Optically Active Microspheres Containing Schiff Base - ACS Publications

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Optically Active Microspheres Containing Schiff-base: Preparation and Enantio-differentiating Release towards Drug Citronellal Danyu Zhao, Huli Yu, Song Mei, Kai Pan, and Jianping Deng Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.8b05307 • Publication Date (Web): 02 Jan 2019 Downloaded from http://pubs.acs.org on January 3, 2019

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Industrial & Engineering Chemistry Research

Optically Active Microspheres Containing Schiffbase:

Preparation

and

Enantio-differentiating

Release towards Drug Citronellal Danyu Zhao,a,b Huli Yu,a,b Song Mei,a,b Kai Pan,*b Jianping Deng*a,b a State

Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China

b

College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China

*E-mail: [email protected]; [email protected] KEYWORDS: Optical activity; Schiff-base; Helical polymeric particle; Enantiodifferentiating release; Citronellal.

ABSTRACT: This article reports an innovative type of drug-loaded microspheres prepared by precipitation polymerization. The microspheres consist of optically active helical substituted polyacetylene main chains and Schiff base side groups, in which the former provides helical chirality while the latter one is used for chiral citronellal loading. SEM images showed that microspheres with average size about 1 µm were synthesized. Circular dichroism (CD) and UV-vis absorption spectra demonstrated that the polymer chains existed in predominantly one-handed helical structures which contributed largely to the optical 1

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activity of the microspheres. The helical structure of polymer and the Schiff base endowed the microspheres with pH- and time-dependent properties and enantio-differentiating resolution capacity towards citronellal. The novel optically active microspheres have potential applications in the fields of chiral drug separation and release, biomedicine, etc.

1. INTRODUCTION The applications of Schiff bases have received ever-increasing attention because the characteristic chemical bond [-(C=N)-] has excellent ion coordinative capability1,2 and pHresponsive ability.3 Schiff bases and the derivatives have been widely used for developing catalyst intermediates,4,5 biological sterilizations,6,7 fluorescent reagents,8,9 self-assembled polymers10,11 and polymer stabilizers.12 More recently, it was reported that Schiff base can be used as electrode for batteries13 and be used to prepare MOFs14,15 and COFs.16 In brief, Schiff bases have been taken as a versatile platform by scientists from diverse disciplines to develop new architectures and materials for respective targets. As an important sub-category of Schiff bases, chiral Schiff bases have been often used as fluorescence-based enantio-selective sensors17 because of their fluorescent variability18,19 and as intermediates to produce chiral materials.20,21 In spite of the excellent studies, there are only few studies focusing on chiral Schiff bases showing excellent pH-responsivity3,22 and especially used in chiral applications. So in the present study we attempted to prepare microspheres integrating chiral Schiff bases and optically active helical polymers, which were expected to show potential applications in enantio-differentiating release of chiral drugs, taking advantage of the pH-responsivity derived from Schiff bases and the enantioselectivity from chiral helical polymers. Optically active microspheres, in particular those consisting of helical polymers, have constituted a new, active research area.23–29 Such chiral microspheres are anticipated to find wide applications in significant fields such as chiral resolution30 and enantioselective 2


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crystallization31 because of the large specific surface area. Compared with other methods for preparing microspheres, including suspension polymerization,32 emulsion polymerization33 and dispersion polymerization,34 precipitation polymerizations are relatively simpler and provide pure particulate products; in particular, precipitation polymerizations can be realized in the absence of water phase.35,36 These advantages become quite significant for the cases involving Schiff base due to its possible water-sensitivity. In the context mentioned above and based on our earlier studies dealing with helical polyacetylenes,27,37–39 we in this study prepared chiral helical polyacetylene microspheres loaded with chiral citronellal drugs by precipitation polymerization. Herein, citronellal was selected as the representative of aldehyde-containing chiral drugs because of its significant medicinal values and wide applications. Specifically, citronellal has been widely used as fungicide and spice.40 (-)-Citronellal was reportedly to cure cancer by affecting cancer cell signaling via an olfactory receptor without damages.41 However, (+)-citronellal would lead to cell membrane disruption and affect hormone balance.42 For this reason, it shows great significance to separate chiral (-)-citronellal from the racemic mixture and release it as a therapeutic drug under appropriate conditions. Based both on the context above and our previous research,43 we first transformed citronellal to a monomer through forming Schiff base and then immobilized citronellal in the resulting microspheres by precipitation copolymerization with one chiral substituted acetylene monomer. The resulting microspheres were not only found to be able to enantio-differentiatingly release citronellal, but also showed pH-responsivity in releasing the chiral drugs. These interesting features make the microspheres have potential application prospects as chiral drug carriers. 2. EXPERIMENTAL SECTION 2.1 Materials. 4-Ethynylaniline (4-EA) (TCI), (R)- and (S)-2-phenylpropanoicacid (BASF), 1,4-diethynylbenzene (DEB), (+)-citronellal (C+) (TCI), (-)-citronellal (C-) (TCI) and rac3



