English

• 1. Introduction

  Nanoscale drug delivery systems (nano-DDSs) have been investigated intensely in tumor chemotherapy, to improve the antitumor efficacy and simultaneously minimize the toxic and side effects on the normal tissues, because of their preferential accumulation in tumor microregions [1]. Especially, polymer-based nano-DDSs have attracted more interests, owing to their programmable stimuli-responsiveness, as well as outstanding controllability on morphology and size via self-assembly [2].

  Compared with the nano-DDSs via chemical synthesis with covalent bonds, the supramolecular assembled ones are complexes of molecules via noncovalent bonds, such as hydrogen bonding, hydrophobic interaction, π-π stacking, electrostatic interaction, host-guest interaction, or metal ligations. Such approaches could effectively avoid the complicated chemical synthesis including purification and separation [3]. Moreover, the supramolecular assembled nano-DDSs possess flexible reversibility [4] and multiple modifiability [5], facilitating the controlled drug release and targeted drug delivery.

  Recently, macrocyclic supramolecular systems have been developed intensely as drug delivery systems for tumor chemotherapy, via host-guest interaction with macrocyclic compounds (such as cyclodextrins (CDs), crown-ethers, calixarene, pillararene, and cucurbituril) as host molecule [6]. Among them, CDs are the most important natural host molecule for biomedical applications with excellent biocompatibility, except some derivatives, such as permethylated cyclodextrins, which exhibit inherent antitumor activity by disrupting endoplasmic reticulum homeostasis, thus achieving conspicuous tumor cell paraptosis and promising antitumor efficacy in vivo without obvious side effects [7]. Owing to the hydrophobic cavities, CDs and their derivatives can form host-guest inclusion complexes with hydrophobic molecules and groups via supramolecular assembly, forming supramolecular polymers [8], supramolecular assemblies [9] and supramolecular hydrogels [10] for various applications. When the hydrophobic drugs were complexed, CD-based drug delivery systems were obtained [11–13].

  Different from the recent reviews on the CD-based drug delivery systems for tumor chemotherapy focusing on the interactions between CD and anticancer drugs [13,14], guest molecules [15,16], stimuli-responsiveness [9,17,18], applications in therapeutics and drug/gene delivery [19], formulation such as nano-/micro-gels [20,21], the CD-based nano-DDSs for tumor chemotherapy was reviewed in the present work from a perspective of molecular and material designing, focusing on the key roles of CDs in the nano-DDS for precise tumor chemotherapy. Such understandings on the engineering fabrication and drug release-controlled mechanism of the CD-based nano-DDSs are expected to promote the design and development of smarter nano-DDSs for future precise tumor chemotherapy.

  2. Structural characteristics of CDs

  CDs are natural cyclic oligosaccharides with a hydrophobic inner cavity and hydrophilic outer surface, consisting of glucose units connected by 1,4-glycosidic linkages. They were discovered in the enzymatic degraded products of starch in 1891 [22]. They were reported as "cyclic polysaccharides" in 1911 [23] and defined as "cyclodextrin" in 1949 [24]. After that, the natural CDs were separated, and their inclusion complexes were reported [25].

  According to the numbers of the glucopyranose units of 6, 7, and 8, natural CDs are divided into three types: α-CD, β-CD, and γ-CD, respectively (Scheme 1) [26]. They possess the similar physiochemical and biological properties to their linear counterparts; however, they are less susceptible towards enzymatic degradation than the linear dextrins, owing to their cyclic structure. They show amphiphilic characteristics due to their torus-like three-dimensional shape with relatively hydrophobic inner cavity and hydrophilic outer surface, which has been used to improve the solubility and stability of hydrophobic drugs for oral administration in pharmaceutical industry in the 1970s, by forming CD-drug host-guest inclusion complex [27].

  Scheme 1

  

  Scheme 1.  Molecular structure, shape and dimension of cyclodextrins.

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  Different from the oral administration, intravenous drip is the main way for the antitumor drugs. Besides the solubilizing effect for the hydrophobic drugs, stimuli-responsiveness is desired to improve the antitumor efficacy and minimize the toxic side effects on the normal cells and tissues. It means that the nano-DDSs for tumor chemotherapy are expected to respond to the specific stimuli, including the endogenous ones such as pH, glutathione (GSH) level, reactive oxygen species (ROS) or enzymes, or exogenous ones including temperature, light, or external fields [28]. CDs have been widely used in the design of stimuli-responsive drug delivery systems for tumor chemotherapy in the last decades [14,21,29]. The most typical structural characteristics of CDs is the amphiphilic torus-like three-dimensional shape with the primary hydroxyl groups on the narrow side and secondary hydroxyl groups on the wider side. Such structural characteristics make them potential applications in the design of nano-DDSs for smart tumor chemotherapy as multifunctional building blocks via covalent bonds or host-guest interaction, by selective modification.

  3. Versatile multifunctional core in the star (co)polymers

  Due to the branched macromolecular architectures with linear "arms" radiating from a central branching point "core", star-shaped polymers exhibit smaller hydrodynamic radius and lower solution viscosity, in comparison with linear polymers with the same molecular weight and composition. As for the amphiphilic star copolymers, linear hydrophobic and hydrophilic blocks coexist as brushes from a central core, forming a well-defined 3D spherical topological structure when the brushes have the well-defined hydrophobic and hydrophilic blocks. Owing to the unique architecture, star-shaped copolymers are easy to form supramolecular micelles via self-assembly, and even unimolecular micelles with superior stability upon dilution than the former ones [30].

