Article Cite This: Macromolecules XXXX, XXX, XXX−XXX
Chiral Particles Consisting of Helical Polylactide and Helical Substituted Polyacetylene: Preparation and Synergistic Effects in Enantio-Differentiating Release Junya Liang and Jianping Deng* State Key Laboratory of Chemical Resource Engineering and College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China S Supporting Information *
ABSTRACT: The present work reports on the synthesis of chiral particles consisting of helical polylactide (PLA) and helical substituted polyacetylene, aiming to investigate the chiral synergetic effects of the two helical components in enantioselectivity. For this purpose, polylactide with polymerizable terminal alkynyl group was prepared and subsequently used as macromer to copolymerize with chiral alkynyl monomer to form the target particles. SEM images demonstrate that the particles possessed porous structures. Circular dichroism shows that the helical substituted polyacetylene had an influence on the helical screw sense of polylactide chains, thereby affecting the enantioselectivity of the chiral particles in releasing the model chiral drug naproxen. Compared with our earlier study on enantioselectivity of PLA, copolymerizing PLA with chiral alkynyl monomer improves PLA’s enantioselectively discriminating ability in naproxen release and even can reverse the particles’ preferential enantioselectivity in releasing naproxen enantiomers.
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INTRODUCTION Polylactide (PLA, also called poly(lactic acid)), as a kind of hydrophobic aliphatic polyesters, is a typical synthetic biopolymer and has been FDA-approved in biomedical applications for clinic due to its biodegradability, biocompatibility, and nontoxicity.1−3 These advantages have made PLAbased materials valuable in stent implants,4 tumor suppressant,5 tissue scaffolds,6 and drug delivery carriers.3,7 Among the various polymer-based drug delivery carriers, micelles/particles have gained significant attention as promising candidates.8−10 However, PLA particles are difficult to form directly in the course of monomer polymerization due to the water/oxygen sensitivity of the widely used Sn catalysts and the high temperature required for them to catalyze the polymerization of lactide.11,12 In addition, the high tendency of PLA to crystallize is another factor unfavorable for PLA to form particles.13 Thus, PLA particles are commonly prepared through emulsification of PLA chains,14 self-assembly of PLA-based block copolymers,15 and graft of PLA chains onto particle cores.16 These preparation methods are tedious and especially show disadvantages in controlling the particle size and morphology. In the present work, we establish a facile and universal approach to fabricate PLA particles using PLA macromer ending with polymerizable groups. PLA particles can be readily prepared by postpolymerizing the polymerizable groups at PLA chain terminals. Following this method, multiple polymerization methods such as emulsion, suspension, and disperse polymerizations can be used to prepare PLA-based particles; moreover, homopolymerization, copolymerization, and even © XXXX American Chemical Society
post-cross-linking of PLA chains also can be realized accordingly. This strategy is also anticipated to provide new approaches for preparing PLA-based brush polymers. PLA is also a chiral helical polymer.17 Poly(L-lactide) (PLLA) and poly(D-lactide) (PDLA) are enantiomeric polymers with opposite helical sense.18 Chiral amplification is reported to occur in PLLA and PDLA due to the helical conformations.19 This behavior is also found via chirality transferring from molecular chirality to hierarchical chirality in assembled PLLA and PDLA.19,20 Additionally, the chirality of PLLA and PDLA, as main chain or side chain, can transfer to other achiral chain segments.21,22 Although the chirality of PLLA and PDLA has attracted much attention, more efforts are still required for exploring PLLA and PDLA as chiral polymers especially in practical applications. Up until now, how the chirality of PLLA and PDLA works in practical applications and what happens when PLLA and PDLA interact with other chiral (macro)molecules have been unexplored yet. Although PLA has been combined with helical substituted polyacetylene22 and helical polyisocyanide,23,24 the chiral effects of PLA in practice remains unknown. In previous studies about chiral helical polymers,25−29 polylactide and substituted polyacetylene can show enantioselectivity in chiral adsorption, chiral release, and induced crystallization.30−32 Moreover, conformational chirality and configurational chirality working together improve the Received: March 18, 2018 Revised: May 2, 2018
A
DOI: 10.1021/acs.macromol.8b00580 Macromolecules XXXX, XXX, XXX−XXX
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Macromolecules enantioselectivity.33 Accordingly, we hypothesize that synergistic effects may occur when helical polylactide and substituted polyacetylene are judiciously combined in one entity. To justify the above-mentioned hypothesis, in this work we first designed and prepared PLLA and PDLA bearing polymerizable alkynyl terminals. Through copolymerizing the obtained polymerizable polylactides with a chiral alkynyl monomer, chiral particles consisting of helical polylactide and helical substituted polyacetylene were prepared and further used as drug carriers to study their enantioselectivity in chiral release. Interestingly, synergistic effects in chiral recognition were indeed observed in the resulting chiral polymeric particles.
