Vol. 66, No. 3207 Chem. Pharm. Bull. 66, 207–216 (2018)
Current Topics
Drug Discovery: Recent Progress and the Future Review
Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules Taishi Higashi,*,a Daisuke Iohara,b Keiichi Motoyama,a and Hidetoshi Arima*,a,c a
Graduate School of Pharmaceutical Sciences, Kumamoto University; 5–1 Oe-honmachi, Chuo-ku, Kumamoto 862–0973, Japan: b Faculty of Pharmaceutical Sciences, Sojo University; 4–22–1 Ikeda, Nishi-ku, Kumamoto 860–0082, Japan: and c Program for Leading Graduate Schools “HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program,” Kumamoto University; 5–1 Oehonmachi, Chuo-ku, Kumamoto 862–0973, Japan. Received September 21, 2017 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. Key words supramolecular chemistry; pharmaceutical sciences; cyclodextrin (CyD); polyrotaxane; polycatenane; supramolecular pharmaceutical sciences
1.
Introduction
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
Fig. 1. Schematic Model of Inclusion Complexation of CyDs with Guest Molecules
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.
2. Cyclodextrin-Based Supramolecular Chemistry for Pharmaceutical Sciences
CyDs are safe and inexpensive materials, and therefore a
To whom correspondence should be addressed. e-mail:
[email protected];
[email protected] * © 2018 The Pharmaceutical Society of Japan
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Fig. 2.
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Schematic Structures of Various CyD-Based Supermolecules
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-Hydroxy-
Fig. 3. Proposed Mechanism for Formation of DM-CyD Polypseudorotaxanes and Polyrotaxanes
propyl 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/polyethyl-
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ene 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 PEGPPG-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).
3. Pharmacokinetics of Cyclodextrin-Based Supermolecules
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 106 –107 M−1) (e.g. Bridion®).60)
4. Cyclodextrin-Based Supramolecular Pharmacology and Drug Discovery
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) GM1gangliosidosis,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. To improve safety and blood retention of CyDs, formation of supramolecular structures is a promising strategy.
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Examples of CyD Derivatives Used as APIs
CyD Sugammadex
HP-β-CyD
HP-γ-CyD
R8-β-CyD
Lac-β-CyD
S-CyDs
Pentacyclic triterpene-M-β-CyD
M-β-CyD
DM-α-CyD
DM-β-CyD
FA-M-β-CyD
DMA-β-CyD
GUG-β-CyD
Substitution (R) R2: R3: R6: R2: R3: R6:
H H Carboxyl thio ether H or CH2CH(OH)CH3 H or CH2CH(OH)CH3 H or CH2CH(OH)CH3
R2: R3: R6: R2: R3: R6: R2: R3: R6: R2: R3: R6: R2: R3: R6: R2: R3: R6:
H or CH2CH(OH)CH3 H or CH2CH(OH)CH3 H or CH2CH(OH)CH3 H H H or octaarginine H H H or lactose H H SO3H CH3 CH3 SO3H H or CH3 H or CH3 H or CH3
R2: R3: R6: R2: R3: R6: R2: R3: R6: R2: R3: R6: R2: R3: R6:
CH3 H CH3 CH3 H CH3 H or H or H or H or H or H or H H H or
CH3 CH3 CH3 or folate CH3 COCH3 CH3
Disease (symptom)
Property
·Neuromuscular blockade by rocuronium
Interacts with rocuronium in the blood and accelerates its elimination
·NPC ·Leukemia ·Hyperlipidemia ·Alzheimer’s disease ·Adjuvant ·Cerebral ischemic injury ·Atherosclerosis ·Diabetic kidney disease ·Chronic renal failure ·NPC
Interacts with cholesterol, phospholipids, proteins and uremic toxins in the blood, on the cells, in the cells and in the gastrointestinal tract
·NPC
Aggressively enters the cells, and interacts with biological membranes
·NPC (hepatosplenomegaly)
Aggressively enters the hepatic parenchymal cells, and interacts with biological membranes
·AIDS
Inhibition of the binding of HIV virions to the cells
·AIDS ·Influenza
Inhibition of the binding of virions to the cells
·NPC ·Sterility ·Solid cancer ·Bacterial growth ·α-Synucleinopathy ·GM1-gangliosidosis ·Septic shock
Interacts with biological membranes and affects the cell or sperm function
·Hypervitaminosis
Interacts with vitamin A in the blood and accelerates its elimination
·Solid cancer
Cancer cell-selective antitumor activity mediated by the regulation of mitophagy
·Septic shock
Directly interacts with lipopolysaccharide
·FAP
Inhibits the formation of the amyloid
Interacts with biological membranes and affects the cell function
Interacts with biological membranes and affects the cell function
glucuronylglucose
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.
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5. Cyclodextrin-Based Supramolecular Physical Pharmaceutics
Fig. 4. Proposed Mechanism for the Cholesterol-Lowering Effect of Biodegradable Polyrotaxanes
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 pseudorotaxanelike 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 pseudorotaxanelike 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 (CDMOF) 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.
6. Fig. 5.
Various CyD-Based Supermolecules for Physical Pharmaceutics
Cyclodextrin-Based Supramolecular Drug Delivery
CyD-based supramolecular drug carriers are being aggressively developed. RONDEL™ is widely acknowledged as one of the most successful examples of CyD-based supramolecular
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Fig. 6.
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Various CyD-Based Supermolecules for Drug Delivery
drug carriers.14,58) RONDEL™ consists of small interfering RNA (siRNA) polyplex with cationic β-CyD polymer, Adgrafted 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