  There are three hydroxyl groups in each glucopyranose unit, thus, α-CD, β-CD, and γ-CD have 18, 21, and 24 hydroxyl groups, respectively. Two-thirds of them are secondary hydroxyl groups on the wider side of the torus-like molecules, while one-third are primary hydroxyl groups on the narrow side. Based on the different activities of the hydroxyl groups on the two sides, the CDs could be selectively modified on the narrow side as versatile core in the star (co)polymers, which self-assembled into micelles as nano-DDSs in tumor chemotherapy.

  Owing to the water solubility of CDs, CD-cored amphiphilic star polymers could be simply synthesized by introducing hydrophobic brushes. Such CD-cored amphiphilic star polymers could self-assemble into supramolecular core-shell micelles with a hydrophobic core and CD-based shell for drug delivery, in which the drugs could be loaded in CD units via host-guest interaction with poly(N-isopropylacrylamide) (PNIPAAm) as hydrophobic core to control the drug release (Scheme 2) [31,32]. The drug-loading capacity is usually very low in such supramolecular core-shell micelles with drug-loaded in CD units, even as low as 2.8% [33]. To solve this problem, the hydrophobic carbon chains [34] or hydrophobic polymers [35] were modified on one side of CDs, while hydrophilic polymers were grafted on the other side, based on the different reactive activities of the two kinds of hydroxyl groups. After self-assembling with drugs, drug-loaded supramolecular core-shell-corona micelles were obtained with the CD-cored star polymers (Scheme 3), with much higher drug-loading capacity up to ~40%. Due to the high modification on CD, the host-guest inclusion of drug might be restricted, while the drug was mainly loaded in the hydrophobic core, as illustrated in Scheme 3.

  Scheme 2

  

  Scheme 2.  Drug-loaded supramolecular core-shell micelles self-assembled with CD-cored star polymer.

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  Scheme 3

  

  Scheme 3.  Drug-loaded supramolecular core-shell-corona micelles self-assembled with CD-cored star polymer.

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  By modifying amphiphilic diblock copolymers onto CDs, various CD-cored amphiphilic star copolymers could be obtained, in which the poly(ethylene glycol) (PEG) or poly[(ethylene glycol)methyl ether methacrylate] (POEGMA) containing PEG brushes as side chains was usually used as the hydrophilic coronal to enhance the stability and blood circulation time of the core-shell-corona micellar nanomedicines, while the hydrophobic block was used to form the hydrophobic shell for drug-loading and stimuli-responsive drug release (Scheme 4). The biodegradable polylactide [36,37] and polycaprolactone [38], and temperature-sensitive PNIPAAm [39] had been used as the functional hydrophobic blocks in the reported works with drug-loading capacity of 17%~32%.

  Scheme 4

  

  Scheme 4.  Drug-loaded supramolecular core-shell-corona micelles self-assembled with CD-cored star copolymer.

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  Most recently, copolymer-based unimolecular micelles have attracted more interest in nano-DDSs for tumor chemotherapy, owing to their superior stability in comparison with the supramolecular ones, which would de-micellize upon dilution. With certain hydrophilic-hydrophobic ratio, the amphiphilic diblock copolymer-modified CD could self-assemble into unimolecular micelles, possessing high drug-loading capacity [40]. Furthermore, bioreducible disulfide bonds were used as linker between the hydrophilic block and the hydrophobic block, endowing GSH-responsive drug release [41].

  Moreover, the star-shaped polymer prodrug-based unimolecular micelles have been developed by conjugating drug onto the side groups of the CD-cored star polymer, to avoid the premature drug leakage from the micellar nanomedicines via non-covalent drug loading [42]. By using acid-labile -C=N- conjugation, acid-triggered star-shaped polymer prodrug-based unimolecular micelles were also designed by modifying random copolymer [43] or di-block copolymer [44] onto the CD core, following drug conjugation. Such architecture ensures the stable structure in blood circulation with minimized premature drug leakage but could release drug in the acidic intracellular microenvironment.

  The star-shaped polymer prodrug-based unimolecular micelles have also been designed for tumor combination chemotherapy. For example, bioreducible camptothecin (CPT)-containing prodrug monomer was designed via the copolymerization of POEGMA and 2-(diisopropylamino)ethyl methacrylate from the modified β-CD via atom transfer radical polymerization technique [45]. The resultant star-shaped polymer prodrug could self-assemble into unimolecular micelles for doxorubicin (DOX)-loading. Owing to the acid-sensitive poly[2-(diisopropylamino)ethyl methacrylate] and GSH-sensitive CPT conjugation, the rational nanomedicine possessed the tumor-specific acid/GSH dual-responsive drug release, showing enhanced therapeutic efficacy.

  4. Host in host-guest inclusion complexes

  Owing to their hydrophobic inner cavity, CDs could form inclusion complexes with hydrophobic guest molecules primarily in aqueous solution, showing promising applications as self-healing materials and biomedical materials [46]. As for nano-DDSs in tumor chemotherapy, CDs have been used to construct diverse supramolecular polymer materials as carriers for the hydrophobic drug loading or drug release controlling. The binding affinity of such host-guest complexation could be tuned by various stimuli-responsiveness, i.e., pH, redox, enzyme, temperature, light [47]. Therefore, smart supramolecular nano-DDSs have been developed for precise tumor chemotherapy.

  The binding affinity between CDs and guest molecules is a key parameter in the resultant host-guest inclusion complexes [48]. The complementary size of the host cavity and guest molecule and their specific interactions (mainly hydrophobic attraction) endow a rapid and high-affinity host-guest complexation via molecular recognition. Such direct molecular recognition approach makes the host-guest complexation ease and scalability of preparation, owing to its high selectivity.

