platinum drug resistance [72]. Macrocycle‐based composite systems can reverse such resistant phenotypes by precisely regulating glutathione metabolism and intracellular oxidative stress levels [53]. Numerous studies have confirmed that excessive glutathione neutralizes the cytotoxicity of platinum agents via chelation‐mediated detoxification, which can be specifically suppressed by various functionally modified macrocycles [73]. Functionally tailored crown ethers directly inhibit the binding of platinum molecules to glutathione [12]. After cellular internalization, pillararene‐ and calixarene‐encapsulated platinum(IV) prodrugs are reduced to biologically active platinum(II) species, which consume substantial endogenous glutathione and reduce the generation of inactive platinum–glutathione adducts [62]. The rigid cavity confinement of cucurbiturils can also shield platinum drugs from thiol‐induced attack, thereby preserving their biological activity. Glutathione depletion significantly increases intracellular reactive oxygen species (ROS) levels. Macrocyclic systems represented by pillararenes further amplify oxidative stress damage and induce apoptosis in drug‐resistant tumor cells, and this cascade is recognized as a key pathway for realizing redox‐modulated platinum resistance reversal [35].

Macrocyclic supramolecular assemblies overcome efflux‐mediated drug resistance barriers in tumor cells by remodeling the intracellular transport pathways of chemotherapeutic agents [74]. Size‐tunable macrocycle‐platinum self‐assembled complexes achieve passive tumor accumulation via the enhanced permeability and retention (EPR) effect. Unlike free small‐molecule drugs, these nanosized systems internalize primarily through endocytosis, effectively evading recognition and clearance by conventional drug efflux pumps represented by P‐glycoprotein [75]. Cyclodextrin‐modified platinum complexes and calixarene‐based supramolecular assemblies have been verified to remarkably improve cellular drug uptake in drug‐resistant tumor models [24]. By elevating intracellular platinum accumulation, these systems remedy the key defects of insufficient drug internalization and excessive drug efflux in resistant tumor cells, thereby restoring the DNA‐damaging cytotoxicity of platinum‐based agents [76].

Building on the aforementioned common regulatory mechanisms, different macrocyclic molecules exert distinctive resistance‐reversing mechanisms originating from their structural diversity. Possessing selective metal‐ion coordination ability and distinctive cavity architectures, crown ethers may enhance the therapeutic efficacy of platinum‐based agents through ionic synergism. They can be fabricated into oxygen‐delivery systems to remodel hypoxic tumor microenvironments, and such strategies are speculated to alleviate hypoxia‐induced acquired drug resistance [11]. Apart from reliable drug‐loading stability, cucurbiturils exhibit prominent immunomodulatory properties that modulate the function of tumor‐infiltrating immune cells, providing innovative insights into combined platinum chemotherapy and immunotherapy for drug resistance reversal [42]. Owing to their facile functionalizability, cyclodextrins are capable of integrating multiple therapeutic modalities, including chemodynamic and photodynamic therapy, and suppressing refractory resistant tumors through multimodal synergistic cytotoxicity [27]. Such diverse structural advantages and functional diversification greatly enrich the strategies of macrocycle‐mediated platinum resistance reversal.

Overall, via supramolecular host–guest interactions, macrocyclic compounds integrate multiple functions, including optimized physicochemical performance, controllable targeted delivery, intracellular microenvironment remodeling, and reprogrammed drug transport pathways, thereby synergistically inhibiting tumor drug resistance through multidimensional and multi‐pathway approaches [13]. These macrocyclic molecules comply with universal supramolecular regulatory rules while possessing structure‐derived unique functions. These interim research advances lay a solid theoretical foundation and offer broad application prospects for the development of next‐generation, high‐efficiency, low‐toxicity supramolecular platinum‐based antitumor agents with robust resistance‐reversing capability [25].

7. Performance Comparison and Clinical Translation Potential of Macrocyclic Delivery Systems

7.1. Performance Comparison of Macrocyclic Delivery Systems

To clearly compare the performance of various macrocyclic compound–platinum drug delivery systems, the key parameters are summarized in the following Table 5.

TABLE 5.

Comparison of key performance parameters of different macrocyclic systems in platinum drug delivery.