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citronellal (TCI) were used without further purification. HCl and NaOH were purchased from Beijing Tong Guang Fine Chemicals Company (China) and used to prepare drug release solutions of different pH. Butanone, n-heptane, N,N-dimethylacetamide (DMAc) and all other solvents were purchased from Beijing Chemical Reagents Co. (China), and were distilled by standard methods before use. Freshly deionized water was used in all of the experiments. Chiral alkyne monomer 1 ((S or R)-2-phenyl-N-(prop-2-yn-1-yl) propanamide, abbreviated as M1R or M1S, as presented in Figure S1) and rhodium catalyst (nbd)Rh+B-(C6H5)4 (nbd=2,5-norbornadiene) were prepared according to the literature.44 2.2 Measurements. Fourier transform infrared spectroscopy (FT-IR) spectra (KBr pellet) were recorded using a Nicolet NEXUS 670 spectrophotometer. 1H-NMR spectra (nuclear magnetic resonance 400 MHz) were recorded by using a Bruker AV400 spectrometer at 20 oC.

Elemental analysis was performed on a Vario EL cube (Elementar Analysensysteme

GmbH). S-4800 electron microscope (SEM, Hitachi) was used to observe the morphology of microspheres. Jasco-810 spectropolarimeter was used as a tool to record circular dichroism (CD) and UV-vis absorption spectra. Using sodium lamp (k=589 nm) as light source, optical rotations were measured on IP-digi300/2 digital polarimeter (Shanghai InsMark Instrument Technology Co.) at room temperature. The content of C+ or C- (i.e. (+)-citronellal and (-)citronellal, respectively) was measured by 756MC UV-vis spectrophotometer (Shanghai Jinghua Technology Instrument) at the specific maximum absorption wavelength (208 nm). The coefficient of variation (CV) was calculated by image analyzer software, and it is the ratio of standard variation to the average diameter (Dn) according to the following equation: 1

𝑘

Average diameter (Dn)=𝑘∑𝑖 = 1𝐷𝑖 1

CV=𝐷𝑛

[

𝑘 ∑𝑖 = 1(𝐷𝑖

― 𝐷𝑛)

𝑘―1

(1)

1 2 2

] ×100%

(2)

4


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In the formula, k is the total number of counted particles; Di means the diameter of the number i particle.45 2.3 Preparation of chiral Schiff base (SCB). In order to increase the drug loading amount, 4-ethynylaniline (4-EA) reacted with citronellal in advance because Schiff base reaction is a reversible process and the reaction rate is much slower than the rate of acetylene polymerization. A typical method to prepare the Schiff base intermediate (SCB) is exemplified below. Under nitrogen atmosphere, 4-EA (0.2 mmol) and citronellal (0.2 mmol, (+)-citronellal, (-)-citronellal or rac-citronellal) were dissolved together in butanone (2 mL). The reaction solution was performed at 45 oC with magnetic stirring at a rate of 300 rpm. After 12 hours, the reaction tube was cooled to room temperature. It should be pointed out that Schiff base reactions are often taken as intermediate reaction in ‘one-pot’ synthesis because the conversion of the reversible reaction is not high enough and the chemical bond [(C=N)-] is easily broken.46,47 In our experiment, the Schiff base intermediate (SCB) could not be purified by recrystallization and chromatographic column. Therefore, the Schiff base intermediate (SCB) was characterized by FT-IR and 1H-NMR measurements directly using the reaction mixture, which was also directly used to perform copolymerization for constructing microspheres. 2.4 Preparation of microspheres. For the preparation of microspheres, Chiral alkyne monomer 1 ((S or R)-2-phenyl-N-(prop-2-yn-1-yl) propargylamide, abbreviated as M1R or M1S 0.3 mmol, characterized by 1H-NMR and FT-IR in Figures S2 and S3) was mixed with SCB solution (2 mL) as-obtained above. After the solids were completely dissolved, nheptane (3 mL) was added into the monomer solution. Then the mixture of DEB (0.085 mmol) and Rh catalyst (6.7×10-3 mmol, 1 mol% of the total amount of alkynyl groups) dissolved in butanone (1 mL) was transferred into the monomer solution. The polymerization was carried out under N2 at 30 oC. After 24 h, the microspheres were collected and purified. To wash off 5



