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Enantioselective Release of Chiral Drugs

Lujie Song , Youping Wu , Jianping Deng

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (9) : 1550 -1559.

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Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (9) : 1550-1559 DOI: 10.7536/PC200827
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Enantioselective Release of Chiral Drugs
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Abstract

The importance of chirality and chiral compounds has been widely recognized. The proportion of chiral drugs increases continuously and rapidly. However, some chiral drugs are still marketed and used in racemic form. How to appropriately and effectively use racemic drugs accordingly becomes a subject of high importance in both academic research and practical applications. ‘Enantioselective release' strategy combines two separate processes in a single one, that is, ‘chiral separation' and ‘controlled release', providing alternative routes for the use of racemic drugs. Up to date, striking advancements have been made in this research area. The review paper summarizes the representative advancements made in recent years. Herein, according to the major materials constituting the chiral releasing carriers, chiral drug releasing systems are classified into three groups: (1) organic materials (hydrogels, particles, etc.), (2) inorganic materials and (3) molecularly imprinted materials based releasing systems. The investigations dealing with enantioselective release and enantioselectivity effects are anticipated to enhance our understanding about the mysterious chiral world.

Contents

1 Introduction

2 Chiral organic material-based releasing systems

2.1 Hydrogels

2.2 Particles

2.3 Self-assembled carriers

2.4 Other chiral carriers

3 Chiral inorganic material-based releasing systems

3.1 Silica particles

3.2 Polymers/silica hybrid particles

4 Molecularly imprinted material-based releasing systems

5 Conclusion and outlook

Graphical abstract

Keywords

chiral drugs / chiral carriers / enantio-selective release / racemate

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Lujie Song, Youping Wu, Jianping Deng. Enantioselective Release of Chiral Drugs. Progress in Chemistry, 2021, 33(9): 1550-1559 DOI:10.7536/PC200827

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1 Introduction

Chiral compounds are indispensable to people's daily life, and play an important role in chiral drugs, pesticides and aromatics[1⇓~3][4⇓~6][7]. The two enantiomers of chiral drugs usually have similar or identical physical and chemical properties, but they are significantly different in physiological activities. In most cases, in a pair of enantiomeric drugs, one enantiomeric drug has efficacy, while the other has little efficacy, and may even have toxic side effects. For example, in the thalidomide case, the R enantiomer of the chiral drug thalidomide had a sedative effect on pregnant women, while the S enantiomer caused malformations in infants[8]. Therefore, the development and preparation of chiral pure drugs has become a major development trend. However, the preparation of pure enantiomeric drugs is not only complicated and costly, but also racemization may occur during subsequent transportation or use. Therefore, for many reasons, some drugs are still produced, sold and used in the form of racemates.
In 1993, Duddu et al. Proposed the concept of "Enantioselective Release" (ESR), which provides a new idea for the rational and efficient use of racemic drugs[9]. ESR combines the two concepts of chiral resolution and controlled release. The core of ESR is that the two enantiomers of racemic drugs interact differently with the chiral carrier during the release process, resulting in the release of one enantiomer first, so as to achieve the selective release of chiral drugs. According to the classical "three-point interaction" theory, the enantiomers interact with the carrier in multiple ways during the release process, at least one of which involves chirality[10]. Multiple interactions include hydrogen bonds, ionic bonds, steric hindrance, π-π interactions, and dipole-dipole interactions. In short, enantioselective drug release can be achieved during chiral drug release based on the difference in force between the drug molecule and the carrier.
Based on the research of our group, this paper reviews the main progress in the field of enantioselective release of chiral substances (including chiral drugs) in recent years. For the convenience of introduction, the enantioselective delivery systems are divided into three categories: organic carrier delivery systems, inorganic carrier delivery systems and molecularly imprinted polymer (MIP) delivery systems.

2 Organic carrier release system

Organic carriers are one of the most widely studied and applied drug delivery systems. The main forms of chiral organic carriers are hydrogel, micro-nano particles and self-assembled materials. They will be described separately below.

2.1 Chiral hydrogel

As a kind of cross-linked network polymer, hydrogel has high similarity with human soft tissue in composition, structure and properties, and has excellent water absorption and biocompatibility, so it has attracted wide attention (refer to the recent review of hydrogel)[11⇓~13]. Studies have shown that chiral hydrogels can exhibit a variety of biological functions, such as cell adhesion, migration and enrichment[14⇓~16]. Chiral hydrogels can also be used in many fields such as chiral adsorption, chiral release and chiral catalysis[17⇓⇓⇓~21].