  With CDs as host molecule, adamantane (Ad) has been usually used as the guest molecules, due to its complementary size for β-CD and high hydrophobicity, showing the highest affinity (K_eq around 10⁵ L/mol) [49]. Besides, azobenzene and ferrocene have also been used as the guest molecules in CD-guest complexes to achieve light-responsiveness [50] and redox-responsiveness [51], respectively.

  4.1 Supramolecular polymer carriers

  By means of supramolecular chemistry via CD-guest complexation, various amphiphilic supramolecular copolymers could be designed with topological structure [46], which could easily self-assemble into micelles for drug loading and controlled release. Besides, the supramolecular hydrogels could be fabricated with the CD-containing molecules and the guest-containing molecules [10,20,52].

  4.1.1   Amphiphilic supramolecular copolymers

  With the help of molecular recognition between CDs and the guest molecules owing to the high binding constant of CD residues with guest residues, amphiphilic supramolecular block copolymers, amphiphilic supramolecular miktoarm star copolymers and amphiphilic supramolecular comb copolymers could be easily constructed with CD- and guest molecule-containing polymers (Scheme 5). Similar as the amphiphilic covalent copolymers, they could self-assemble into micelles for drug delivery.

  Scheme 5

  

  Scheme 5.  Design of amphiphilic supramolecular copolymers via CD-guest complexation.

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  Benzimidazole (BM) shows an acid-base equilibrium with pK_a of 5.7, 12.6, which is ideally located within the physiological range of acidic organelles, such as lysosome (pH 4.5–5.5) and endosome (pH 4.5–6.8). As a result, the host-guest complexation between BM and β-CD possesses pH-responsiveness in the intracellular acidic microenvironment. Chen group developed pH-sensitive supramolecular amphiphilic diblock copolymer via the host-guest interaction between BM-terminated poly(3-caprolactone) and β-CD terminated dextran [53] and PEG-BM and β-CD-modified poly(L-lactide) [54]. Their supramolecular micelles were self-assembled for DOX loading and intracellular controlled release. The host-guest interaction conjugation in the supramolecular diblock copolymer endowed the DOX-loaded micelles faster DOX release in the intracellular microenvironment (pH 5.5) with less premature drug leakage in the simulated normal physiological medium (pH 7.4) than the ones self-assembled with the covalent diblock. Lim group reported the DOX release system by the supramolecular diblock copolymer via host-guest interaction between β-CD and AD groups [55].

  The well-defined β-CD based PNIPAAm star host polymer [39] and β-CD based poly(N-vinylpyrrolidone) star host polymer [56] were designed to construct supramolecular amphiphilic star copolymer via the host-guest interaction for temperature- and pH-responsive DOX release. Shi group synthesized the adamantane-terminated four-armed pillar[5]arene-based nonionic polyrotaxane and star-shaped β-CD-capped pH-sensitive poly(acrylic acid) to form the supramolecular pseudoblock polymer via a host-guest interaction [57]. The DOX-loaded micelles with much higher DOX-loading capacity showed extremely low toxicity, highly efficient intratumoral accumulation and substantial antitumor efficacy in vivo. Wang et al. reported the pH-responsive core–shell tecto dendrimers formed using BM-modified G3 poly(amidoamine) (PAMAM) dendrimers as shell and β-CD-multifunctionalized G5 PAMAM dendrimer as core via host-guest interaction for pH-responsive DOX release [58].

  Stang group developed supramolecular hyperbranched polymer assemblies with dimer of β-CD containing Pt(Ⅱ) metallacycle and three-armed PEG functionalized ferrocene for the redox/NO dual-responsive DOX release [59]. Synergistic effect was achieved with the proposed drug codelivery system.

  The comb-like supramolecular amphiphilic copolymers were designed by the host−guest interaction of polymers with β-CD side groups and BM-terminated polymer or covalent diblock copolymer to form core-shell and core-shell-corona micelles for pH-responsive DOX release [60–62]. Besides the pH-responsiveness of the host-guest interaction between β-CD and BM, the temperature-responsiveness was also explored for drug release [62].

  4.1.2   Supramolecular hydrogels

  As a promising candidate, supramolecular hydrogels could be facile constructed via the host-guest interaction between the multifunctional host polymers and multifunctional guest polymers (Scheme 6). For the purpose, tetraphenylethylene-bridged β-CD tetramers and AD-grafted hyaluronic acid were synthesized for the fabrication of supramolecular hydrogels [63]. With the help of the supramolecular hydrogels, higher anticancer efficacy was achieved with less side effects than free DOX.

  Scheme 6

  

  Scheme 6.  Formation of supramolecular hydrogels with multifunctional host polymer and guest polymer.

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  Besides, prodrug of DOX, modified with β-CD via acid-labile conjugation, was loaded in the supramolecular hydrogels of AD-modified carboxyethyl hydroxyethyl cellulose and β-CD-grafted glycerol ethoxylate, via the host-guest complexation with the excessive AD groups [64]. The premature DOX leakage could be minimized to ~20% in 48 h, with a cumulative DOX release at pH 5.0 of > 50%.

  Owing to the facile construction, supramolecular hybrid hydrogel has also been developed with β-CD-grafted hyaluronic acid and AD-modified gold nanoparticles for the pH-responsive release of antitumor drugs with high encapsulation efficiency [65]. After that, the supramolecular hydrogels have been widely used as gate-keeper in the metal-organic framework and silica-based nano-DDSs [66–70], showing a better gatekeeping effect than the single molecular layer of CD or its derivatives [71,72].