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unreacted monomers and drugs, the products from precipitation polymerization were welldispersed in DMAc and centrifuged at a speed of 10000 rpm. The process was repeated in THF until the supernatant became colorless and showed no UV-vis absorption. Then the microspheres were dispersed in THF (2 mL), which was dropped into n-hexane (50 mL). After 6 hours, the microspheres precipitated at the bottom and were collected by filtering. The other copolymer microspheres were prepared in the same method. Table 1 shows the recipes for preparing six kinds of microspheres. Table 1. Recipes for Preparing Microspheresa SCB

Chiral Alkyne Monomer 1 (mmol)

4-EA (mmol)

Citronellal (mmol)

P[M1R-co-SCB(-)]

M1R 0.3

0.2

C- 0.2

P[M1R-co-SCB(+)]

M1R 0.3

0.2

C+ 0.2

P[M1S-co-SCB(-)]

M1S 0.3

0.2

C- 0.2

P[M1S-co-SCB(+)]

M1S 0.3

0.2

C- 0.2

P[M1R-co-SCB(rac)]

M1R 0.3

0.2

Rac 0.2

P[M1S-co-SCB(rac)]

M1S 0.3

0.2

Rac 0.2

aDEB,

0.085 mmol; Rh cat., 6.7×10-3 mmol (1 mol% of the total amount of alkynyl groups).

2.5 Enantio-differentiating release of microspheres. Release experiments were conducted in the mixed solvent of aqueous/ethanol (volume ratio, 1/9). To test the effects of acidity or alkalinity on enantio-differentiating release, we adjusted the pH value of aqueous/ethanol solution by adding a little amount of HCl or NaOH. For analysis, solution (pH-7) indicates a neutral condition, while pH 7 mean acidic and alkaline conditions, respectively. Final drug release amount (Q) was calculated by the following formula: Q=cV/M

(3)

6


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In the formula, V is the amount of solvent volume in the release system; c is the concentration of citronellal in release solution (determined by UV absorption at the wavelength of 208 nm); M is the weight of microspheres used for release experiment. In our measurements, citronellal was found to be unable to pass through HPLC columns and might cause damage to columns. Therefore, enantiomer excess (e.e.) values were measured by CD and UV-vis spectra and calculated according to the equation (4) 48: 𝜃

Enantiomer excess (e.e.) (%) = 𝜃𝑚𝑎𝑥×100

(4)

where θ is CD value of the released solution and θmax is CD value of the single enantiomer solution at the wavelength of 300 nm. The release solution and single enantiomer solution were kept at the same condition according to the UV absorption. 3. RESULTS AND DISCUSSION 3.1 Preparation of microspheres

Scheme 1. Schematic strategy for preparing optically active microspheres containing Schiffbase and for enantio-differentiating release towards citronellal enantiomers. Optically active microspheres containing Schiff base were prepared by precipitation polymerization in Scheme 1, in which 4-EA simultaneously provides alkyne groups to copolymerize with chiral alkyne monomer 1 and amino groups to form Schiff base for drug 7



loading. Citronellal is chosen as the chiral drug model, which combines with 4-EA to form SCB before polymerization. For conducting release applications, optically active microspheres are cross-linked by DEB, which is selected as cross-linker because of its high polymerization activity.49 Release profiles are all applied in water/ethanol solution with varied pH of water, and the detailed results will be discussed below.

