2018 Volume 66 Issue 3 Pages 207-216
Supramolecular chemistry is an extremely useful and important domain for understanding pharmaceutical sciences because various physiological reactions and drug activities are based on supramolecular chemistry. However, it is not a major domain in the pharmaceutical field. In this review, we propose a new concept in pharmaceutical sciences termed “supramolecular pharmaceutical sciences,” which combines pharmaceutical sciences and supramolecular chemistry. This concept could be useful for developing new ideas, methods, hypotheses, strategies, materials, and mechanisms in pharmaceutical sciences. Herein, we focus on cyclodextrin (CyD)-based supermolecules, because CyDs have been used not only as pharmaceutical excipients or active pharmaceutical ingredients but also as components of supermolecules.
Supramolecular chemistry is defined as the chemistry of intermolecular bonds, covering the structure and functions of entities formed by the association of two or more chemical species.1–3) It includes molecular self-assembly, folding, molecular recognition, host-guest chemistry, mechanically interlocked molecular architectures, and dynamic covalent chemistry.4) Recently, a large number of supermolecules have been developed in various fields, including materials science and engineering, environmental engineering, mechanical engineering, nanotechnology, and biotechnology. In the pharmaceutical field, supermolecules such as liposomes,5) micelles,6) nanoparticles,7,8) hydrogels,9,10) nanogels,11,12) and inclusion complexes13–15) are widely used. Moreover, aspects such as cell structure, DNA structure, receptor/substrate reaction, and drug activity are based on supramolecular chemistry. Although not a major domain in the pharmaceutical field, supramolecular chemistry is an extremely useful and important domain for understanding pharmaceutical sciences. Introducing the concept of supramolecular chemistry to pharmaceutical sciences could help develop new ideas, methods, hypotheses, strategies, materials, and mechanisms.
Cyclodextrins (CyDs) are known to form inclusion complexes with hydrophobic guest compounds (Fig. 1). CyDs and their derivatives are widely used as pharmaceutical excipients to improve pharmaceutical properties such as stability, solubility, bioavailability, and taste of drugs.13,14,16) Notably, CyDs have been used as building blocks of supermolecules,17–20) as well as crown ethers,21) cucurbituril,22) pillar[n]arenes,23,24) cryptand,25) and calixarene.26) Therefore CyDs can play the role of mediators between supramolecular chemistry and pharmaceutical sciences.
Based on these notions, we herein propose a new concept for pharmaceutical sciences termed “supramolecular pharmaceutical sciences,” which combines supramolecular chemistry and pharmaceutical sciences. In this review, we focus on the use of CyD-based supermolecules in pharmaceutical sciences.
CyDs are safe and inexpensive materials, and therefore a large number of CyD-based supermolecules have been developed (Fig. 2). Mechanically interlocked molecules, such as rotaxanes and catenanes, are representative CyD-based supermolecules. Rotaxanes are obtained by threading linear compounds through macrocyclic compounds (pseudorotaxanes, Fig. 2a) and capping their terminals with bulky compounds (Fig. 2b). In contrast, catenanes are obtained by cyclization of pseudorotaxanes (Fig. 2c). In 1981, Ogino27) prepared a rotaxane containing α-CyD and α,ω-diaminoalkanes capped with cis-[CoCl2(en)2]Cl2, and thereby first reported on CyD-based interlocked molecules. Additionally, Harada et al.28) reported CyD-based polyrotaxanes (Fig. 2e) in 1992. This was breakthrough research in material sciences because the polymeric structures of polyrotaxane can render new properties. Notably, topological gels based on polyrotaxane were commercially used as coating materials for devices such as cellular phones and speakers.29,30) Furthermore, various biomaterials and drug carriers based on CyD polyrotaxanes have been developed by many researchers.31–34) Thus CyD-based mechanically interlocked molecules, especially polyrotaxanes, are very useful materials in various fields.