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Table 1. Ring-Opening Polymerization of Lactide Initiated by 4-Ethynylaniline and Catalyzed by DBUa sample
monomer
[M]/[I]
yieldb (wt %)
Mnc (g/mol)
DPc
PLLA1 PLLA2 PDLA2
L-LA L-LA D-LA
20 50 50
88 83 86
6700 17900 17800
1.14 1.21 1.13
a
[M] = monomer concentration; [I] = 4-ethynylaniline concentration; reaction conditions: [M] = 1 mol/L, [DBU]/[M] = 0.04, [BA]/[I] = 2 (in mol), in CH2Cl2 at 30 °C. bEthanol-insoluble part. cMeasured by GPC (polystyrene as standards; THF as eluent). an ice bath. After 30 min, a solution of Rh catalyst (0.002 g, 0.003 mmol, [Rh catalyst]/[CC] = 0.02, in mol) in 0.5 mL of CHCl3 was added in the above reaction system. The system maintained at 0 °C for 4 h. Subsequently, the reaction system was heated at a rate of 10 °C/h until the temperature reached 30 °C and kept for 2 h at the temperature to complete the polymerization. The obtained yellow particles were collected after filtration. Then they were repeatedly washing by ethanol until no stabilizer was in the eluate and dried in a vacuum at room temperature. The particles were denoted as P(PLLA1-co-R-CM). The samples P(PLLA2-co-R-CM), P(PLLA2-coS-CM), P(PDLA2-co-R-CM), and P(PDLA2-co-S-CM) were prepared in the same way. In addition, the particles without CM were also prepared and denoted as P(PLLA1). Enantioselective Release Experiments. Release of naproxen enantiomers from chiral particles was conducted as below. Naproxen (R, S, or racemate; 30 mg) was dissolved in CHCl3, together with PLLA and CM for suspension polymerization. Such a process led to the particles loaded with naproxen. The thus-obtained particles were immersed in EtOH (50 mL) to release naproxen drug. The concentration of the outer solution was determined by UV−vis spectroscopy to calculate the release amount. The enantiomeric excess (e.e.%) was determined by chiral phase HPLC analysis (Chiralpak ADH; n-hexane/i-PrOH = 4/1, v/v; 1.0 mL min−1, 273 nm). The retention times of R- and S-naproxen are tR = 6.6 min and tS = 7.1 min. The e.e. was calculated by the integral ratio of enantiomeric naproxen peak to total R- and S-naproxen peaks. All the release experiments were repeatedly conducted three times, and the averages were used to analyze the release results.