2.1.1 Chiral Hydrogel Delivery System Based on Amino Acid

Chiral amino acids are often used to prepare chiral hydrogels[22]. Deng, Wu et al. prepared chiral pH-responsive amphiphilic polymer networks (APCNs) by copolymerization of N-acrylyl-L-alanine (NAA) as a chiral hydrophilic monomer and methacrylate-terminated polydimethylsiloxane (M-PDMS) as a hydrophobic monomer[23]. L/D-proline was used as a chiral model for adsorption/release experiments. The results show that APCNs preferentially adsorb D-proline and release L-proline, and have the ability of chiral adsorption and enantioselective release. Due to the pH sensitivity of NAA, APCNs exhibit a reversible swelling-deswelling transition when the pH of the release medium changes periodically, which is beneficial to the regulation of the release properties of hydrogels.
In order to further optimize the performance of chiral hydrogels, Xie et al. prepared pH-responsive chiral hydrogels by free radical copolymerization of NAA with glycidyl methacrylate (GMA) and hydroxypropyl-β-cyclodextrin (HP-β-CD) as hydrophobic comonomers[24]. The enantioselective release behavior of chiral hydrogels was investigated by using chiral proline as a chiral drug model and using two release modes. The two modes of release are: (1) single enantiomer release and (2) racemate release. The main differences are as follows: in the release mode (1), the chiral hydrogel is firstly prepared, and the hydrogel adsorbs D- and L-proline respectively and then releases the D- and L-proline; In the release mode (2), the proline racemate is added during the preparation of the hydrogel and then released. The results of the study are shown in fig. 1. In both release modes, the hydrogel preferentially releases D-proline; A comparison of that enantiomeric release difference between the two modes show that the enantiomer has a higher release difference (enantiomeric excess value ee, Max. 16% in panel B and Max. 12% in panel C) in the single enantiomer release mode.
In order to prepare chiral hydrogels with better comprehensive properties, Cheng et al. Prepared chiral pH-responsive hydrogels by "micellar polymerization" of hydrophobic monomer octadecyl acrylate (C18) and chiral hydrophilic monomer NAA[25][26]. Proline was released in deionized water in the two modes mentioned above. The results showed that D-proline was preferentially released from the hydrogel in both release modes. The hydrogel exhibited a higher enantiomeric release difference (ee, 19%) compared to the hydrogel described above, indicating that the hydrogel has better enantioselective recognition properties[24]. However, D- and L-proline had the same release difference (ee = 19%) in the two release modes, indicating that the release mode had little effect on the release results, i.e., there was no competition between the two enantiomers during the release process. This is significantly different from the release results mentioned above, and the reasons for this need to be further explored[24].

2.1.2 Chiral Hydrogel Delivery System Based on Helical Polymer

Chiral helical polymers have been widely used in the fields of chiral resolution, chiral adsorption, enantioselective release and enantioselective induced crystallization[27⇓~29]. Compared with chiral non-helical polymers, the single-handed helical structure makes chiral helical polymers have the effect of "chiral amplification". Wang et al. Synthesized hydrophilic substituted polyacetylene (HPA) with vinyl group in the side chain, and the obtained HPA chain formed a single-handed helical structure in aqueous solution[30]. Thermoresponsive hydrogels (R-HGs and S-HGs) with opposite chirality were prepared by free radical polymerization of HPA and N-isopropylacrylamide (NIPAm). The mandelic acid was used in the drug release experiment, and the release behavior of the hydrogel was studied by single enantiomer release and racemate release. R-HGs released D-mandelic acid preferentially in both release modes. However, for S-HGs, D-mandelic acid and L-mandelic acid were released in similar amounts in the single enantiomer release experiment, indicating that S-HGs hydrogels had no enantioselectivity. In the racemate release pattern, L-mandelic acid is released preferentially. The different release results of S-HGs in the two modes can be explained as follows: in the single enantiomer release mode, only one enantiomer is immobilized on the hydrogel, and there is no competition between the enantiomers during the release process; In the racemate release mode, racemic drug molecules will compete in the release process, that is, once one enantiomer preferentially interacts with the chiral helical polymer chain, the chance of the other enantiomer will be reduced.

2.2 Chiral micro-nano particle

Chiral polymer particles have attracted much attention due to their optical activity and high specific surface area[31⇓⇓⇓~35]. In recent years, a series of chiral helical polymer-based micro-nano particles have been successfully prepared[36⇓⇓⇓~40]. The single-handed helical structure formed by the polymer chain endows the particles with chiral characteristics and optical activity, which lays the foundation for the study of enantioselective release performance.

2.2.1 Chiral helically substitute polyacetylene particle

Among chiral helical polymers, helically substituted polyacetylenes have been extensively studied due to their relatively simple structure. Deng et al. Prepared chiral particles by suspension polymerization of chiral helical polyacetylene and acrylate under the action of crosslinking agent trimethylolpropane triacrylate (TMPTA)[36]. The acrylate polymer chain endows the particles with good swelling property, so that the drug can be easily released when the carrier is swollen. Adsorption/release experiments showed that the chiral polymer particles preferentially adsorbed Boc-D-alanine and preferentially released Boc-L-alanine, which indicated that the prepared chiral helical polymer particles had chiral recognition and enantioselective release ability. On the basis of the study of the above chiral particles, they prepared chiral particles by suspension polymerization with cyclodextrin derivatives (β-CD-a) instead of TMPTA, and β-CD-a made the particles have better oil absorption-swelling properties[37]. Chiral menthol was used as a drug model for adsorption/release experiments, and the results showed that the particles preferentially adsorbed D-menthol and preferentially released L-menthol.

2.2.2 Chiral polylactic acid particle

Poly (lactic acid) (PLA) can form a helical structure under certain conditions, and its two isomers (PLLA and PDLA) have chiral properties. Since polylactic acid is easy to crystallize, it is not easy to form spherical particles. Deng et al. Successfully prepared PLA chiral particles by introducing flexible olefinic polymer chains through copolymerization[41]. The chiral drug Naproxen was released through the above two release modes (see above). In the single enantiomer release mode, the PLLA-particles preferentially released S-Naproxen, while the PDLA-particles showed no enantioselectivity. In the racemate release pattern, both PLLA- and PDLA- particles preferentially release S-naproxen. This indicates that the enantioselectivity of the PDLA chain is not significant and only enantioselective for the racemic drug. However, PLLA with the opposite chirality, as a chiral carrier, releases the same enantiomer preferentially, which is different from the previous studies on chiral helical polyacetylenes[42,43]. In previous studies of helically substituted polyacetylenes, polymers of opposite chirality have shown opposite enantioselectivity in enantioselective crystallization, enantioselective adsorption, and release, e.g., the L-enantiomer is released preferentially from a levorotatory polymer support and the D-enantiomer is released preferentially from a dextrorotatory support. In view of the fact that polylactic acid has been widely used to construct biomaterials, its chiral characteristics, especially the relationship between chirality and biological properties, deserve further study.