To design CyD polyrotaxane-based biomaterials and drug carriers, chemical modification of CyD in the polyrotaxanes is often required35) because CyD polyrotaxanes are generally poorly water-soluble in water.28,31,36) However, to yield CyD polyrotaxane derivatives, multi-step synthesis pathways are often needed. To obtain CyD polyrotaxane derivatives through a synthesis pathway with few steps, simple and facile preparation methods have recently been developed. Takata and colleagues reported one-pot synthesis of polyrotaxanes with 2,3,6-tri-O-methyl α-CyD (TM-α-CyD).37,38) In these methods, as TM-α-CyD is directly used for the synthesis of polyrotaxanes, chemical modification of the parent polyrotaxanes is not necessary. Thompson and colleagues39) prepared hydroxypropylated polyrotaxanes through Takata’s method. 2-Hydroxypropyl β-CyD (HP-β-CyD) was directly used to yield polyrotaxanes, and the reaction was performed in organic solvents such as hexane. His group also prepared various water-soluble polyrotaxanes including HP-β-CyD and 4-sulfobutyl ether β-CyD (SBE-β-CyD) using the same method.40)
We recently demonstrated a novel strategy for the efficient preparation of polypseudorotaxanes and polyrotaxanes with 2,6-di-O-methyl α-CyD (DM-α-CyD) and DM-β-CyD by using the cloud points of DM-CyDs.41) Both DM-α-CyD and DM-β-CyD easily formed polypseudorotaxanes in water at high temperature (Fig. 3). Subsequently, polyrotaxanes were obtained by adding 2,4,6-trinitrobenzenesulfonic acid (TNBS) as an end-cap, resulting in the one-pot synthesis of DM-CyD polyrotaxanes in water. These methods are very useful because polyrotaxane derivatives are prepared easily without organic solvents.
Meanwhile, only a few reports on CyD-based catenanes and polycatenanes are available to date.42) Lüttringhaus et al.43) tried to prepare a CyD catenane with dithiol and α-CyD in 1958, and that was the first report on a CyD catenane. Nonetheless, they could not prepare any catenanes. The first report on the successful synthesis of CyD catenanes was by Stoddart and colleagues44) who prepared CyD catenanes consisting of one or two DM-β-CyD molecules, namely [2] or [3] catenanes, in 1993. Thereafter, only a few reports on CyD catenanes have been published.45–47)
Very few reports on CyD polycatenanes possessing a number of CyD molecules have been acknowledged. Okada and Harada48) reported the formation of a CyD polycatenane through cyclization of 9-anthracene-capped α-CyD/polyethylene glycol (PEG) polyrotaxane as the only example of CyD polycatenane. However, detailed studies, such as purification and characterization of CyD polycatenanes, have not been performed to date. We recently prepared CyD polycatenanes consisting of β-CyD or γ-CyD and PEG-polypropylene glycol (PPG)-PEG copolymer (pluronic, PEG-PPG-PEG) through a one-pot facile synthesis (submitted) (Fig. 2f). These polycatenanes were prepared by cyclization of CyD/thiolized PEG-PPG-PEG polypseudorotaxanes through disulfide formation in water, and are therefore biodegradable, expecting their appreciation in the pharmaceutical field.
As described above, various CyD-based supermolecules have been developed, and these molecules would be useful for fabrication of materials in the pharmaceutical field, because they not only have unique structures, but also flexible and topological properties over traditional macromolecules. Other CyD-based supermolecules, such as daisy chain49) (Fig. 2g), stacking polymer50) (Fig. 2h), and poly[2]rotaxane,51) have been developed by Harada’s group (Fig. 2i).