EXPERIMENT
Materials. The rhodium catalyst (nbd)Rh+B−(C6H5)4 (nbd = 2,5norbornadiene) was prepared by a method in the literature.34 Chiral acetylenic monomers (CM, R and S, the polymers are defined as RPCM and S-PCM, collectively referred to as PCM) were prepared according to the method reported earlier.35 The L- and D-lactide (L-LA and D-LA) were purchased from Tokyo Chemical Industry Co., Ltd. (TCI), and purified by recrystallizing twice from ethyl acetate. 1,8Diazabicyclo[5.4.0]undec-7-ene (DBU) was purchased from J&K Scientific Co., Ltd., and used without further purification. The chemicals 1,4-diethynylbenzene (1,4-DEB) and 4-ethynylaniline (PAPAC) from TCI, benzoic acid (BA) and polyvinylpyrrolidone (PVP K90) from Beijing Chemical Reagent Co., Ltd., and R- and S-naproxen from Ark Pharm, Inc., were used as received. All solvents were purchased from Beijing Chemical Reagent Co., Ltd., and distilled under reduced pressure before use. Measurements. Fourier transform infrared (FT-IR) spectra were recorded with a Nicolet NEXUS 670 spectrophotometer (in KBr tablet). 1H NMR spectra were recorded on a Bruker AV 400 spectrometer. The molecular weights and molecular weight polydispersities (Mw/Mn) were determined by GPC/SEC (Agilent Technologies 1200 Series) with THF as the eluent. The morphology of samples was observed with a Hitachi S-4800 scanning electron microscope (SEM). Circular dichroism (CD) and UV−vis absorption spectra were recorded using a Jasco-810 spectropolarimeter. Powder X-ray diffraction (XRD) patterns were recorded on a D/max2500 VB2+/PC X-ray diffractometer (Rigaku) using Cu Kα radiation. Differential scanning calorimetry (DSC) measurements were conducted using a Netzsch DSC204F1 instrument under a flow of nitrogen at a heating rate of 10 °C/min. Thermogravimetric analysis (TGA) was carried out with a Q50 TGA at a scanning rate of 10 °C/ min under N2. High performance liquid chromatography (HPLC) analysis was performed on a FL2200-2 (FL2200-2 pump and absorbance detector). The Chiralpak AD-H column was purchased from Daicel Chemical Industries Ltd. Preparation of Alkynyl PLLA/PDLA. Alkynyl PLLA/PDLA was prepared by using 4-ethynylaniline as initiator and DBU as catalyst. The procedure is referred to the literature36 and performed as follows. Lactide and 4-ethynylaniline were dissolved in CH2Cl2 under a nitrogen atmosphere. The mixture was stirred for 10 min. Then a DBU/CH2Cl2 solution was added to the above mixture. After 20 min, DBU was quenched with BA. The resultant mixture was precipitated into ethanol yielding PLLA or PDLA with terminal polymerizable alkynyl groups. The detailed reactant amount, product yield, and molecular weight are listed in Table 1. Preparation of Chiral Particles. Chiral particles were prepared through suspension polymerization referring to our previous study.33 Taking the polymerization of PLLA1 and R-CM (Scheme 1) as an example, the major procedure is as follows. The polymerization was performed in a 100 mL glass reaction vessel attached with Teflon stirrer and a glass inlet, in which a solution of PLLA1 (0.108 g, 1.5 mmol of lactic acid units), R-CM (0.028 g, 0.15 mmol), and 1,4-DEB (0.006 g, 0.05 mmol, [1,4-DEB]/[CC] = 0.3, in mol) in CHCl3 (2 mL) was added. Afterward, PVP aqueous solution (2 wt %, 50 mL) was added under vigorous stirring at a rate of 350 rpm and cooled in
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RESULTS AND DISCUSSION Preparation and Characterization of Chiral Particles. In the present work, chiral particles consisting of substituted polyacetylene and polylactide were successfully prepared. The two components, substituted polyacetylene and polylactide, both have been proved to form helical conformations in the literature.19,27 Preparation of the chiral particles aims to study the effects of different chiral conformations on enantioselective discrimination. The schematic strategy is depicted in Scheme 1. As shown in it, a two-step method is utilized to prepare the chiral particles, as to be reported below. In step 1, alkynyl poly(L-lactide) (PLLA) and poly(D-lactide) (PDLA) were prepared through ring-opening polymerization of L- and D-lactide by using 4-ethynylaniline (P-APAC) as initiator and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst. Besides acting as initiator, P-APAC also afforded alkynyl groups for the subsequent coordination polymerization. Herein, alkynyl PLA with two kinds of molecular weight were synthesized through adjusting the ratio of [M]/[I], as listed in Table 1. Alkynyl PLLA2 and PDLA2 in Table 1 were taken as representative to conduct circular dichroism (CD) and UV− vis measurements. The spectra are shown in Figure 1. Symmetrical CD signals and obvious UV−vis absorption peaks can be seen at 225 nm, indicating the formation of helical conformations with opposite screw senses in PLLA and B