Figure 1. FT-IR spectra of (A) citronellal, (B) 4-EA, (C) SCB and (D) microspheres. The FT-IR spectra were measured by KBr tablet. Considering that Schiff base reaction is a reversible process and the reaction rate is much slower than the rate of acetylene polymerization, 4-EA and citronellal reacted in advance to increase the drug loading amount. The SCB intermediate was characterized by FT-IR and 1HNMR measurements because the Schiff base intermediate decomposed when it passed through the chromatographic column and could not be purified by recrystallization. As shown in Figure 1, the sharp peaks at 3385 cm-1 and 3487 cm-1 were ascribed to primary amine groups vibration absorption in 4-EA (Figure 1B), which became obviously weaker in the 8


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SCB intermediate from the Schiff base reaction (Figure 1C). In addition, the vibration absorption peaks of aldehyde groups at 1723 cm-1 and 2715 cm-1 in citronellal (Figure 1A) almost disappeared after the Schiff base reaction (Figure 1C), and a new peak at 1645 cm-1 was attributed to [-(C=N)-] in the SCB intermediate (Figure 1C). It was worth noting that the characteristic peak of the (-C ≡ C-) at 2100 cm-1 was reserved. Therefore, these results indicated the formation of SCB intermediate and [-(C=N)-], by which the chiral drug of citronellal was loaded. The drug loading amount was calculated by the conversion rate of the SCB reaction, which was 47.0% according to 1H-NMR spectrum (Figure S4) and elemental analysis experiment (Table S1). By precipitation polymerization, microspheres composed of helical polymers and chiral drugs were prepared (Figure 1D). As expected, the absorption peak of the bond (-C≡C-) in raw materials at 2096 cm-1 disappeared after polymerization. The characteristic peak of [(C=N)-] was observed at 1645 cm-1 and there was no absorption signal at 1723 cm-1 and 2715 cm-1, indicating that [-(C=N)-] was not decomposed into amino groups (-NH2) and aldehyde groups (-CHO) because the precipitation polymerization system was completely anhydrous. These results showed that the polymerization process did not destroy the Schiff base and the chiral drugs of citronellal were successfully immobilized in the microspheres. To explore the morphology of microspheres, SEM images were observed. On the basis of the earlier studies,43 we set the ratio of butanone/n-heptane to 3.0/3.0 (mL/mL) in the reaction system. Considering that the stereo-configuration of citronellal may influence the morphology of microspheres, chiral alkyne monomer 1 (M1R or M1S) copolymerized with SCB containing (+)-citronellal, (-)-citronellal and rac-citronellal, respectively. As shown in Figure 2, six kinds of microspheres all demonstrated regular spherical shape and smooth surface. 9



Figure 2. SEM images of microspheres prepared under the ratio of butanone/nheptane=3.0/3.0 (mL/ mL). (A) P[M1-co-SCB(-)], (B) P[M1R-co-SCB(+)], (C) P[M1S-coSCB(-)], (D) P[M1S-co-SCB(+)], (E) P[M1R-co-SCB(rac)], (F) P[M1S-co-SCB(rac)]. The particle size distributions of microspheres were almost the same and the average sizes were 0.90±0.07 µm, determined by image analyzer software (based on 200 particles), as demonstrated in Table 2. Therefore, microspheres containing chiral citronellal drugs were successfully prepared by precipitation polymerization and the stereo-configuration of chirality citronellal had no effect on the morphology of resulting microspheres. To ensure the 10


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purity of the drug when it was released, the microspheres were cleaned 7 times in different organic solvents (DMAc and THF) by ultrasound and centrifugation, and the final yields of all kinds of particles were about 60%. Table 2. Average particle size of microspheres Microsphere

Yield (%)

Average particle size (µm)

CV (%)

P[M1R-co-SCB(-)]

59.3

0.95

5.3

P[M1R-co-SCB(+)]

57.8

0.87

7.9

P[M1S-co-SCB(-)]

60.2

0.84

6.5

P[M1S-co-SCB(+)]

62.6

0.92

7.6

P[M1R-co-SCB(rac)]

64.4

0.83

7.8

P[M1S-co-SCB(rac)]

60.6

0.93

7.0

The number of particle size statistics i was set at 200.