2.2.3 Chiral polymer composite particle

In order to enrich the types of chiral polymer particles and further study their enantioselective release properties, Deng et al designed and prepared composite particles composed of two chiral helical polymers, and then tested the enantioselective release behavior of the particles for chiral drugs. They prepared chiral composite particles composed of chiral helically substituted polyacetylene (PCM) and polylactic acid by suspension polymerization[44]. The preparation process of the chiral composite particles is shown in fig. 2. Preparing PLA macromonomer (alkynyl PLLA and alkynyl PDLA); The macromonomer is then subjected to suspension copolymerization with a chiral acetylene monomer (CM, the polymer of which is defined as PCM) to prepare the chiral composite particles. According to the chiral components of the particles, the particles can be divided into four categories: PLLA/S-PCM, PLLA/R-PCM, PDLA/R-PCM and PDLA/S-PCM. The release experiments of chiral drug naproxen were carried out. The results showed that for PLLA/S-PCM and PDLA/R-PCM particles (PLLA and S-PCM have positive Cotton effect, PDLA and R-PCM have negative Cotton effect), both particles release R-naproxen preferentially. For both PLLA/R-PCM and PDLA/S-PCM particles (the Cotton effect of the two chiral polymers constituting the particles is opposite), both particles release S-naproxen preferentially. According to their analysis, when the two polymer chains have the same helical orientation, the composite particles release R-naproxen preferentially[44]. S-naproxen is release preferentially when that two polymer chains have opposite helical orientation. The above results show that the composite particles constructed by two kinds of chiral helical polymers have more complex molecular chain structure and chiral characteristics, which provides more controllable factors for the study of their chiral functions. The above research also provides a new design and preparation strategy for the design and preparation of multi-level chiral materials and the organic combination of different chiral polymers.

2.2.4 Polymer particle carriers with different morphologies

The polymer particles mentioned above are all spherical, while the study of non-spherical chiral particles is still rare. Compared with traditional spherical particles, non-spherical particles have more excellent properties than spherical particles in some fields[45]. Although there has been a great deal of research on non-spherical particles in the literature, these particles do not possess chirality[46⇓~48]. Chiral non-spherical particles have the unique advantages and chiral properties of non-spherical particles, which are a new class of chiral materials with important research value[49⇓⇓⇓~53]. Deng et al prepared spherical and spindle-shaped microparticles (Sphe-MPs and Spin-MPs) by simply controlling the stirring rate during suspension polymerization of acetylenated carboxymethyl cellulose (A-CMC) and acetylenic monomers[54]. Chiral drugs (+) -cinchonine and (-) -cinchonidine (enantiomers of each other) were used in the adsorption/release experiments. The drugs were bound to the carrier via hydrogen bonding, and both particles showed chiral adsorption and enantioselective release. In the release process, Sphe-MPs has only one release process due to the different release distance, while Spin-MPs has a two-step release process (as shown in Figure 3), resulting in different release amounts of drug molecules along the horizontal axis and the vertical axis.

2.2.5 Polymer particles containing dynamic covalent bond

The enantioselective release of the chiral carrier and the chiral drug described above is achieved mainly by physical interaction. That is, the chiral polymer chain forms a three-dimensional structure with a certain chirality so that it preferentially interacts with one of a pair of enantiomers. In theory, if there are more interactions between the released substance and the release carrier, such as the formation of dynamic covalent bonds, it is more advantageous to control the enantioselective release process. To this end, Deng et al. Prepared chiral particles with dynamically reversible borate ester structure and Schiff base structure, respectively, in which the phenylboronic acid group can form a reversible borate ester structure with the catechol group, while the amino group and the aldehyde group form a reversible Schiff base structure[39,40].
The reversible characteristics of phenylborate ester and Schiff base structure provide more control means for drug immobilization and release. Deng et al. Prepared chiral particles by copolymerization of chiral acetylene monomer and achiral acetylene monomer containing phenylboronic acid, and further immobilized the chiral drug DOPA containing catechol group through borate ester bond[39]. In the adsorption/release experiments, the chiral particles preferentially adsorb L-DOPA and preferentially release D-DOPA, showing significant chiral recognition and enantioselective release. Experiments prove that the chiral helical polymer chain and the phenylboronic acid group have a synergistic effect, and the chiral particles also have drug adsorption-release reusability which changes with pH.
Based on the reversible Schiff base bond formed by the reaction between the amino group and the aldehyde group, Deng et al. Introduced the amino group into the chiral polyacetylene, and then reacted with the aldehyde-containing drug citronellal to prepare the chiral drug-carrying particles with Schiff base structure. The preparation results are shown in Figure 4[40]. The microsphere is composed of polyacetylene containing Schiff base side groups, the main chain of the polymer provides helical chirality, and the Schiff base structure is used for immobilizing chiral drugs. The racemate of citronellal was used in the release experiment, and the particles showed enantioselective release behavior under neutral conditions. However, the enantioselective release effect is not obvious in strong alkaline and acidic environments due to the dominant role of the reversibility of the Schiff base bond. After the structure, composition and morphology of the chiral particles are further optimized, the particles are expected to realize the controlled release of chiral drugs with the change of pH and environmental temperature. Some commonly used anticancer drugs, such as doxorubicin (DOX), contain amino groups and have chiral structures, and their controlled release can be achieved by Schiff base bonds[55]. Because the cancer site is acidic, the pH is lower than the normal site, and the pH in the cancer cell is lower, the Schiff base structure is broken after the particle enters the lesion site, and then the drug is released to achieve targeted therapy[56][57]. Unfortunately, the chiral and enantioselectivity are rarely studied in this direction, so it needs to be discussed systematically.