  4.1.3   Poly(pseudo)rotaxane hydrogels

  Poly(pseudo)rotaxanes/polyrotaxanes are supramolecular polymers with CDs threading onto the polymer chains, constructed by incorporating (pseudo)rotaxane/rotaxane moieties into polymers via non-covalent interaction [73,74]. Such structural feature endows them unique property different from the crosslinked polymers with covalently interconnected structure and interpenetrating polymer networks with interlocked structure. The CD-based poly(pseudo)rotaxanes could be designed with various threads, such as PEG, polypropylene glycol (PPG), polyethyleneimine (PEI), poly(4,4′-diphenylenevinylene) and poly(fluorene) [75]. As hydrogels for biomedical application, the water-soluble and biodegradable ones, PEG, PPG and PEI, were usually used [76].

  In nano-DDSs for tumor chemotherapy, the poly(pseudo)rotaxanes have been used to fabricate supramolecular hydrogels [77–81] and supramolecular hybrid hydrogels [82] for better drug encapsulation and controlled drug release. Ni group synthesized acid-labile PEGylated polyphosphoester-doxorubicin prodrug to fabricate supramolecular hydrogel by inclusion complexation with α-CD [83]. Excellent pH-responsive DOX release was achieved with cumulative release of about 47% at pH 5.0 after 75 h, whereas the premature leakage was < 5% at pH 7.4. Liu group reported the pH/reduction dual-responsive prodrug nanohydrogels, which were fabricated by crosslinking the oxidized alginate-doxorubicin prodrug via poly(pseudo)rotaxane with CD and disulfide bond with cystamine [84]. Better pH/reduction dual-responsive controlled release performance could be achieved by inclusion complexation first, regardless of the CD species. Ma and Xue group developed poly(pseudo)rotaxane hydrogels with hyperbranched polyglycerol derivative and α-CD for co-delivery of CPT and DOX [85]. An obvious synergistic effect was achieved in vitro and in vivo, inducing effective growth inhibition of tumor.

  4.2 Recipients for direct and indirect drug-loading

  Various hydrophobic chemotherapeutic drugs could be loaded in the hydrophobic inner cavity of CDs as drug pocket, according to the cavity size of α-CD, β-CD, and γ-CD. Therefore, the CD-containing polymer carriers, including micelles, nanohydrogels, and nanosponges, could be fabricated for direct or indirect drug-loading (Scheme 7).

  Scheme 7

  

  Scheme 7.  Drug-loading modes in CD-containing carriers.

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  4.2.1   Direct drug-loading

  Various CD-containing drug carriers have been designed for the loading of antitumor drugs via host-guest inclusion complexation between CD units and drug molecules, such as CD-containing copolymer-based micelles and nanoparticles (Table 1), nanohydrogels (Table 2), and nanosponges (Table 3).

  Table 1

  

  Table 1.  CD-containing copolymer-based micelles and nanoparticles for antitumor drugs loading and controlled release.

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  Copolymers	Drug and content	Drug leakage	Drug release	Ref.
  mPEG-PLG(CD)	CPT, 2.45%	24.5% at pH 7.4 in 24 h	–	[86]
  CβR4D15 copolymers	DOX, 15%	70% at pH 7.4 in 24 h	–	[87]
  CDPF	DOX, -	~100% at pH 7.4 in 7 days	~100% at pH 5.5 in 7 days	[88]
  β-CD-PEG-G)	DOX, (79 ± 6.3)%	~65% at pH 7.4 in 84 h	~90% at pH 5.5 in 84 h	[89]
  Bio-CDPu	DOX, (8.2 ± 0.3)%	~70% at pH 7.4 in 48 h	~88% at pH 3.5 in 48 h	[90]
  GCDPu	DOX, 8.39%	~70% at pH 7.4 in 48 h	~88% at pH 3.5 in 48 h	[91]
  PCDAA	PTX, 36.02%	~80% at pH 7.4 in 120 h	–	[92]
  βCD-PAMAM-PEG-cRGD	DOX, 16.8%	44% at pH 7.4 in 96 h	97% at pH 5.3 in 96 h	[93]
  βCDg-PMA-co-PLGA	DOX and Conf, 20%	10% (DOX) and 10% (Conf) at pH 7.4 in 24 h	30% (DOX) and 30% (Conf) at pH 5.0 in 24 h	[94]
  mPEG-P(Glu-CD)	CUR, (6.0 ± 0.1)%; CPT, (7.5 ± 0.1)%; DOX, (9.0 ± 0.1)%	–	–	[95]
  HA-CD	β-CD/Cur-Pt of 1:1	11% (Cur) and 16% (Oxo-Pt) at pH 7.4 in 48 h	79% (Cur) and 75% (Oxo-Pt) at pH 5.0 in 48 h	[96]

  Table 2

  

  Table 2.  CD-containing nanohydrogels for antitumor drugs loading and controlled release.

  DownLoad: CSV

  Nanohydrogels	Drug and content	Drug leakage	Drug release	Ref.
  P(FPA-co-ACD)	DOX, 53%	17.0% at pH 7.4 + 10 µmol/L GSH in 60 h	74.3% at pH 5.0 + 10 mmol/L GSH in 60 h	[97]
  β-CD-appended hyper-cross-linked polymer	DOX, 22.6%	11.0% at pH 7.4 in 96 h	~77.0% at pH 5.0 + 10 mmol/L GSH in 96 h	[98]
  Ad-SS-Ad/CD-CS	DOX, 15.9%	3% at pH 7.4 + 10 µmol/L GSH in 60 h	82.3% at pH 5.0 + 10 mmol/L GSH in 84 h	[99]
  PPEICD/p53	MTO, -	–	–	[100]
  CD-OEI/p53	DOX, 4.7%	–	–	[101]
  pPTX/pCD	PTX, 5.1%	–	–	[102]

  Table 3

  

  Table 3.  CD-based nanosponges for antitumor drugs loading and controlled release.