Interlocked molecules such as polyrotaxanes and polycatenanes can maintain their structure in the body after parenteral administration. Zhou et al.52) reported that a polyrotaxane consisting of HP-β-CyD and pluronic F127 provides >100-fold vascular enhancement compared to HP-β-CyD after intravenous administration. Collins et al.53) demonstrated that the lowly threaded HP-β-CyD polyrotaxanes show rapid clearance and accumulation in the lung. In contrast, highly threaded HP-β-CyD polyrotaxanes exhibit prolonged circulation in blood and high accumulation in the liver. These polyrotaxanes mainly adsorb lipoproteins because of the presence of cholesterol moieties as end-caps. Polyrotaxanes possessing high blood retention are expected to show enhanced permeability and retention (EPR) effect, and a number of antitumor drug conjugates with polyrotaxanes have been developed.54–56)
Contrastingly, supermolecules based on noncovalent bonds often dissociate after administration. Hence to design supramolecular materials based on noncovalent bond, attention should be focused on the stability constant (Kc) between CyDs and guest molecules. The selection of guest molecule is very important for fabrication of CyD supermolecules based on noncovalent bonds. Adamantane (Ad) has been widely used for fabrication of CyD-based supramolecular materials in the pharmaceutical field because it strongly interacts with β-CyDs.20,57) For instance, Davis and co-workers14,58) developed supramolecular drug carriers based on the interaction between β-CyD and Ad. They prepared a complex of the drug or nucleic acids with β-CyD polymer; then, the targeting ligands were modified by mixing Ad-appended ligands such as transferrin and sugars. Targeting ligands are modified through supramolecular noncovalent bonds rather than covalent bonds. This strategy is excellent because adjusting the degree of modification becomes very easy.
What is the Kc value required to maintain supramolecular complex in vivo? Stella et al.59) reported that in parenteral administration, the major driving force for dissociation of weakly or moderately interacting guest molecules with CyDs is simple dilution. In the case of CyD complexes having high Kc values (>104 M−1), a competitive interaction of CyDs with endogenous compounds, drug binding to plasma and tissue components, drug distribution into tissues, rapid elimination of CyDs, and the effects of pH or temperature may be important factors for the dissociation of CyD complexes.
Kurkov et al.60) investigated the effects of CyDs on drug pharmacokinetics after parenteral administration. In the case of telmisartan (Kc=4×104 M−1), only 2.9% of the drug bound to HP-β-CyD in plasma, indicating that CyD complexes easily dissociate in plasma. However, telmisartan strongly binds to plasma proteins (>99%). Meanwhile, 7.5% of betamethasone (Kc=3×103 M−1) and 3.8% of acyclovir (Kc=8×102 M−1) bound to CyDs in plasma; however, their Kc values were smaller than that of telmisartan. Betamethasone and acyclovir bound to plasma proteins weakly (64, 33%, respectively).
In the case of Ad and its derivatives, a Kc value of approximately 2×104 M−1 with CyDs may be a standard to maintain the complex in vivo. Leong et al.61) examined the effects of SBE-β-CyD on the pharmacokinetics of Ad and its derivatives after intravenous administration. They used three kinds of Ad derivatives (amantadine, memantine, and rimantadine) and their Kc values with SBE-β-CyD were determined as 5×103, 1×104, and 2×104 M−1, respectively. Moreover, their degree of protein binding was 29, 58, and 61%, respectively. Of these Ad derivatives, the pharmacokinetics of rimantadine was altered by complexation with SBE-β-CyD. These findings suggest that a Kc value of approximately 2×104 M−1 with CyDs would be required to fabricate supramolecular drug carriers containing Ad for parenteral administration.
To fabricate CyD-based supramolecular carriers, the Kc value between CyDs and guest molecules should be >104–105 M−1. If Kc is <104 M−1, other parameters such as protein binding of guest molecules, competitive interaction of CyDs with endogenous compounds, and elimination of CyDs should be reduced. Multivalent interaction between some CyD molecules and some guest molecules may also be useful in preventing the dissociation of the complex. Meanwhile, we should note that to form an inclusion complex in the blood with separately administered drugs, CyDs should show higher Kc (>106–107 M−1) (e.g. Bridion®).60)
Recently, various bioactivities of CyDs have been demonstrated, and CyDs have been used as active pharmaceutical ingredients (APIs) against Niemann–Pick disease type C (NPC),62–76) leukemia,77) hyperlipidemia,78) Alzheimer’s disease,79–84) cerebral ischemic injury,85) atherosclerosis,86) diabetic kidney disease,87) chronic renal failure,88) AIDS,89,90) influenza,91) peripheral artery disease,92) sterility,93–95) solid cancers,96–101) bacterial growth,102) α-synucleinopathy,103) GM1-gangliosidosis,104) septic shock,105–107) hypervitaminosis,108) and transthyretin-related familial amyloidotic polyneuropathy (FAP)109,110) (Table 1). CyDs are also useful in inhibiting neuromuscular blockade by rocuronium (trade name: Bridion®)111) and in increasing the immune responses of vaccines (adjuvant).112,113) However, CyDs occasionally show toxicity in the lung,114) bone,115) ears,116) and kidney.117) Moreover, blood retention of CyDs is generally short,13,117) resulting in low bioactivities.