2.3 Lf-assembled chiral carrier material

It has become an important research topic to design and develop new micro-nano scale materials by self-assembly strategy[58]. For example, polypeptide molecules can form chiral nanostructures with optical activity and specific structures through self-assembly, such as nanospheres, nanotubes and nanofibers, which can be used for controlled release of drugs and small molecular proteins[59][60]. Lee and Kim et al. Prepared a chiral α-peptide chain assembly, which can undergo a reversible assembly-disassembly transition at different temperatures, and this transition is related to the conformational change of the peptide chain[61]. The.alpha.-helical peptide chain forms a vesicle with a hollow structure as shown in fig. 5. The hollow vesicle has a heat-responsive vesicle wall and can adsorb a racemic mixture to realize enantioselective release through preferential diffusion on the vesicle wall, and the hollow vesicle shows chiral recognition/selective release characteristics in the adsorption/release of a racemic substance 1- (4-Bromophenyl) ethanol.
As a new type of nanomaterials, self-assembled vesicles have attracted more and more attention and have been used for controlled drug release[62]. Liu et al. used α-cyclodextrin (α-CD) and M-spiro quinoline amide oligomers to self-assemble in water to form chiral photoresponsive vesicles, in which the azobenzene (quinoline) group provided photoresponsiveness, so that the vesicles showed dynamic decomposition-reassembly structural changes under alternative irradiation of ultraviolet and visible light[63]. α-CD can specifically recognize the trans-azobenzene group, while the cis-isomer is easy to be released from the hydrophobic cavity of α-CD due to the spatial conformational mismatch. Propranolol, a racemic drug, was used as a drug model for release experiments, and the vesicles preferentially released R-Propranolol, showing excellent chiral recognition and enantioselective release ability.

2.4 Other chiral carrier

Because polylactic acid has good biocompatibility, biodegradability, non-toxicity and mechanical properties, Deng and Wu prepared chiral porous polylactic acid bulk materials (polyHIPEs) by using high internal phase emulsion (HIPE) template method (the process of material preparation and drug controlled release is shown in Figure 6)[64][65]. The HIPE template method has the advantages that the preparation process is simple, the pore diameter can be adjusted in a large range, the product has high porosity and the like[66]. Chiral drugs cinchonine and cinchonidine were used as models for drug release experiments. The results showed that only PLLA-based HIPEs showed enantioselectivity, while PDLA-based HIPEs showed no enantioselectivity. The same results were obtained when naproxen, a chiral drug, was used for the release test. It is worth noting here that PDLA particles also show weak enantioselectivity in the literature mentioned above[41]. These experimental results suggest that PDLA chains may have lower chiral recognition ability for guest molecules than PLLA molecules, but the specific reasons need to be further explored.
Membrane materials have been widely used in many fields, such as material separation and solar cells[67]. The use of chiral membranes for controlled drug release has also begun to attract attention. Yuan et al synthesized poly (L-glutamate) chiral membrane from poly (amino acid) which was synthesized by NCA. The chiral membrane was used to release D, L-p-hydroxyphenylglycine, and the chiral membrane showed enantioselective release characteristics[68].

3 Inorganic material

In recent years, mesoporous silica nanoparticles (MSN) have been widely used as drug carriers because of their good biocompatibility, non-toxic biodegradability, high specific surface area, regular pore structure and good physical stability[69⇓~71]. MSN can be prepared by sol-gel method using different templates (cationic surfactant, anionic surfactant and nonionic surfactant)[72][73,74][75,76]. The results showed that the drug release of mesoporous materials was a diffusion process mainly controlled by the mesoporous structure, and the drug release characteristics of mesoporous silica could be improved by the large pore size and high accessibility of the microporous structure[77⇓~79]. In recent years, chiral silica particles have become increasingly popular and have been used in the study of chiral drug release.

3.1 Chiral silica particle

Chiral mesoporous silica (CMS) nanoparticles are an important branch of MSN, and the preparation process of CMS is shown in Figure 7[80]. Yang et al synthesized spherical CMS nanoparticles using histidine derivative (C16-L-histidine) as a template, and immobilized the insoluble drug nimodipine (NMP) on the CMS nanoparticles through hydrogen bonding[81]. Compared with MCM-41, which has long and straight ordered pores, CMS has short and curved interconnected pore structure, so it has higher drug immobilization capacity and better drug release ability[82]. The curved chiral channel can accommodate more drug molecules, while the shorter channel length makes the drug easier to release. The results show that the pore size, geometric structure and pore connectivity of mesoporous silica have a significant impact on the controlled release of drugs.
Using cetyltrimethylammonium bromide (CTAB) as a template, n-heptanol or n-nonanol as a structure-directing agent (CSDA), and tetraethoxysilane (TEOS) as a silicon source, Xu et al. Synthesized two kinds of helical rod-like CMS with opposite chirality (marked as S1 and S2, respectively)[83]. Levofloxacin (LOFT), a chiral drug, was used in the release experiment. The results showed that CMS significantly inhibited the release of LOFL, and the inhibition of S2 on the release of LOFL was more obvious. In the same environment, S1 and S2 showed different drug loading capacity, which proved that the drug loading was related to the chirality of the carrier. In this study, the chirality of CMS was controlled by using different alcohol/CTAB molar ratios, while the chirality of template molecules had little effect on the formation of CMS. In addition, the alkyl chain of the alcohol plays an important role in the morphology control[84,85]. This study provides a new method for the design and preparation of novel chiral silica particles.
Li et al synthesized CMS with twisted rod-like structure by using chiral L- and D-alanine derivatives as anionic surfactant templates, 3-aminopropyltriethoxysilane (APTES) as CSDA and TEOS as silicon source, and used it as a carrier for the poorly soluble racemic drug ibuprofen (IBU)[86]. In vitro release experiments were carried out in simulated intestinal fluid (SIF, pH = 6.8) and simulated gastric fluid (SGF, pH = 1), respectively. The release results showed that the two kinds of particles could inhibit the release of IBU in SIF compared with the release of pure IBU, and had the function of slow release. In the SGF environment, both particles with opposite chirality promote the release of IBU. According to their analysis, in SIF environment, the geometric structure of particle aperture plays a leading role in drug release and inhibits drug release[86]. In the SGF environment, the particle structure is no longer dominant, and the crystalline drug is more easily released due to the crystalline transformation after being immobilized. In this study, it was also found that the chiral inversion of CMS was induced by alanine derivatives as surfactant templates. Special attention should be paid to the phenomenon of chiral reversal of chiral substances.