  DownLoad: CSV

  Nanosponges	Drug and content	Drug leakage	Drug release	Ref.
  Cyclodextrin-based nanosponges (NS)	Resveratrol: NS of 1:5 and 1:10	> 50% and ~100% in H2O in 2 h	–	[103]
  β-Cyclodextrin nanosponge (CN)	CPT, 38%	4% at pH 7.4 in 2 h	–	[104]
  pγ-CyD	DOX, γ-CD/DOX of 1:1 or 1:2	–	–	[105]
  CDNS	CUR, 38.36%	37% at pH 7.4 in 48 h	–	[106]
  Cyclodextrin-based nanosponges (NS)	DOX, -	~25% at pH 7.4 in 48 h	–	[107]
  β-CDP	DOX, DOX: β-CDP of 1:10 and 1:20	64.2% and 52% at pH 7.4 in 24 h	–	[108]
  β-CDP	QCT, 8.25%; DOX, 7.99%	69.56% (QCT) and 79.14% (DOX) at pH 7.4 in 48 h	72.90% (QCT) and 84.63% (DOX) at pH 5.4 in 48 h	[109]
  PDOP NCs	DOX, 12.8%	30% at pH 7.4 in 48 h	80% at 10 mmol/L DTT in 48 h	[110]
  GSH—NSs	DOX, 13%	0.7% without GSH in 6 h	1.0% with 10 mmol/L GSH in 6 h	[111]
  β-CD-CQD	DOX, 39.5%	19% at pH 7.4 in 100 h	61% at pH 5.0 in 100 h	[112]
  MNPs-NSs	CYC, (29.9 ± 4.1)%	< 20% without AMF	> 80% with AMF	[113]

  4.2.1.1   CD-containing copolymer-based micelles and nanoparticles

  CD-containing copolymers were designed by introducing CD units onto the side groups of the copolymers, which could be self-assembled into supramolecular unimolecular micelles or nanoparticles for anti-tumor drug delivery [86–92]. In the CD-containing copolymer-based micelles and nanoparticles (Table 1), PAMAM-cored unimolecular micelles were designed for DOX delivery [93], which could avoid the de-micellization of the conventional supramolecular micelles and therefore inhibit the drug leakage. β-CDg-PMA-co-PLGA and mPEG-P(Glu-CD) were designed for the co-delivery of DOX and Conferone (Conf) [94] and curcumin (CUR), camptothecin (CPT) and DOX [95].

  Bai et al. designed active targeting β-cyclodextrin-modified hyaluronic acid (HA-CD) for the pH- and esterase- dual-responsive CUR and oxoplatin (Oxo-Pt) co-delivery, by inclusion of the Cur units of the drug-drug conjugates (curcumin-oxoplatin, Cur-Pt) in β-CD [96]. Owing to the ester conjugation between CUR and Oxo-Pt, the premature drug leakage was efficiently inhibited, while an esterase-responsive drug release was achieved.

  4.2.1.2   CD-containing nanohydrogels

  Besides, CD-containing nanohydrogels have been fabricated via various strategies as carriers for antitumor drugs via host-guest inclusion complexation between CD units and drugs, via one-step polymerization [97,98] and supramolecular interaction [99–102] (Table 2).

  Based on the higher GSH level in tumor cells than the normal cells and intercellular environment, GSH-responsive nano-DDSs could be designed for the tumor-specific drug delivery [18]. Bioreducible CD-containing nanohydrogels could be designed via a facile one-step polymerization of CD-containing monomer and comonomers with N,N-bis(acryloyl)cystamine (BACy) as crosslinker. Liu group reported the pH/reduction dual-responsive poly(4-formylphenyl acrylate-co-acryloyl-β-cyclodextrin) (P(FPA-co-ACD)) microspheres as multifunctional vehicle for tumor-specific DOX delivery, via emulsion copolymerization of acryloyl-β-cyclodextrin (ACD) and 4-formylphenyl acrylate (FPA), with BACy as crosslinker [97], in which DOX could be loaded via both acid-labile covalent conjugation and host-guest inclusion complexation. The in vitro DOX release indicated that the proposed dual-modal drug-loading could efficiently modulate the drug release behavior. Dai et al. designed β-CD-appended hyper-cross-linked polymer by one-pot polymerization of acryloyl-6-ethylenediamine-6-deoxy-β-Cyclodextrin (β-CD-NH-ACy), acrylic acid (AA) and BACy [98]. Owing to the GSH bioresponsive crosslinking, the pH/GSH dual-responsive DOX release was achieved.

  Li and Liu designed chitosan-based supramolecular nanogels as pH/reduction dual-stimuli responsive carrier for DOX, by bioreducible crosslinking of the β-cyclodextrin modified chitosan (CD-CS) with disulfide bond embedded crosslinker (Ad-SS-Ad) via host-guest inclusion and simultaneous DOX loading [99]. The premature DOX leakage in the simulated blood circulation was efficiently restricted with a pH/GSH dual-triggered sustained DOX release.

  Supramolecular combination therapy systems were also developed by electrostatic interaction between CD-functional polycations and gene encoding tumor suppressor protein p53 for antitumor drugs (mitoxantrone (MTO) or DOX) loading [100,101]. Such supramolecular drug and gene codelivery system showed high gene transfection efficiency and effective protein expression in cancer cells.