DOI: 10.1021/acs.macromol.8b00580 Macromolecules XXXX, XXX, XXX−XXX
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Macromolecules Scheme 1. Illustrative Strategy for Preparing the Chiral Particles and the Process for Enantioselective Release
successfully initiated the polymerization of lactide. The XRD pattern of PLLA2 in Figure S2 shows the crystalline structure of PLLA2. The crystallinity of PLLA2 reached 59%, calculated by the ratio of the integral of the melting peak in DSC curve (Figure S3) to the standard melting enthalpy. In step 2, the aforementioned alkynyl PLA was utilized to fabricate the chiral particles by copolymerizing with chiral monomer CM through suspension polymerization. In the suspension polymerization, the continuous phase consisted of PVP aqueous solution; the disperse phase consisted of monomers (alkynyl PLA and CM), cross-linker (1,4-DEB), and Rh catalyst with CHCl3 as solvent. CHCl3 is selected not only because it is a good solvent for the monomers, but also it has suitable boiling point and can gradually evaporate under the polymerization conditions. Herein, chiral particles were prepared using PLLA with different molecular weight as presented in Table 1. The resulting particles were observed by SEM (Figure 3). As shown in Figure 3, when the particles were constructed by PLLA1 without CM, abundant pores appeared both on the surface and in the inner of the particles, resulting in the high brittleness of the particles (Figure 3A). When PLLA1 copolymerized with CM, both the size and the amount of the pores on the surface decreased, so the brittleness of the particles was slightly modified, but fragments still can be seen in Figure 3B. When PLLA2 with higher molecular weight copolymerized with CM, the pores on the surface disappeared (Figure 3C-1); however, the pores inside the particles still remained (Figure 3C-2), and the particles became more regular. The results are attributed to the hydroxyl groups of PLA referring to the literature.37 Hydroxyl groups in PLA can stabilize the monomer solution/ PVP aqueous solution interface due to the high affinity of hydroxyl to H2O. As a result, double or multiple emulsions can form in the dispersed droplets during polymerization, leading to the pores in the final particles.37 As the hydroxyl groups were derived from the addition reaction of P-APAC and lactide in the absence of catalyst and then initiated the ring-opening polymerization (step 1 in Scheme 1), hydroxyl groups only existed at the terminal of PLA chains. Therefore, with the same mass of PLA, the higher the molecular weight, the lower the hydroxyl content. In Figure 3A, P(PLLA1) was exclusively
Figure 1. (A) CD and (B) UV−vis absorption spectra of alkynyl PLLA2 and PDLA2 in CH2Cl2 solution (c = 0.01 M, by lactic acid unit). Detailed conditions are presented in Table 1.
PDLA chains.19 The FT-IR spectrum of alkynyl PLLA2 is displayed in Figure 2. Compared with the spectrum of P-APAC, PLLA2 spectrum retained the peak at 2095 cm−1 which is assigned to the CC stretching vibration, and an additional peak appeared at 1761 cm−1, belonging to the ester group in PLA. GPC data (Table 1), together with the FT-IR and the 1H NMR spectra of PLLA2 in Figure S1, prove that P-APAC
Figure 2. FT-IR spectra of P-APAC, PLLA2, and P(PLLA2-co-R-CM) (in KBr tablet). C
DOI: 10.1021/acs.macromol.8b00580 Macromolecules XXXX, XXX, XXX−XXX
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Figure 3. SEM images of chiral particles: (A-1) P(PLLA1) without PCM chains, (A-2) pores of P(PLLA1); (B-1) P(PLLA1-co-R-CM), (B-2) pores of P(PLLA1-co-R-CM); (C-1) P(PLLA2-co-R-CM), (C-2) inner pores in P(PLLA2-co-R-CM). The Mn of PLLA1 and PLLA2 is 6700 and 17 900 g/ mol, respectively, as shown in Table 1.