System	Binding constants	Drug loading efficiency	Release profiles	Tumor inhibition rate (in vivo)	Toxicity reduction	Relevant literature
Crown ethers	Ka = 5–6.3M−1	Moderate(PFCE carrier system reaches 39% loading)	Sustained release	in vitro IC50 = 7.8–9.3µM	Markedly alleviates hepatorenal toxicity	[9, 11, 12]
Cyclodextrins	Ka​ = 8.4 × 102–4.39 × 107 M−1	Tunable loading capacity with maximum loading efficiency up to 93%	pH/GSH‐responsive release	sixfold increased cellular uptake; reduced IC50; maximum in vivo tumor inhibition rate of 63%	Low inherent carrier toxicity; alleviates hepatorenal damage	[15, 18, 20, 23, 26, 28, 29]
Cucurbiturils	Ka​ = 5.3 × 104–2.89 × 106 M−1	High loading capacity; CB[7]‐PEG loading capacity: 12.1% (w/w)	Competitive/pH‐responsive release	1.6‐fold stronger tumor suppression than free platinum agents in resistant tumor models; tumor inhibition rate > 60%	Markedly alleviates platinum‐induced cardiotoxicity, myotoxicity, and myelosuppression	[1, 39, 41, 43, 45, 47, 48, 57]
Calixarenes/ Pillararenes	Ka​ = 5.07 × 104–9.8 × 104 M−1/ Far stronger binding affinity for spermine than platinum drugs	CPT loading 8.79% ± 0.28%, PTX loading 3.88% ± 0.86%; maximum single drug loading up to 11.5% ± 2.8%/Stable drug loading performance	pH‐responsive / Redox, enzyme‐responsive	Reduced IC50​; HT‐29 cell apoptosis rate up to 56.6%/ Antitumor activity elevated by approximately 20%	Low inherent carrier toxicity; alleviates hepatorenal injury/Markedly attenuates cytotoxicity toward normal cells	[55, 56, 58, 60, 61]

7.2. Clinical Translation Prospects of Macrocyclic Delivery Systems

In terms of biodistribution, free platinum‐based drugs lack targeting capability and tend to accumulate extensively in normal organs such as the liver and kidneys, thereby causing severe systemic toxicities [77]. Various macrocyclic supramolecular carriers have been shown to form stable nanoscale delivery systems via host–guest assembly and exhibit passive tumor targeting through the enhanced permeability and retention effect, which can increase drug accumulation in tumor tissues in certain animal models [45]. Meanwhile, these systems minimize non‐specific drug accumulation in vital organs, including the heart, liver, and kidneys, reshape in vivo drug distribution profiles, and reduce off‐target damage to normal tissues induced by chemotherapeutics [48].

From the perspective of pharmacokinetics, small‐molecule platinum drugs suffer from poor in vivo stability, high susceptibility to hydrolytic inactivation, short circulating half‐life, and rapid systemic clearance [78]. Encapsulation within macrocyclic scaffolds and supramolecular functionalization can protect drug molecules from physiological degradation in vitro and in some animal studies [79]. Such strategies may prolong systemic circulation time and slow down metabolic clearance, leading to altered absorption, distribution, metabolism, and excretion profiles [80]. Through structural regulation and functional decoration, diversified macrocyclic frameworks further optimize in vivo metabolic behaviors, achieve sustained drug release, and improve the in vivo bioavailability of loaded platinum drugs [17].

In the assessment of in vivo toxicity, unmodified platinum chemotherapeutics often induce obvious acute toxicity, nephrotoxicity, neurotoxicity, and oxidative stress injury [81]. Natural or semi‐synthetic macrocyclic backbones (e.g., cyclodextrins and cucurbiturils) exhibit excellent biocompatibility, which mitigates the systemic side effects of platinum drugs and alleviates organ inflammation and pathological damage [22]. Many macrocyclic delivery systems can decrease drug exposure in healthy tissues via sustained release and EPR‐mediated tumor accumulation, which may contribute to detoxification and antitumor efficacy [29]. However, most existing studies only conduct short‐term in vivo toxicity evaluation. Solid evidence concerning long‐term tissue accumulation, slow metabolic elimination, chronic toxicity, and prolonged biosafety risks of macrocyclic materials remains insufficient, and unified long‐term biosafety evaluation criteria are still lacking [82].