Figure 3. (A) CD spectra and (B) UV-vis spectra of microspheres (P[M1R-co-SCB(-)], P[M1Rco-SCB(+)], P[M1S-co-SCB(-)], P[M1S-co-SCB(+)], P[M1R-co-SCB(rac)], P[M1S-co-SCB(rac)]) prepared at the ratio of butanone/n-heptane=3.0/3.0 (mL/mL). The microspheres (0.2 mg/mL) were dispersed in CHCl3 by sonication for the measurement. 3.2 Optical activity of microspheres. 11



All the helical structures mentioned in the manuscript refer to the polymer conformations at molecular level, which are still difficult to be directly observed by HRTEM or AFM due to the limited resolution and especially the limited macromolecular scales. As a typical helical polymer, polyacetylenes with polymer chains forming predominantly one-handed helical structures demonstrated optical activity, which have been confirmed by CD and UV-vis measurements.50,51 In our experiment, optical activity of microspheres was due to the helical polyacetylenes with polymer chains adopting predominantly one-handed helicity, as proved by CD and UV-vis spectra in Figure 3. The samples were measured in CHCl3 by ultrasonic dispersion with a concentration of 0.2 mg/mL. As showed in Figure 3A, microspheres all showed obvious CD signals at the wavelength between 400 and 600 nm, indicating that microspheres were optically active. According to our early studies, the conjugated substituted polyacetylene chains derived from chiral monomers can maintain stable one-handed helical structure, contributing to the optical activity of microspheres.52,53 Herein, the microspheres were constructed by helical polymers from chiral alkyne monomers, and meanwhile contained chiral citronellal drugs. To explore the origin of microspheres’ optical activity, microspheres (P[M1R-co-SCB(-)], P[M1Rco-SCB(+)], P[M1S-co-SCB(-)], P[M1S-co-SCB(+)], P[M1R-co-SCB(rac)], P[M1S-co-SCB(rac)]) were all measured by CD spectra. The results were demonstrated in Figure 3A. Both P[M1Rco-SCB(-)], P[M1R-co-SCB(+)] and P[M1R-co-SCB(rac)] had negative cotton effect, while P[M1S-co-SCB(-)], P[M1S-co-SCB(+)] and P[M1S-co-SCB(rac)] showed positive cotton effect, and there was no CD absorptions in SCB intermediate at 330 nm (Figure S5). Besides, corresponding UV absorptions (Figure 3B) could be observed at wavelength between 400 and 600 nm due to conjugated substituted polyacetylene chains.52,53 The intensity difference in the UV absorptions was due to insolubility of microspheres, which was measured by dispersion in CHCl3. The results are in accordance with CD spectra of non-crosslinked 12


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copolymer (Figure S6). Without DEB, the copolymer (M1R-co-SCB(rac)) demonstrated negative cotton effect, while the copolymer (M1S-co-SCB(rac)) demonstrated positive cotton effect at wavelength between 400 and 600 nm, further proving that the optical activity of microspheres was decided by helical polymers and the helicity of the copolymer was at molecular level. Further the polymers helicity was originated from chiral alkyne monomers but not chiral citronellal drugs. 3.3 Enantio-differentiating release of microspheres

Figure 4. Time-release curves of (-)-citronellal released by P[M1R-co-SCB(-)] (A) and the maximum release amounts of P[M1R-co-SCB(-)] in solutions (the volume ratio, water/ethanol =1/9) at different pH (B). For clear expression in the diagram, the solution for release at pH=1 is abbreviated as Sol. 1 in Figure 4B, and the same for the others. Owing to the reversible property of SCB, we first investigated the release behavior of chiral drugs covalently bonded by [-(C=N)-] in microspheres under different pH values. Taking the release profile of (-)-citronellal in P[M1R-co-SCB(-)] as an example, the release process was carried out in the mixed solution (volume ratio, water/ethanol=1/9) because the citronellal is only slightly soluble in water. The release systems were recorded as solution (pH-1, 3, 5, 7, 11). By UV-vis spectra analysis, the results are shown in Figure 4. Calculated by 1H-NMR spectrum (Figure S4), the theoretical value of citronellal released by microspheres was 167 13