 | |||
|---|---|---|---|
| CyD | Substitution (R) | Disease (symptom) | Property |
| Sugammadex | R2: H | ·Neuromuscular blockade by rocuronium | Interacts with rocuronium in the blood and accelerates its elimination |
| R3: H | |||
| R6: Carboxyl thio ether | |||
| HP-β-CyD | R2: H or CH2CH(OH)CH3 | ·NPC | Interacts with cholesterol, phospholipids, proteins and uremic toxins in the blood, on the cells, in the cells and in the gastrointestinal tract |
| R3: H or CH2CH(OH)CH3 | ·Leukemia | ||
| R6: H or CH2CH(OH)CH3 | ·Hyperlipidemia | ||
| ·Alzheimer’s disease | |||
| ·Adjuvant | |||
| ·Cerebral ischemic injury | |||
| ·Atherosclerosis | |||
| ·Diabetic kidney disease | |||
| ·Chronic renal failure | |||
| HP-γ-CyD | R2: H or CH2CH(OH)CH3 | ·NPC | Interacts with biological membranes and affects the cell function |
| R3: H or CH2CH(OH)CH3 | |||
| R6: H or CH2CH(OH)CH3 | |||
| R8-β-CyD | R2: H | ·NPC | Aggressively enters the cells, and interacts with biological membranes |
| R3: H | |||
| R6: H or octaarginine | |||
| Lac-β-CyD | R2: H | ·NPC (hepatosplenomegaly) | Aggressively enters the hepatic parenchymal cells, and interacts with biological membranes |
| R3: H | |||
| R6: H or lactose | |||
| S-CyDs | R2: H | ·AIDS | Inhibition of the binding of HIV virions to the cells |
| R3: H | |||
| R6: SO3H | |||
| Pentacyclic triterpene-M-β-CyD | R2: CH3 | ·AIDS | Inhibition of the binding of virions to the cells |
| R3: CH3 | ·Influenza | ||
| R6: SO3H | |||
| M-β-CyD | R2: H or CH3 | ·NPC | Interacts with biological membranes and affects the cell or sperm function |
| R3: H or CH3 | ·Sterility | ||
| R6: H or CH3 | ·Solid cancer | ||
| ·Bacterial growth | |||
| ·α-Synucleinopathy | |||
| DM-α-CyD | R2: CH3 | ·GM1-gangliosidosis | Interacts with biological membranes and affects the cell function |
| R3: H | ·Septic shock | ||
| R6: CH3 | |||
| DM-β-CyD | R2: CH3 | ·Hypervitaminosis | Interacts with vitamin A in the blood and accelerates its elimination |
| R3: H | |||
| R6: CH3 | |||
| FA-M-β-CyD | R2: H or CH3 | ·Solid cancer | Cancer cell-selective antitumor activity mediated by the regulation of mitophagy |
| R3: H or CH3 | |||
| R6: H or CH3 or folate | |||
| DMA-β-CyD | R2: H or CH3 | ·Septic shock | Directly interacts with lipopolysaccharide |
| R3: H or COCH3 | |||
| R6: H or CH3 | |||
| GUG-β-CyD | R2: H | ·FAP | Inhibits the formation of the amyloid |
| R3: H | |||
| R6: H or glucuronylglucose | |||
To improve safety and blood retention of CyDs, formation of supramolecular structures is a promising strategy. Tamura et al.32,118–121) developed biodegradable polyrotaxanes including 2-(2-hydroxyethoxy)ethyl β-CyD (HEE-β-CyD) and demonstrated their therapeutic effects for NPC (Fig. 4). Blood retention of HEE-β-CyD was dramatically improved by the formation of polyrotaxane. In addition, HEE-β-CyD polyrotaxane showed negligible toxicity because the axile molecule occupied the CyD cavity. Notably, the polyrotaxane released HEE-β-CyD in the target cells through degradation of polyrotaxane in the acidic environment of the cells (Fig. 4). Thompson and co-workers39,40,122,123) also developed polyrotaxanes comprising HP-β-CyD and used them for NPC treatment. These findings suggest the potential of CyD-based supermolecules as advanced APIs.