made of PLLA1 with lower molecular weight, so the hydroxyl group content was the highest, making the aqueous solution the most easily emulsified in the dispersed droplets. As a result, P(PLLA1) is the most porous and brittle. Relative to P(PLLA1), CM was added in P(PLLA1-co-R-CM) (Figure 3B), and accordingly the hydroxyl group content became lower than that of P(PLLA1), so the morphology of the particles was improved. Compared with P(PLLA1-co-R-CM), P(PLLA2-coR-CM) (Figure 3C) was constructed by PLLA2 with higher molecular weight, so the hydroxyl group content was the lowest and the amount of pores largely decreased. As abundant pores on the particles surface would cause burst release in the later release experiments, P(PLLA2-co-R-CM) with only inner pores was explored below. In addition, PDLA2 was also used to prepare chiral particles (Figure S4), which also show similar pore structure as observed in P(PLLA2-co-R-CM) owing to the similar molecular weight of PDLA2 and PLLA2. To further confirm the polymerization of alkynyl PLA and CM, P(PLLA2-co-R-CM) was characterized by FT-IR spectroscopy, as shown in Figure 2. Compared with the spectrum of PLLA2, the peak at 2095 cm−1 disappeared in the particle spectrum, indicating the complete polymerization of alkynyl groups in PLLA2. The additional peaks at 1663 and 1510 cm−1 are assigned to amide group, revealing the existence of CM units in the particles. The crystalline structure of P(PLLA2-coR-CM) was characterized by XRD analysis, as displayed in Figure S2. Compared with the XRD pattern of PLLA2, the XRD pattern of P(PLLA2-co-R-CM) shows the disappearance of the reflection of (004)/(103), (010), (014)/(203), and (015) planes and the changed interlayer spacing of the reflection of the (200)/(110) plane, illustrating the destruction of PLLA crystalline structure due to copolymerization. Further, P(PLLA2-co-R-CM) was also characterized by DSC analysis to determine the crystallinity, as shown in Figure S3. Compared with the DSC curve of PLLA2, the melting peak of P(PLLA2co-R-CM) became quite weak, and the melting temperature decreased to 125 °C. The crystallinity of PLLA2 chains in P(PLLA2-co-R-CM) also decreased, from 59% to 3%, evidently demonstrating that copolymerization with CM effectively prevented PLLA from crystallizing. According to the DSC analysis mentioned above, the melting temperature changed when PLLA2 copolymerized with acetylenic monomer. This encourages us to consider another question: did the thermal decomposition temperature also change after copolymerization? To answer this question, the
particles were further studied by TGA analysis, as shown in Figure 4. PLLA2 and the homopolymer of R-CM (R-PCM, the
Figure 4. (A) TGA and (B) DTG curves of P(PLLA2-co-R-CM), PLLA2, and R-PCM. The test was measured at a scanning rate of 10 °C/min in N2.
enantiomeric polymer is defined as S-PCM) have thermal decomposition temperature of 282 and 394 °C, respectively. As the P(PLLA2-co-R-CM) particles were constructed by the two polymers, two thermal decomposition stages were reasonably observed in Figure 4, and the corresponding decomposition temperatures were 320 and 394 °C. Obviously, the decomposition temperature of PLA chains in P(PLLA2-co-RCM) increased by 38 °C compared with pure PLLA2, but the decomposition temperature of PCM chains in P(PLLA2-co-RCM) did not change. The result demonstrates that copolymerizing with alkynyl monomer could improve the thermal stability of PLA chains but without changing that of polyacetylene chains. PLA (PLLA and PDLA) and CM (R-CM and S-CM) both possess chirality and the polymer chains of PLA and PCM both form helical conformations.19,31 So it is interesting to know whether the two chiral helical components would affect each other when integrated in one entity. To elucidate this issue, apart from P(PLLA2-co-R-CM), P(PLLA2-co-S-CM), P(PDLA2-co-R-CM), and P(PDLA2-co-S-CM) were also prepared and characterized by circular dichroism (CD) and UV− vis spectropolarimetry. For a vivid comparison, R-PCM and SD
DOI: 10.1021/acs.macromol.8b00580 Macromolecules XXXX, XXX, XXX−XXX
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Figure 5. (A-a) CD and (A-b) UV−vis spectra of P(PLLA2-co-R-CM), P(PLLA2-co-S-CM), P(PDLA2-co-R-CM), and P(PDLA2-co-S-CM) (the samples after swelling in CHCl3 were qualitatively measured through compressed between two pieces of quartz glass). (B-a) CD and (B-b) UV−vis spectra of R-PCM and S-PCM in CHCl3 solution (c = 0.6 mM, by CM unit).