mg/g. In systems of solution (pH-1, 3, 5), the maximum release amounts were about 160 mg/g. With pH increasing, the maximum release amounts reduced to 107 and 15 in solution (pH-7) and solution (pH-11), respectively. Besides, the release rate of (-)-citronellal slowed down with the decreasing of acidity from solution (pH-1) to solution (pH-11). The above experimental phenomena can be explained by the pH-dependence of Schiff base. According to earlier reports,54,55 Schiff base can be hydrolyzed completely by acid in the presence of water, but keep stable in alkaline environment. To explore the effects of different enantiomers of monomer 1 and SCB on drug loading and release results, the curves of other microspheres (P[M1R-co-SCB(+)],P[M1S-co-SCB(-)],P[M1Sco-SCB(+)]) released under the same experimental conditions are shown in Figure S7. The results showed that these microspheres all have similar release behavior, as observed in P[M1R-co-SCB(-)]. Therefore, the release amounts of chiral drugs could be controlled by varying acidity or alkalinity of the release systems. Except for the SCB in microspheres, the helical structures of polymer were also interesting and worthy to be explored, since they largely contributed to the optical activity of microspheres. Therefore, the enantioselective release properties of four kinds of microspheres were investigated and the maximum release amounts of citronellal under different pH values are shown in Figure 5. The maximum release amounts in acidic condition [solution (pH-1, 3, 5)] were almost the same as the calculated theoretical value, because SCB could be broken completely under acidic conditions. As shown in Figure 5A, the maximum drug release amounts from the four microspheres were very close in solution (pH-3), indicating the chirality of monomers and SCB have no influence on the drug loading. Under basic condition solution (pH-11), a little amount of (-)-citronellal or (+)-citronellal was released from the four kinds of microspheres, due to the inhibition of Schiff base decomposition in alkaline environment (pH-11) (Figure 14


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5C). Therefore, no enantioselectivity was demonstrated in either acidic or alkaline solutions. However, there was obvious difference in the release amounts of citronellal in solution (pH-7) (Figure 5B), namely, about 67% of (-)-citronellal and 50% of (+)-citronellal cumulative amount released from P[M1R-co-SCB(-)] and P[M1R-co-SCB(+)] respectively, while 65% of (+)-citronellal and 51% of (-)-citronellal in P[M1S-co-SCB(+)] and P[M1S-co-SCB(-)], respectively (Figure 5D). Thus, (-)-citronellal was released preferentially from microspheres prepared from M1R, while (+)-citronellal was released preferentially from microspheres prepared from M1S. Therefore, optically active microspheres demonstrated the capability of enantio-differentiating towards citronellal drugs in solution (pH-7).

Figure 5. The maximum release amounts of citronellal from four kinds of microspheres (P[M1R-co-SCB(-)], P[M1R-co-SCB(+)], P[M1S-co-SCB(-)], P[M1S-co-SCB(+)]) under (A) acid condition, (B) neutral condition and (C) alkaline condition; (D) ratios of release amount of neutral condition to acid condition. PR-(-) represents P[M1R-co-SCB(-)], in which R means1R, and (-) means (-)-citronellal; similar definition was taken for the others. 15



The CD and UV-vis absorption curves of drugs released from microspheres in solution (pH-7) are compared to monomer 1 and single enantiomer of citronellal in Figure S8. For more comprehensive information of the release process, we conducted CD and UV-vis absorption measurements directly using release solution sample which contained a few microspheres. Multiple absorption bands were observed from 230 to 370 nm in the UV-vis spectra possibly due to the existence of citronellal with little polymeric microspheres. As we can see, M1R exhibited negative cotton effect at wavelength about 225 nm, and a strong peak also appeared in the corresponding UV-vis absorption spectrum. However, for citronellal, the maximum CD signal and UV-vis absorption appeared at 300 and 208 nm, respectively. which were different from monomer 1. The drugs released from microspheres showed CD signals and UV-vis absorption at the same wavelength of 208 and 300 nm, indicating that the released chiral substance was citronellal. Enantiopure chiral drugs are attracting more and more attention, since in most instances only one of the stereoisomers exhibits the desired pharmacological effect. Developing single enantiomer of chiral drugs meets the requirements of the Food and Drug Administration (FDA).56 During the pharmaceutical or storage process, however, some pure enantiomers may become racemic because of their instability.57 Therefore, it is necessary to build alternative drug delivery systems to realize enantio-differentiating release in some special cases. The new delivery systems may not only decrease the expensive cost of enantiopure chiral drugs, but also may avoid the tedious process for chiral resolution.58 Moreover, enantioselective drug release may provide a novel alternative for realizing selective administration of the preferred stereoisome (eutomer; the opposite isomer is defined as distomer). The above investigations showed that optically active microspheres had enantiodifferentiating ability during the release process in solution (pH-7). To further confirm our

16


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hypothesis, the microspheres P[M1R-co-SCB(rac)] and P[M1S-co-SCB(rac)] loaded racemic citronellal were prepared and the release process was performed in solution (pH-7).