In terms of clinical translation potential, macrocyclic compounds possess high structural designability and versatile modifiability. They can be facilely integrated with targeting moieties, stimuli‐responsive units, and multifunctional therapeutic modules to meet the requirements of individualized chemotherapy [83]. Combined with favorable drug loading capacity, tumor microenvironment‐responsive release, and reversal of platinum resistance in vitro/in vivo, macrocyclic platforms have shown potential to address some forms of platinum resistance, though clinical evidence is still absent [18]. Different macrocyclic types exhibit distinct superiorities: cyclodextrins present high biocompatibility and mature industrial translation foundations; cucurbiturils possess strong binding affinity and tunable release behavior; calixarenes and pillararenes with high structural plasticity are suitable for multi‐target synergistic modification, offering potential delivery strategies for drug‐resistant tumor treatment [84].

Even so, such supramolecular delivery systems still face considerable bottlenecks in clinical translation. The functional modification of macrocyclic molecules involves complex synthetic routes, tedious purification procedures, and high preparation costs, which greatly limit large‐scale standardized production [57]. Moreover, the in vivo metabolic pathways and degradation‐related toxicity of some artificially synthesized macrocycles remain unclear, and the potential risks of long‐term in vivo retention and repeated administration require further systematic verification [48]. These critical challenges, together with the lack of long‐term biosafety data as mentioned above, restrict the bench‐to‐bedside translation of macrocyclic platinum delivery systems [85].

8. Conclusions

The combined application of platinum‐based drugs and macrocyclic compounds has brought breakthrough progress to cancer treatment. The supramolecular complexes formed by the host‐guest interaction between the two not only significantly improve the water solubility, stability, and targeting of platinum‐based drugs but also show unique advantages in overcoming drug resistance and reducing toxic side effects. For example, crown ethers enhance drug delivery efficiency through membrane transport promotion and lysosomal escape mechanisms; cyclodextrins achieve pH‐responsive drug release by encapsulating drugs with their hydrophobic inner cavities; cucurbiturils build intelligent delivery systems by utilizing their high‐selectivity recognition capabilities; and calixarenes and pillararenes realize multi‐drug co‐loading and tumor microenvironment‐responsive release through functional modification. These strategies have successfully achieved multiple effects in basic research, such as chemotherapy‐phototherapy synergy, immune regulation, and drug resistance reversal. For instance, the platinum(IV) prodrug‐cucurbituril system can real‐time monitor the drug reduction process, and cyclodextrin polymer nanocarriers can significantly reduce the cytotoxicity to normal cells.

However, this field still confronts challenges such as inadequate in vivo stability, complex large‐scale fabrication processes, and long‐term biosafety concerns. From a clinical translation perspective, further optimization of macrocyclic compound structural design is imperative to balance host‐guest binding affinity with drug release kinetics—for example, by integrating multiple stimulus‐responsive moieties (pH‐, glutathione‐, and enzyme‐responsive) to enable spatiotemporally precise controlled release. Meanwhile, constructing an integrated “diagnosis‐treatment‐prognostic evaluation” platform through the integration of multimodal imaging technologies and developing multifunctional nanoplatforms by synergizing with cutting‐edge modalities like immunotherapy and gene editing will be pivotal for advancing precision medicine. Future research could focus on expanding novel macrocyclic compound libraries via computer‐aided design, leveraging deep learning algorithms to predict host‐guest interaction patterns, and accelerating the screening of highly selective carriers. Additionally, in‐depth mechanistic elucidation of supramolecular assembly‐tumor microenvironment interactions—particularly protein thiol‐mediated platinum(IV) reduction pathways—will provide clearer molecular targets for reversing drug resistance. With the synergistic innovation of synthetic chemistry and nanotechnology, platinum‐based macrocyclic compound supramolecular systems are poised to pioneer entirely new paradigms in personalized therapy, offering safer and more efficacious solutions for overcoming solid tumors and metastatic cancers.

Author Contributions

Li Yang: conceptualization, investigation, data curation, writing – original draft. Pengmin Shi: investigation, data curation, writing – review & editing. Jing Yang: conceptualization, supervision, writing – review & editing. Jian Zhao: data curation, writing – review & editing. Bo Yang: conceptualization, supervision, writing – review & editing. Chuanzhu Gao: conceptualization, supervision, funding acquisition, writing – review & editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

No data was used for the research described in the article.