  Numgung et al. developed nano-assembled nano-DDSs via multivalent host–guest interactions between a polymer–cyclodextrin conjugate and a polymer-paclitaxel (PTX) conjugate, in which the ester conjugation between PTX and the polymer backbone permit efficient release of PTX within the cell by degradation [102]. The proposed multivalent inclusion complexes could efficiently targeted deliver PTX via both passive and active targeting mechanisms.

  4.2.1.3   CD-based nanosponges

  Different from the above CD-containing copolymers and hydrogels in which CDs were introduced on the side groups, CD-based nanosponges could be fabricated with CD as structural unit in the crosslinked framework by the polymerization with CDs as multifunctional monomers (Table 3) [103–108]. Thus, more CD units could be introduced in the drug carriers for higher drug loading capacity via the host-guest inclusion complexation between CD unit and drugs. Pawar et al. reported a β-CD polymer (β-CDP) for co-loading quercetin (QCT) and DOX via freeze-dried approach to combat P-glycoprotein (P-gp) mediated multidrug resistance in KB-ChR 8–5 cancer cells [109]. As expected, the released QCT has improved the intracellular availability of DOX via modulating P-gp drug efflux function in KB-ChR 8–5 cancer cells and MCF-7/DOX resistant cancer cells. Furthermore, the GSH-triggered tumor-specific drug delivery could also be achieved by using disulfide-containing monomers [110,111].

  Liu group reported the fluorescent hyper-cross-linked β-cyclodextrin-carbon quantum dot (β-CD-CQD) hybrid nanosponges with excellent biocompatibility and strong bright blue fluorescence for tumor theranostic application by facile condensation polymerization of carbon quantum dots (CQDs) with β-CD, following with DOX-loading via host−guest complexation [112], showing an enhanced antitumor efficacy than free DOX.

  Sandoval et al. developed a β-CD nanosponge (NS) using diphenyl carbonate (DPC) as a cross-linker to encapsulate the antitumor drug cyclophosphamide (CYC) [113]. Associated with magnetite nanoparticles (MNPs), the CYC release was accelerated by utilizing magnetic hyperthermia upon the exposure of an alternating magnetic field (AMF). Furthermore, the tertiary system could induce the apoptosis in HeLa cells, indicating that the MNPs maintained their properties to generate hyperthermia.

  4.2.1.4   CD-modified hybrid carriers

  Besides the CD-containing polymer materials in various forms, several CD-modified hybrid carriers have also been reported for antitumor drug-loading via host-guest inclusion complexation, by introducing inorganic nanomaterials or nanocomposites. For examples, graphene oxide (GO) was used as support for CDs to enhance the drug loading capacity and control the drug release via the drug-loading on GO via π-π stacking and electrostatic interaction [114,115]. CD-modified CdSe/ZnS quantum dots [116] and g-C₃N₄ nanosheet [117] have been developed as fluorescent drug carriers for stimuli-responsive drug release and fluorescent imaging in cells. Gold nanoparticles have also been used as support for CD groups for photothermal release of the loaded drugs via host-guest inclusion [118], and chemo-photothermal synergistic therapy [119].

  Among them, the magnetic nanomaterials and nanocomposites showed the most promising potential in multifunctional applications in tumor treatment. Besides the targeted delivery of antitumor drugs with a magnetic field [120–124], magnetic resonance imaging could be achieved in the tumor chemotherapy [125]. The magnetic hyperthermia in AMF could also be obtained to control drug release [126].

  Although CD-based carriers have been widely designed for drug-loading in tumor chemotherapy, the CD-drug inclusion complexes are not so stable due to the binding affinity. The premature drug leakage was significant, even up to 100%. In the above works, controlled drug release could be achieved in a certain degree by designing stimuli-responsive frameworks via pH-triggered swelling, enzyme- or GSH-triggered degradation, and magnetic hyperthermia-triggered system to accelerate the drug diffusion out the carriers.

  4.2.2   Indirect drug-loading

  To avoid the premature drug leakage and minimize the toxic side effects of the chemotherapeutic drugs on the normal cells and tissues, indirect drug-loading approach has been developed by designing the guest-drug conjugates as prodrugs containing high-affinity guest molecule for the host-guest complexation in the CD-containing carriers (Scheme 7B).

  Owing to the high association constant between β-CD and Ad moiety (K_eq ≈ 10⁵ L/mol) [127], the β-CD-Ad inclusion complex has been widely. For an indirect drug-loading, Ad-drug conjugates were designed for the drug-loading via β-CD-Ad inclusion complexation on the carriers. Among them, the Ad-DOX guest-drug conjugate has been widely used (Scheme 8) [128–131]. The slow sustained Ad-DOX release was reported in the in vitro drug release profiles [128], while it was accelerated by increasing the acidity of the releasing media [129,130]. Wang et al. explained the accelerated release by faster hydrolysis of amide bond under acidic condition [131]. By now, there is no cogent argument on the released drug (Ad-DOX or DOX) with direct evidence. The derivatization on the amino group on DOX declines its water solubility and insertion in DNA [132], therefore, a lower antitumor efficacy could be achieved with the Ad-DOX conjugate in comparison with free DOX. Maybe, the amide linker between Ad and DOX could be hydrolyzed with the amidase in the cells.

  Scheme 8

  

  Scheme 8.  Synthesis of Ad-DOX as guest-drug conjugate.

  DownLoad: Full-Size Img PowerPoint

  Acid-labile β-CD-DOX prodrug was designed as host-drug conjugate and loaded in the supramolecular hydrogels of AD-modified carboxyethyl hydroxyethyl cellulose and β-CD-grafted glycerol ethoxylate, via the host-guest complexation with the excessive AD groups (Scheme 9) [64]. Desired pH-triggered DOX release was achieved by cleaving the hydrazone bonds in CD-DOX, with cumulative DOX release of > 52.0% at pH 5.0 while a leakage of 19.8% at pH 7.4 in 48 h.