3.2 Chiral polymer/silica hybrid particle

Liang et al. Prepared chiral hybrid particles by combining chiral helical polyacetylene with silica[38]. The particles showed enantioselective release of the chiral drugs cinchonine and cinchonidine. The release experiments under different conditions showed that the enantioselectivity of the hybrid particles was related to the temperature, and the enantioselective release was easier at low temperature. The above studies have shown that inorganic chiral carriers can promote or inhibit the release of chiral drugs due to their unique structure. In addition, the achiral drugs immobilized in inorganic chiral carriers also show some enantioselective release characteristics, which provides a new strategy for the controlled release of achiral drugs[87].

4 Molecularly imprinted material

Molecularly imprinted polymers (MIPs) can provide specific recognition sites and have specific recognition function for specific molecules. MIP has been systematically studied in the fields of analytical science, biotechnology and drug controlled release[88⇓~90]. The preparation methods and applications of MIP are introduced in detail in some reviews[91⇓⇓~94]. The main preparation process of MIP is shown in Figure 8, which can be summarized as follows: a molecule is used as a template, the functional monomer coats the template molecule through non-covalent interaction (such as hydrogen bonding, ionic or hydrophobic interaction), and the MIP is prepared after monomer copolymerization and template removal[95]. Chiral MIP is a special kind of molecularly imprinted polymer, which has the ability to recognize chiral template molecules or molecules with similar structure. Chiral MIP materials have been applied in the fields of chiral recognition, adsorption and separation due to their high selectivity[96⇓⇓⇓⇓⇓~102].
Liang et al. Prepared chiral MIP particles by suspension polymerization using Boc-D/L-proline as template and chiral substituted acetylene monomer as functional monomer[103]. When the template molecule is removed, a cavity similar to the configuration of the chiral template proline is formed in the particle, and the helical structure of the polyacetylene also endows the particle with chiral characteristics. The chiral MIP particles were used in adsorption experiments, and it was found that when the helical conformation chirality of the substituted polyacetylene was matched with the configuration chirality of the template molecule, they could play a synergistic role, resulting in a significant improvement in the enantioselectivity of the material. When the two chiralities are mismatched, their chiral effects cancel each other out.
Inorganic materials can also be used to prepare molecularly imprinted materials. Yin and Yang et al prepared chiral molecularly imprinted nanotubes using S-propranolol as a template[104]. The chiral drug propranolol was used in the release experiment, and the results showed that the MIP nanotubes preferentially adsorbed and released S-propranolol, following the rule of "easy to bind, easy to release". Kuei et al. Prepared chiral imprinted silica nanospheres with hollow and mesoporous structures by one-pot method[105]. The chiral drug DOPA was used in the release experiment, and the MIP nanospheres showed excellent drug molecule immobilization and enantioselective release ability. The combination of MIP with other materials, especially porous materials, can greatly improve the comprehensive performance of MIP. Mathew et al. Obtained vinyl-functionalized multi-walled carbon nanotubes (MWCNTs) by strong acid modification, and used the photoresponsive monomer 4- [ (4-methacryloxy) phenylazo] benzoic acid (MPABA) as a functional monomer and L-phenylalanine benzyl ester (L-PABE) as a template to form a MIP structure on the surface of MWCNTs[106]. MWCNTs have high specific surface area, which makes MIP have good adsorption and selectivity for template molecules.
Szekely et al. Synthesized pH-responsive MIP materials, which have the ability of chiral recognition and selective release of chiral amines[107]. The molecularly imprinted polymer has good enantiomeric enrichment capability and enantioselective controlled release performance. Bodhibukkana et al. prepared MIP-cellulose composite membrane, which showed good enantioselectivity in the release experiment of S-propranolol[49].

5 Conclusion and prospect

Based on the research of our group, this paper reviews the recent studies on the enantioselective release of chiral drugs from chiral carriers. Significant progress has been made in the design and preparation of chiral carrier materials and enantioselective release. The importance of chirality and chiral substances is needless to say, and the development of chiral drugs will have an important impact on chemistry, materials, environment and even forensic science[108,109]. At the same time, the continuous progress of asymmetric catalysis and chiral resolution technology also helps to promote the development of chiral drugs and their controlled release. From the practical application, enantioselective release is applicable to a pair of enantiomers, while the Eutomer plays a role, the Distomer has no obvious toxic side effects.
At present, the study of selective release of chiral drugs is almost completed in vitro. If the study of release in vivo is carried out, the complex human environment will have an unexpected impact on the selective release of chiral drugs. In vivo release studies, other issues also need to be concerned, such as whether chiral drugs, even chiral carriers and other chiral substances will be racemized and toxic to the human body after entering the human body.
High efficacy, less side effects and less dosage are the development trend of current drug research. Chiral pure drugs can meet these requirements, so they are becoming the main direction of new drug research and development in the future. With more and more attention paid to chiral drugs, their production and consumption will also increase, so the use of chiral drugs needs to be rationalized and standardized. The irrational use and over-exploitation of chiral drugs may destroy the original chiral balance of nature and bring new problems to nature and human beings themselves.
It should also be emphasized that the chiral reversal phenomenon during the release of chiral drugs and the enantioselectivity of achiral drugs in chiral environment need to be systematically and thoroughly studied. These studies will further enhance our understanding of chirality and the chiral world, and may also provide more clues to solve the scientific problem of "the origin of chirality".