CyDs have been widely used for the improvement of pharmaceutical and physicochemical properties of drugs through their inclusion complexation.13,14) In this context, a number of CyD-based supramolecular materials for physical pharmaceutics have recently been developed. Higashi et al.124–126) investigated the usefulness of PEG/CyD polypseudorotaxanes as pharmaceutical materials for hydrophilic drugs such as salicylic acid, salicylamide, piroxicam, and hydrocortisone. Notably, the drugs were incorporated into the intermolecular spaces of CyD columns in PEG/CyD polypseudorotaxanes (Fig. 5a). The resulting solid dispersion-like formulation improved the dissolution rate of the drugs. Higashi et al.127–129) also prepared a ternary crystalline complex including two guest molecules. In this complex, one guest molecule was incorporated into the cavity of γ-CyD, while the other was incorporated into the intermolecular spaces between the γ-CyD columns. These findings provided an important concept for the design of pharmaceutical formulations of CyD/drug complexes.
In the case of slender drugs, CyDs often form supramolecular complexes with the drugs. We reported that isoprenoid compounds, such as coenzyme Q10 (CoQ10), reduced CoQ10, squalene, tocotrienol, and teprenone, form pseudorotaxane-like structures with a number of β-CyD or γ-CyD130–132) (Fig. 5b). Notably, solubility and photostability of the isoprenoid compounds were improved dramatically by pseudorotaxane-like supramolecular complexation.
Recently, APIs have been evolving from low-molecular weight drugs to peptides, proteins, and antibodies. However, proteins and antibodies often show low physicochemical stability during storage or transport or both. In this context, CyD/PEG polypseudorotaxanes markedly improved the stability of proteins and antibodies.133–138) We previously prepared supramolecular hydrogels based on high-molecular weight PEG/CyD polypseudorotaxanes containing highly concentrated antibodies (up to 240 mg/mL)136–138) (Fig. 5c). The encapsulation of antibodies such as human immunoglobulin G (IgG), omalizumab, palivizumab, panitumumab, and ranibizumab in the hydrogels dramatically improved their shaking stability. Thus CyD/PEG polypseudorotaxanes work as a stabilizer for not only low-molecular weight drugs but also proteins and antibodies.
Recently, a CyD-based metal-organic framework (CD-MOF) has been developed139) (Fig. 5d). CD-MOFs are prepared from γ-CyD in aqueous alcohol containing alkali metal salts. Eight-coordinate alkali metal cations orderly link the six γ-CyD molecules, resulting in a cubic structure. CD-MOFs are stable, porous, and capable of storing gases and small molecules within their pores. Currently, a considerable amount of research on CD-MOFs as pharmaceutical excipients is being aggressively performed. For instance, CD-MOF improved the stability of curcumin,140) thermal stability of sucralose,141) and bioavailability of ibuprofen.142,143) We believe that research on CD-MOFs in pharmaceutical sciences will accelerate dramatically in future.