  Scheme 9

  

  Scheme 9.  Synthesis of CD-DOX as host-drug conjugate.

  DownLoad: Full-Size Img PowerPoint

  Zhang et al. designed an adamantine modified camptothecin/naphthalimide conjugate for loading on HA-CD via host-guest inclusion [133]. Owing to the unique traceless conjugation, CPT and Nap could only be released in presence of dithiothreitol (DTT), showing tumor-specific chemotherapy and photothermal therapy (Scheme 10). The tumor growth in the tumor-bearing mice has been efficiently inhibited under laser irradiation, demonstrating the combined photothermal-chemotherapy of cancer.

  Scheme 10

  

  Scheme 10.  Molecular structure of Nap-CPT-Ad.

  DownLoad: Full-Size Img PowerPoint

  Ferrocene (Fc) could also act as guest molecule to form stable β-CD-Fc inclusion complex with formation constant of ca. 4100 L/mol, and such interaction could be distorted under oxidation stimulus by converting Fc into Fc⁺, declining the formation constant to about 65 L/mol [134]. Such oxidation-responsive inclusion complexation has been used to achieve an oxidation-triggered tumor-specific antitumor drug release, responding to the higher ROS level in tumor cells than the normal cells.

  Fu et al. designed a ferrocene-camptothecin prodrug (Fc-CPT) for supramolecular assembly on HA-CD for a tumor-targeted CPT release (Scheme 11) [135]. Triggered by ROS in tumor cells, the proposed supramolecular assembles could be disassembled by oxidation of Fc to Fc⁺, leading to an efficient release of Fc⁺-CPT. While the prodrug could be cleaved off to release the parent drug CPT responding to the higher GSH level in tumor cells. Thus, higher anticancer efficiency was achieved than free CPT, accompanied by negligible side effects.

  Scheme 11

  

  Scheme 11.  Molecular structure of Fc-CPT.

  DownLoad: Full-Size Img PowerPoint

  Lu et al. designed a cyclopalladated ferrocene compound as guest-drug conjugate for inclusion in PEGylated β-CD, and the resultant supramolecular polymer was self-assembled into micelles for DOX-loading via electrostatic interaction (Scheme 12) [136]. pH/ROS dual-triggered CP and DOX release was achieved, achieving an enhanced inhibition tumor cell growth effect on A549 cells, superior to free CP or DOX alone.

  Scheme 12

  

  Scheme 12.  Molecular structure of cyclopalladated ferrocene compound and its DOX salt.

  DownLoad: Full-Size Img PowerPoint

  5. Conclusions and perspectives

  In summary, CDs have been widely used as a versatile supramolecular building block in the fabrication of the smart nano-DDSs for precise tumor chemotherapy. Owing to the unique molecular structure with hydrophilic exterior, hydrophobic inner cavity and plentiful hydroxyl groups at both ends with different reactivities, CDs could be used to design various drug carriers, i.e. unimolecular micelles, covalent or supramolecular nanohydrogels for antitumor drug delivery.

  With CD units as recipient for antitumor drug loading, the premature drug leakage was significant via the direct drug-loading mode due to the low binding constant between CDs and drugs, unless the guest-drug prodrugs were designed for the indirect drug-loading, with specific guest molecules such as Ad, which possessed a high formation constant in the inclusion complexation in CD. With such supramolecular assembly, another issue is the drug release, meaning the parent drugs should be released, triggered by the higher acidity, or higher GSH and ROS levels in tumor cells. Thus, the guest-drug prodrugs should be designed with traceless acid-labile or redox-triggered cleavable conjugations. The last issue is the tumor-specific drug release, requiring the nano-DDSs are stable and could not release drugs in the normal cells, besides the intercellular environment such as blood circulation. Due to the similar acidity in both normal cells and tumor cells, the desired tumor-specific drug release could not be obtained by using the acid-labile conjugations [137]. Therefore, the indirect drug-loading of guest-drug prodrugs based on a high affinity to CDs with a traceless redox-triggered conjugation should be the future developing trend, by which the high-performance tumor chemotherapy could be expected with high antitumor efficacy but no toxic side effects.

  Furthermore, the drug release of such redox-triggered nano-DDSs in the microenvironment in normal cells should be evaluated, because of the relatively lower GSH and ROS levels in comparison with tumor cells, but it is still much higher than the intercellular environment. Besides, the tumor-targeting groups (such as folic acid [138]) or materials (such as hyaluronic acid [96]) could be incorporated to improve the internalization by tumor cells, to minimize the toxic side effects on normal cells.

  Finally, the combination tumor therapy might be a dominant approach with the help of the multifunctionalities of CDs which could be used as versatile supramolecular building block to design more intelligent nanomedicines, by combination chemotherapy via dual-drug or multi-drug co-delivery to affect cancer cells at different points in the cell cycle [109], drug and gene co-delivery [139], or combination therapy of chemo-, chemodynamic, photodynamic, and so on [140–142].

  Based on the great efforts and enormous achievement in the last decades, it is confidently predicted that the small torus-like polysaccharides will come in quite handy in biomedical fields, including precise tumor treatment.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Peng Liu: Writing – review & editing, Writing – original draft, Visualization, Methodology, Investigation, Conceptualization.

  
  
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  Scheme 1  Molecular structure, shape and dimension of cyclodextrins.

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  Scheme 2  Drug-loaded supramolecular core-shell micelles self-assembled with CD-cored star polymer.