References

Publishing order | Descend order by publishing year | Descend order by cited within
[1]

Asghar W, Pittman E, Jamali F. DARU J. Pharm. Sci., 2015, 23(1): 1.
[2]

Eriksson T, Björkman S, Höglund P. Eur. J. Clin. Pharmacol., 2001, 57(5): 365.
[3]

Agranat I, Wainschtein S R, Zusman E Z. Nat. Rev. Drug Discov., 2012, 11(12): 972.
[4]

Cheng J, Huang Y D, Mi L, Chen W J, Wang D, Wang Q H. J. Ind. Microbiol. Biotechnol., 2018, 45(6): 405.
[5]

Pérez-García F, Max Risse J, Friehs K, Wendisch V F. Biotechnol. J., 2017, 12(7): 1600646.
[6]

Shaw S, White J D. Chem. Rev., 2019, 119(16): 9381.
[7]

Chrzanowska M, Grajewska A, Rozwadowska M D. Chem. Rev., 2016, 116(19): 12369.
[8]

Gu Z G, Zhan C H, Zhang J, Bu X H. Chem. Soc. Rev., 2016, 45(11): 3122.
[9]

Huang X Y, Pei D, Liu J F, Di D L. J. Chromatogr. A, 2018, 1531: 1.
[10]

Meyer V R, Rais M. Chirality, 1989, 1(2): 167.
[11]

Sanjoy M, Sujoy D, Arun N K. Soft Matter, 2020, 16(6): 1404.
[12]

Yazdi M K, Vatanpour V, Taghizadeh A, Taghizadeh M, Ganjali M R, Munir M T, Habibzadeh S, Saeb M R, Ghaedi M. Mater. Sci. Eng.: C, 2020, 114: 111023.
[13]

Maiorov V A. Opt. Spectrosc., 2020, 128(3): 367.
[14]

Motealleh A, Seda Kehr N. ACS Appl. Mater. Interfaces, 2017, 9(39): 33674.
[15]

Dou X Q, Mehwish N, Zhao C L, Liu J Y, Xing C, Feng C L. Acc. Chem. Res., 2020, 53(4): 852.
[16]

Zhou Q, Dong C Y, Fan W F, Jiang H P, Xiang J J, Qiu N S, Piao Y, Xie T, Luo Y W, Li Z C, Liu F S, Shen Y Q. Biomaterials, 2020, 240: 119902.
[17]

Song W Q, Qian L W. Sep. Purif. Technol., 2017, 182: 247.
[18]

McNeel K E, Siraj N, Negulescu I, Warner I M. Talanta, 2018, 177: 66.
[19]

Sacchetti A, Rossi F, Rossetti A, Pesa R, Mauri E. Chem. Pap., 2016, 70(4): 436.
[20]

Zhang Y N, Yang D, Han J L, Zhou J, Jin Q X, Liu M H, Duan P F. Langmuir, 2018, 34(20): 5821.
[21]

Motealleh A, Hermes H, Jose J, Kehr N S. Nanomed.: Nanotechnol. Biol. Med., 2018, 14(2): 247.
[22]

Tobis J, Thomann Y, Tiller J C. Polymer, 2010, 51(1): 35.
[23]

Shi L, Xie P, Li Z M, Wu Y P, Deng J P. Macromol. Chem. Phys., 2013, 214(12): 1375.
[24]

Xie P, Liu X, Cheng R, Wu Y P, Deng J P. Ind. Eng. Chem. Res., 2014, 53(19): 8069.
[25]

Cheng R, Liu J, Xie P, Wu Y P, Deng J P. Polymer, 2015, 68: 246.
[26]

Candau F, Selb J. Adv. Colloid Interface Sci., 1999, 79(2/3): 149.
[27]

Zheng X D, Tong Y P, Xie F Y. Guangdong Trace Elem. Sci., 2016, 23(12): 59.
[28]

(郑晓丹, 童义平, 谢飞燕. 广东微量元素科学, 2016, 23(12): 59.)
[29]

Schuur B, Verkuijl B J V, Minnaard A J, de Vries J G, Heeres H J,, Feringa B L. Org. Biomol. Chem., 2011, 9(1): 36.
[30]

Wang R, Wan X H, Zhang J. Chem. Commun., 2019, 55(32): 4711.
[31]

Wang H L, Yong X Y, Huang H J, Yu H L, Wu Y P, Deng J P. Polym. Chem., 2019, 10(14): 1780.
[32]

Medina D D, Mastai Y. Isr. J. Chem., 2018, 58(12): 1330.
[33]

Zhao Y B, Zhang X C, Li W, Zhang A. Eur. Polym. J., 2019, 118: 275.
[34]

Siriwardane D A, Kulikov O, Reuther J F, Novak B M. Macromolecules, 2017, 50(3): 832.
[35]

Wang Q, Huang J, Jiang Z Q, Zhou L, Liu N, Wu Z Q. Polymer, 2018, 136: 92.
[36]

Wang Q, Chu B F, Chu J H, Liu N, Wu Z Q. ACS Macro Lett., 2018, 7(2): 127.
[37]

Chen B, Song C, Luo X F, Deng J P, Yang W T. Macromol. Rapid Commun., 2011, 32(24): 1986.
[38]

Song C, Zhang C H, Wang F J, Yang W T, Deng J P. Polym. Chem., 2013, 4(3): 645.
[39]