CyD-based supramolecular drug carriers are being aggressively developed. RONDEL™ is widely acknowledged as one of the most successful examples of CyD-based supramolecular drug carriers.14,58) RONDEL™ consists of small interfering RNA (siRNA) polyplex with cationic β-CyD polymer, Ad-grafted PEG, and Ad-PEG-grafted transferrin (Fig. 6a). Transferrin, a tumor-targeting ligand, is grafted to the polyplex through the interaction between Ad and β-CyD. This strategy has been widely used by many researchers.20)
We recently developed a reversible PEGylation technology for protein drugs through host-guest interaction between Ad and β-CyD144,145) (Fig. 6b). Ad was modified to a protein, followed by mixing with a PEGylated β-CyD (mw of PEG, 20 kDa) to form a supramolecular complex of both components (Kc>104–105 M−1). We termed this “self-assembly PEGylation retaining activity (SPRA) technology.” Conventional PEGylation is based on covalent bonding, which results in loss of bioactivity of proteins due to steric hindrance of PEG chains. In contrast, PEGylated insulin prepared by SPRA technology (SPRA-insulin) completely retained the hypoglycemic effect of insulin. Notably, the enzymatic stability and thermal stability of insulin were dramatically improved by SPRA-insulin formation, and the blood retention and hypoglycemic effect of SPRA-insulin were prolonged. Hence PEGylation through supramolecular chemistry (SPRA technology) renders advanced pharmaceutical benefits over conventional PEGylation.
As described above, weak interaction (Kc<104 M−1) leads to drug dissociation in blood after injection. In this context, Kim and colleagues146,147) fabricated a supramolecular nanoparticle formed by multivalent host–guest interactions between a polymeric β-CyD and polymeric paclitaxel. The interaction between monomeric β-CyD and paclitaxel is not strong, but the resulting supramolecular nanoparticle is stable because of the multivalent host-guest interactions. This nanoparticle accumulates in tumors by the EPR effect and shows antitumor activity in vivo.
CyD-based polyrotaxanes are also used to fabricate drug carriers for low-molecular weight drugs,55,56,148,149) proteins,150,151) and genes or oligonucleotides34,152,153) (Fig. 6c). A number of methods for loading drugs to polyrotaxanes, such as drug conjugation at end of the axile molecule or CyD molecule of the polyrotaxane and complexation with drugs through an electrostatic interaction, have been reported.33) Although only a few reports describing in vivo studies were known till relatively recently,33) it is noteworthy that in vivo experiments have been since performed on polyrotaxane-based drug carriers.
Polypseudorotaxanes, a precursor of polyrotaxanes, are also useful as promising drug carriers.33,154,155) We have developed various CyD polypseudorotaxane-based drug carriers for low-molecular weight drugs, proteins, genes, and siRNA. For instance, we demonstrated that α-CyD and γ-CyD form water-insoluble polypseudorotaxanes with covalently PEGylated insulin (mw of PEG, 2 kDa) through inclusion complexation with one PEG chain and two PEG chains, respectively135,156–158) (Fig. 6d). The release of PEGylated insulin from the polypseudorotaxanes was sustained in vitro. Moreover, the blood insulin level and hypoglycemic effect of PEGylated insulin/γ-CyD polypseudorotaxane were markedly sustained after subcutaneous administration to rats. Importantly, PEGylated insulin alone did not show prolonged blood retention and hypoglycemic effect because of the low molecular weight of PEG (2 kDa). Hence modification of supermolecule, i.e., polypseudorotaxane, improves the pharmaceutical properties of proteins compared to conventional modification with macromolecules such as PEG. To the best of our knowledge, this is the first report on the successful sustained drug release system based on polyrotaxane or polypseudorotaxane in vivo. This technology is also applicable for PEGylated liposome159) (Fig. 6e), PEGylated gene and siRNA carriers160–162) (Fig. 6f), and SPRA-proteins163) (Fig. 6g).