Figure 6. Time-release curves of citronellal released by P[M1R-co-SCB(rac)] and P[M1S-coSCB(rac)] (A); Enantiomeric excess (e.e) value of P[M1R-co-SCB(rac)] and P[M1S-co-SCB(rac)] (B) released in solution (pH-7). According to the definition, enantiomer excess (e.e.) formula can be written as (e.e.) (%) = 𝑄( + ) ― 𝑄( ― ) 𝑄( + ) + 𝑄( ― )

×100 (Q represents the release amount of one enantiomer). The average release

rate of one enantiomer means the release amount within a period of time. In Figure 6, taking P[M1R-co-SCB(rac)] as an example, the maximum enantiomeric excess (e.e) value was about 15% at 100 min and [Q(+)+Q(-)] was 29 mg. Therefore, for 1 g microspheres, the average release rate of (-)-citronellal was about 2.6 mg/h higher than (+)-citronellal within 100 min. However, with longer time, the release rate of (+)-citronellal gradually increased due to more (+)-citronellal than (-)-citronellal remaining in P[M1R-co-SCB(rac)]. Finally, the release gradually tended to reach equilibrium and the release rates of (-)-citronellal and (+)citronellal became nearly equal, which demonstrated a 2% enantiomeric excess. An opposite process occurred in P[M1S-co-SCB(rac)], from which (+)-citronellal was released preferentially due to opposite optical activity compared with P[M1R-co-SCB(rac)]. Accordingly, the enantio17



differentiating release of chiral drugs could be achieved by controlling the optical activity of microspheres. 4. CONCLUSION Optically active microspheres containing helical polymer and Schiff-base were successfully prepared by precipitation polymerization. The microspheres exhibited remarkable optical activity due to the one-handed helical structures, which endowed microspheres with enantiodifferentiating release ability. Besides, it is worth noting that the release behavior of citronellal could be controlled by regulating the pH of release solution due to the pH sensitivity of Schiff base: the release process was facilitated under acidic conditions, but was inhibited under alkaline conditions; in neutral releasing solutions, the chirality of microspheres became the key factor. The present strategy for preparing Schiff basecontaining microspheres provides an innovative method for further designing and fabricating drug-loaded microspheres. The study also builds a bridge linking together polymer chemistry, material science and pharmaceutics. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge. Structure of (S or R)-2-phenyl-N-(prop-2-yn-1-yl) propargylamide (chiral alkyne monomer 1); 1H NMR spectrum and FT-IR spectrum of monomer 1; 1H NMR spectrum of SCB; elemental analysis data for monomer 1 and microsphere; CD spectrum and UV-vis spectrum of SCB(-); CD and UV-vis absorption spectra of non-crosslinked copolymer (M1R-co-SCB(rac) or M1S-co-SCB(rac), 0.015 mg/mL) dispersed in CHCl3; Time-release curves of citronellal released by P[M1R-co-SCB(+)], P[M1S-co-SCB(-)] and P[M1S-co-SCB(+)]; CD spectra and UVvis spectra of M1R, pure chiral citronellal and drugs released from microspheres in Solution (pH-7). 18


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Corresponding Authors *E-mail: [email protected] (Deng); [email protected] (Pan) Notes The authors declare no competing financial interest. Acknowledgements This work was supported by the National Natural Science Foundation of China (21774009, 21474007).

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Optically Active Microspheres Containing Schiffbase:

Preparation

and

Enantio-differentiating

Release towards Drug Citronellal Danyu Zhao,a,b Huli Yu,a,b Song Mei,a,b Kai Pan,*b Jianping Deng*a,b

For Table of Contents use only Synopsis ： Schiff-base containing optically active microspheres were synthesized and applied to enantio-differentiating release towards chiral drug citronellal.

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Optically Active Microspheres Containing Schiff Base - ACS Publications

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