Liang J Y, Deng J P. J. Mater. Chem. B, 2016, 4(39): 6437.
[40]

Deng X S, Liang J Y, Deng J P. Chem. Eng. J., 2016, 306: 1162.
[41]

Zhao D Y, Yu H L, Mei S, Pan K, Deng J P. Ind. Eng. Chem. Res., 2019, 58(2): 1105.
[42]

Liang J Y, Yang B W, Deng J P. Chem. Eng. J., 2018, 344: 262.
[43]

Chen B, Deng J P, Yang W T. Adv. Funct. Mater., 2011, 21(12): 2345.
[44]

Yang B W, Deng J P. J. Mater. Sci., 2018, 53(16): 11932.
[45]

Liang J Y, Deng J P. Macromolecules, 2018, 51(11): 4003.
[46]

Li H F, Zhang B M, Guo X L. Prog. Chem., 2011, 23(6): 1196.
[47]

(李宏福, 张博明, 郭兴林. 化学进展, 2011, 23(6): 1196.)
[48]

Manoharan V N, Elsesser M T, Pine D J. Science, 2003, 301: 483.
[49]

Walther A, Müller A H E. Chem. Rev., 2013, 113(7): 5194.
[50]

Gong Z, Hueckel T, Yi G R, Sacanna S. Nature, 2017, 550(7675): 234.
[51]

Zhang Y J, Kang L, Huang H J, Deng J P. ACS Appl. Mater. Interfaces, 2020, 12(5): 6319.
[52]

Li P P, Pan K, Deng J P. Nanoscale, 2019, 11(48): 23197.
[53]

Zhao B, Lin J F, Deng J P, Liu D. Macromol. Rapid Commun., 2018, 39(20): 1800072.
[54]

Li W F, Deng J P. ACS Appl. Mater. Interfaces, 2016, 8(25): 16273.
[55]

Siriwardane D A, Kulikov O, Reuther J F, Novak B M. Macromolecules, 2017, 50(3): 832.
[56]

Yu H L, Pan K, Deng J P. Macromolecules, 2018, 51(15): 5656.
[57]

Pourjavadi A, Kohestanian M, Streb C. Mater. Sci. Eng.: C, 2020, 108: 110418.
[58]

Schmaljohann D. Adv. Drug Deliv. Rev., 2006, 58(15): 1655.
[59]

Duan B C, Zou S W, Sun Y, Xu X J. Biomacromolecules, 2019, 20(4): 1567.
[60]

Wang J, Wang T, Chem. J. Chin. Univ., 2020, 41(3): 377.
[61]

(王军, 王铁. 高等学校化学学报, 2020, 41(3): 377.)
[62]

Luo Z L, Yue Y Y, Zhang Y F, Yuan X, Gong J P, Wang L L, He B, Liu Z, Sun Y L, Liu J, Hu M F, Zheng J. Biomaterials, 2013, 34(21): 4902.
[63]

Lin D W, Xing Q G, Wang Y F, Qi W, Su R X, He Z M. Prog. Chem., 2019, 31(12): 1623.
[64]

(林代武, 邢起国, 王跃飞, 齐崴, 苏荣欣, 何志敏. 化学进展, 2019, 31(12): 1623.)
[65]

Chen X, He Y, Kim Y, Lee M. J. Am. Chem. Soc., 2016, 138(18): 5773.
[66]

Cao W J, Xiong X Y, Gong Y C, Li Z L, Li Y P. China Biotechnol., 2019, 6: 62.
[67]

(曹文杰, 熊向源, 龚妍春, 李资玲, 李玉萍. 中国生物工程杂志, 2019, 6: 62.).
[68]

Yan T F, Li F, Qi S W, Tian J, Tian R Z, Hou J X, Luo Q, Dong Z Y, Xu J Y, Liu J Q. Chem. Commun., 2020, 56(1): 149.
[69]

Farah S, Anderson D G, Langer R. Adv. Drug Deliv. Rev., 2016, 107: 367.
[70]

Yong X Y, Hu Q S, Zhou E G, Deng J P, Wu Y P. ACS Biomater. Sci. Eng., 2019, 5(10): 5072.
[71]

Khodabandeh A, Arrua R D, Coad B R, Rodemann T, Ohigashi T, Kosugi N, Thickett S C, Hilder E F. Polym. Chem., 2018, 9(2): 213.
[72]

Zhao C S, Nie S Q, Tang M, Sun S D. Prog. Polym. Sci., 2011, 36(11): 1499.
[73]

Chen X X, Sun W W, Yang C Y, Yang R, Yuan L M. Membr. Sci. Technol., 2020, 40(1): 78.
[74]

(谌学先, 孙维维, 杨璨瑜, 杨蕊, 袁黎明. 膜科学与技术, 2020, 40(1): 78.)
[75]

Wang S B. Microporous Mesoporous Mater., 2009, 117(1/2): 1.
[76]

Bagheri E, Ansari L, Abnous K, Taghdisi S M, Charbgoo F, Ramezani M, Alibolandi M. J. Control. Release, 2018, 277: 57.
[77]

Bakhshian Nik A, Zare H, Razavi S, Mohammadi H, Torab Ahmadi P, Yazdani N, Bayandori M, Rabiee N, Izadi Mobarakeh J. Microporous Mesoporous Mater., 2020, 299: 110115.
[78]

Wang J G, Wang W Q, Sun P C, Yuan Z Y, Li B H, Jin Q H, Ding D T, Chen T H. J. Mater. Chem., 2006, 16(42): 4117.
[79]

Zengin A, Cinar G, Guler M O. Curr. Appl. Phys., 2017, 17(5): 785.
[80]

Yokoi T, Yamataka Y, Ara Y, Sato S, Kubota Y, Tatsumi T. Microporous Mesoporous Mater., 2007, 103(1/3): 20.
[81]