Recently, advanced gels such as topological gels based on polyrotaxane29,30) and supramolecular gels based on crosslinking through host-guest interactions19,164–173) have become a trend in material sciences. However, application of these materials in pharmaceutical sciences is limited so far. Bin et al.174) developed extremely stretchable thermosensitive hydrogels with good toughness using α-CyD/PEG polyrotaxane derivatives as cross-linkers and introducing ionic groups into the polymer network (Fig. 6h). These gels could be promising biomaterials because of their safe components. Hörning et al.173) prepared supramolecular hydrogels cross-linked by host-guest interactions between β-CyD and Ad, and used them as a substrate for cell culture. These gels enable adjustment of the magnitude of softening and stiffening of the substrate by varying the concentrations of free β-CyD. Application of these materials in the pharmaceutical field is under consideration, and innovative biomaterials and drug carriers consisting of these materials will be developed in the near future.
CyDs have been used as pharmaceutical excipients because of their high safety.13,14) However, as described above CyDs occasionally show toxicity in the lung,114) bone,115) ears,116) and kidney.117) In contrast to the abundant safety data of CyDs, very few data are available on the safety of CyD-based supermolecules. Tamura and Yui118) reported that HEE-β-CyD polyrotaxane shows markedly lower hemolytic activity and cytotoxicity than DM-β-CyD and HP-β-CyD because the axile molecule occupies the CyD cavity. Collins et al.53) investigated the acute toxicity of HP-β-CyD polyrotaxanes with PEG-PPG-PEGs. The polyrotaxanes were intravenously administered twice over 3 weeks to male Balb/c mice. After administration, negligible body weight change was observed, indicating that the polyrotaxanes did not exhibit acute toxicity in mice. Moreover, blood chemistry parameters, such as blood urea nitrogen (BUN), alkaline phosphatase (ALKP), alanine transaminase (ALT), and blood CO2 did not change after administration of polyrotaxanes, suggesting the absence of acute toxicity in the kidney, liver, and lung. Furthermore, administration of polyrotaxanes did not stimulate IgG production, suggesting their low immunogenicity.
We recently examined the safety profiles of polypseudorotaxane hydrogels consisting of α-CyD or γ-CyD and PEG (mw, 20 kDa) after subcutaneous administration to rats.138) It was observed that 28 blood chemistry parameters changed negligibly 7 and 14 d after single administration. In addition, the administration did not alter the weight of organs such as the lung, spleen, heart, liver, and kidney. Moreover, no severe injury was observed in histological observations, suggesting no serious toxicity of CyD polypseudorotaxane hydrogels after subcutaneous administration. We also examined the safety profiles of polypseudorotaxane hydrogels after frequent subcutaneous administration to rats, and no adverse effects were observed (unpublished data).
In this review article, we describe various CyD-based supermolecules and their use as biomaterials, pharmaceutical excipients, drug carriers, and APIs. Additionally, we discussed the chemistry, pharmacokinetics, and toxicology of CyD-based supermolecules. Currently, drugs are undergoing evolution from low-molecular weight synthetics to peptides, proteins, and antibodies. Moreover, genes, oligonucleotides, cells, and machines are promising APIs for next-generation. To improve the pharmaceutical properties of these APIs, advanced pharmaceutical technologies are needed. We believe that the incorporation of supramolecular chemistry into pharmaceutical sciences can create advanced pharmaceutical technologies (Fig. 7). Indeed, as described in this review, PEGylation of proteins through supramolecular chemistry (i.e. SPRA technology) renders advanced pharmaceutical benefits over conventional PEGylation (i.e. covalent bond). In addition, modification of supermolecules (i.e. polypseudorotaxane) improves the pharmaceutical properties of proteins compared to conventional modification with macromolecules (i.e. PEG). Thus supramolecular chemistry as an alternative to chemistry and supermolecules as an alternative to macromolecules may help create advanced technologies. Furthermore, CyD-based supermolecules work as APIs by themselves, facilitating the development of new kinds of drugs (Fig. 7). In conclusion, fusion of supramolecular chemistry and pharmaceutical sciences, namely supramolecular pharmaceutical sciences, could be an important domain to develop new pharmaceutical sciences.
The authors declare no conflict of interest.