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  Scheme 3  Drug-loaded supramolecular core-shell-corona micelles self-assembled with CD-cored star polymer.

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  Scheme 4  Drug-loaded supramolecular core-shell-corona micelles self-assembled with CD-cored star copolymer.

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  Scheme 5  Design of amphiphilic supramolecular copolymers via CD-guest complexation.

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  Scheme 6  Formation of supramolecular hydrogels with multifunctional host polymer and guest polymer.

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  Scheme 7  Drug-loading modes in CD-containing carriers.

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  Scheme 8  Synthesis of Ad-DOX as guest-drug conjugate.

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  Scheme 9  Synthesis of CD-DOX as host-drug conjugate.

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  Scheme 10  Molecular structure of Nap-CPT-Ad.

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  Scheme 11  Molecular structure of Fc-CPT.

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  Scheme 12  Molecular structure of cyclopalladated ferrocene compound and its DOX salt.

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  Table 1.  CD-containing copolymer-based micelles and nanoparticles for antitumor drugs loading and controlled release.

  Copolymers	Drug and content	Drug leakage	Drug release	Ref.
  mPEG-PLG(CD)	CPT, 2.45%	24.5% at pH 7.4 in 24 h	–	[86]
  CβR4D15 copolymers	DOX, 15%	70% at pH 7.4 in 24 h	–	[87]
  CDPF	DOX, -	~100% at pH 7.4 in 7 days	~100% at pH 5.5 in 7 days	[88]
  β-CD-PEG-G)	DOX, (79 ± 6.3)%	~65% at pH 7.4 in 84 h	~90% at pH 5.5 in 84 h	[89]
  Bio-CDPu	DOX, (8.2 ± 0.3)%	~70% at pH 7.4 in 48 h	~88% at pH 3.5 in 48 h	[90]
  GCDPu	DOX, 8.39%	~70% at pH 7.4 in 48 h	~88% at pH 3.5 in 48 h	[91]
  PCDAA	PTX, 36.02%	~80% at pH 7.4 in 120 h	–	[92]
  βCD-PAMAM-PEG-cRGD	DOX, 16.8%	44% at pH 7.4 in 96 h	97% at pH 5.3 in 96 h	[93]
  βCDg-PMA-co-PLGA	DOX and Conf, 20%	10% (DOX) and 10% (Conf) at pH 7.4 in 24 h	30% (DOX) and 30% (Conf) at pH 5.0 in 24 h	[94]
  mPEG-P(Glu-CD)	CUR, (6.0 ± 0.1)%; CPT, (7.5 ± 0.1)%; DOX, (9.0 ± 0.1)%	–	–	[95]
  HA-CD	β-CD/Cur-Pt of 1:1	11% (Cur) and 16% (Oxo-Pt) at pH 7.4 in 48 h	79% (Cur) and 75% (Oxo-Pt) at pH 5.0 in 48 h	[96]

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  Table 2.  CD-containing nanohydrogels for antitumor drugs loading and controlled release.

  Nanohydrogels	Drug and content	Drug leakage	Drug release	Ref.
  P(FPA-co-ACD)	DOX, 53%	17.0% at pH 7.4 + 10 µmol/L GSH in 60 h	74.3% at pH 5.0 + 10 mmol/L GSH in 60 h	[97]
  β-CD-appended hyper-cross-linked polymer	DOX, 22.6%	11.0% at pH 7.4 in 96 h	~77.0% at pH 5.0 + 10 mmol/L GSH in 96 h	[98]
  Ad-SS-Ad/CD-CS	DOX, 15.9%	3% at pH 7.4 + 10 µmol/L GSH in 60 h	82.3% at pH 5.0 + 10 mmol/L GSH in 84 h	[99]
  PPEICD/p53	MTO, -	–	–	[100]
  CD-OEI/p53	DOX, 4.7%	–	–	[101]
  pPTX/pCD	PTX, 5.1%	–	–	[102]

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  Table 3.  CD-based nanosponges for antitumor drugs loading and controlled release.

  Nanosponges	Drug and content	Drug leakage	Drug release	Ref.
  Cyclodextrin-based nanosponges (NS)	Resveratrol: NS of 1:5 and 1:10	> 50% and ~100% in H2O in 2 h	–	[103]
  β-Cyclodextrin nanosponge (CN)	CPT, 38%	4% at pH 7.4 in 2 h	–	[104]
  pγ-CyD	DOX, γ-CD/DOX of 1:1 or 1:2	–	–	[105]
  CDNS	CUR, 38.36%	37% at pH 7.4 in 48 h	–	[106]
  Cyclodextrin-based nanosponges (NS)	DOX, -	~25% at pH 7.4 in 48 h	–	[107]
  β-CDP	DOX, DOX: β-CDP of 1:10 and 1:20	64.2% and 52% at pH 7.4 in 24 h	–	[108]
  β-CDP	QCT, 8.25%; DOX, 7.99%	69.56% (QCT) and 79.14% (DOX) at pH 7.4 in 48 h	72.90% (QCT) and 84.63% (DOX) at pH 5.4 in 48 h	[109]
  PDOP NCs	DOX, 12.8%	30% at pH 7.4 in 48 h	80% at 10 mmol/L DTT in 48 h	[110]
  GSH—NSs	DOX, 13%	0.7% without GSH in 6 h	1.0% with 10 mmol/L GSH in 6 h	[111]
  β-CD-CQD	DOX, 39.5%	19% at pH 7.4 in 100 h	61% at pH 5.0 in 100 h	[112]
  MNPs-NSs	CYC, (29.9 ± 4.1)%	< 20% without AMF	> 80% with AMF	[113]

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