Park K W, Kim J Y, Seo H J, Kwon O Y. Sci. Rep., 2019, 9(1): 13360.
[82]

Wang B, Chi C, Shan W, Zhang Y H, Ren N, Yang W L, Tang Y. Angew. Chem. Int. Ed., 2006, 45(13): 2088.
[83]

Li J, Xu L, Yang B X, Bao Z H, Pan W S, Li S M. Mater. Sci. Eng.: C, 2015, 55: 367.
[84]

Lu T, Li G J, Li J. Microporous Mesoporous Mater., 2020, 294: 109834.
[85]

Yu H L, Yong X Y, Liang J Y, Deng J P, Wu Y P. Ind. Eng. Chem. Res., 2016, 55(21): 6037.
[86]

Song L J, Pan M, Zhao R, Deng J P, Wu Y P. J. Control. Release, 2020, 324: 156.
[87]

Li H R, Li H T, Wei C, Ke J, Li J, Xu L, Liu H Z, Yang Y, Li S M, Yang M S. Eur. J. Pharm. Sci., 2018, 117: 321.
[88]

Li H R, Song L N, Hu B B, Li Z, Li S M, Wang Z Y. J. Shenyang Pharmaceut. Univ., 2017, 4: 15.
[89]

(李鹤然, 宋立娜, 胡贝贝, 李贞, 李三鸣, 王中彦. 沈阳药科大学学报, 2017, 4: 15.).
[90]

Cui M S, Xie L Y, Zhang S W, Chen L, Xi Y R, Wang Y M, Guo Y Y, Xu L. Colloids Surf. B: Biointerfaces, 2019, 184: 110483.
[91]

Pu Y Y, Li Y, Zhuang W, Zhang M, Li B Z, Yang Y G. Chin. Chem. Lett., 2012, 23(10): 1201.
[92]

Zhang W, Zheng N, Chen L, Xie L Y, Cui M S, Li S M, Xu L. Pharmaceutics, 2018, 11(1): 4.
[93]

Wang Y M, Li W, Liu T T, Xu L, Guo Y Y, Ke J, Li S M, Li H R. Mater. Sci. Eng.: C, 2019, 103: 109737.
[94]

Guo Z, Du Y, Liu X B, Ng S C, Chen Y, Yang Y H. Nanotechnology, 2010, 21(16): 165103.
[95]

Wulff G, Sarhan A, Zabrocki K. Tetrahedron Lett., 1973, 14(44): 4329.
[96]

Andersson L, Ekberg B, Mosbach K. Tetrahedron Lett., 1985, 26(30): 3623.
[97]

Hosoya K, Yoshizako K, Shirasu Y, Kimata K, Araki T, Tanaka N, Haginaka J. J. Chromatogr. A, 1996, 728(1/2): 139.
[98]

Luliński P. Mater. Sci. Eng.: C, 2017, 76: 1344.
[99]

Zhang H Q. Adv. Mater., 2020, 32(3): 1806328.
[100]

Tuwahatu C A, Yeung C C, Lam Y W, Roy V A L. J. Control. Release, 2018, 287: 24.
[101]

Beyazit S, Tse Sum Bui B, Haupt K, Gonzato C. Prog. Polym. Sci., 2016, 62: 1.
[102]

Haupt K, Medina Rangel P X, Bui B T S. Chem. Rev., 2020, 120(17): 9554.
[103]

Gaálová J, Yalcinkaya F, Cuřínová P, Kohout M, Yalcinkaya B, Koštejn M, Jirsák J, Stibor I, Bara J E, van der Bruggen B, Izák P. J. Membr. Sci., 2020, 596: 117728.
[104]

Goyal G, Bhakta S, Mishra P. ACS Appl. Nano Mater., 2019, 2(10): 6747.
[105]

Liu Y, Li Z Q, Jia L. J. Chromatogr. A, 2020, 1622: 461147.
[106]

Li Z Y, Liu Z S, Zhang Q W, Duan H Q. Chin. Chem. Lett., 2007, 18(3): 322.
[107]

Jaiswal L, Rakkit S, Pochin K, Jaisamut P, Tanthana C, Tanmanee N, Srichana T, Suedee R. Process. Biochem., 2015, 50(12): 2035.
[108]

Monier M, Youssef I, Abdel-Latif D A. Chem. Eng. J., 2019, 356: 693.
[109]

Liu Y J, Liu Y C, Liu Z M, Zhao X C, Wei J T, Liu H C, Si X X, Xu Z G, Cai Z W. J. Hazard. Mater., 2020, 392: 122251.
[110]

Liang J Y, Wu Y, Deng J P. ACS Appl. Mater. Interfaces, 2016, 8(19): 12494.
[111]

Yin J F, Cui Y, Yang G L, Wang H L. Chem. Commun., 2010, 46(41): 7688.
[112]

Kao C L, Chen Y F, Huang P C, Hsu C Y, Kuei C H. RSC Adv., 2015, 5(20): 15511.
[113]

Sajini T, Thomas R, Mathew B. Polymer, 2019, 173: 127.
[114]

Kupai J, Rojik E, Huszthy P, Szekely G. ACS Appl. Mater. Interfaces, 2015, 7(18): 9516.
[115]

Ribeiro A R L, Maia A S, Ribeiro C, Tiritan M E. Trac Trends Anal. Chem., 2020, 124: 115783.
[116]

Ribeiro C, Santos C, Gonçalves V, Ramos A, Afonso C, Tiritan M. Molecules, 2018, 23(2): 262.

Funding

National Natural Science Foundation of China(21774009)

National Natural Science Foundation of China(51973011)

National Natural Science Foundation of China(21474007)

Fundamental Research Funds for the Central Universities(XK1802-02)

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