Figure 6. Accumulative release−time profiles of single naproxen enantiomer from (A) P(PLLA2-co-R-CM), (B) P(PLLA2-co-S-CM), (C) P(PDLA2-co-R-CM), and (D) P(PDLA2-co-S-CM) in EtOH.
investigate whether peak 2 is derived from the chiral units in PCM, R-PCM and S-PCM solutions at different concentrations were measured by the CD spectropolarimeter, as shown in Figure S5. Special attention was paid to the partial spectra below 250 nm in Figure 5B and Figure S5, since peak 2 appeared in this region. However, no discernible CD signals but only irregular noise signals appeared in this region, indicating that peak 2 is not attributed to chiral units in PCM. Therefore, peak 2 is supposed to be originated in PLA chains. However, the wavelength of peak 2 is slightly higher than the characteristic CD signals of PLA chains, indicating that the helical pitch of PLA chains partially became larger due to the chiral helical PCM chains. Further, the Cotton effects at peak 2 are consistent with the corresponding PCM chains, also indicating the strong effects of chiral helical PCM chains on the helical screw sense of PLA chains.
PCM were also characterized. All the spectra are shown in Figure 5. In Figure 5B, the CD signals of R-PCM and S-PCM are symmetric at a wavelength of approximately 415 nm. Furthermore, R-PCM has a negative CD signal while S-PCM has a positive one, indicating the helical conformations with opposite helical screw senses formed in R-PCM and S-PCM, which is consistent with our previous studies.31 Compared with the CD spectra of PCM in Figure 5B, the signals (peak 3) in Figure 5A appear at the same wavelength, illustrating that the CD signals at peak 3 should be assigned to the helical conformations of PCM chains. Also referring to Figure 1, the signals at peak 1 in Figure 5A belong to the helical conformation of PLA chains. Besides the two characteristic peaks, new signals appear in Figure 5A, namely peak 2. Peak 2 has the same Cotton effect with PCM, but the position is quite near to peak 1 which belongs to PLA chains. To further E
DOI: 10.1021/acs.macromol.8b00580 Macromolecules XXXX, XXX, XXX−XXX
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Figure 7. Accumulative release−time profiles of racemic naproxen from (A) P(PLLA2-co-R-CM) and P(PLLA2-co-S-CM) (C) P(PDLA2-co-R-CM) and P(PDLA2-co-S-CM) in EtOH, measured by UV−vis absorbance at 316 nm; e.e.−time profiles of racemic naproxen from (B) P(PLLA2-co-RCM) and P(PLLA2-co-S-CM) and (D) P(PDLA2-co-R-CM) and P(PDLA2-co-S-CM) in EtOH, measured by HPLC with the mobile phase of isopropanol/n-hexane (1/4, v/v).
Enantioselective Release Experiments. In our previous studies, both chiral helical polyacetylenes and polylactides are proved to exert enantioselectivity in inducing enantioselective crystallization, chiral adsorption, and chiral release.30−32 Also, it has been found that when conformational chirality and configurational chirality combine properly, synergistic effects occur to improve the enantioselectivity.33 Inspired by the above studies, the particles prepared in this work are expected to show enantioselectivity, so how the two chiral helical polymers work is worthy to be studied. The following release experiments are accordingly conducted to study the enantioselectivity using P(PLLA2-co-R-CM), P(PLLA2-co-S-CM), P(PDLA2-co-RCM), and P(PDLA2-co-S-CM) discussed above. Herein, the chiral drug naproxen was chosen as a drug model to conduct the release experiments. To study the enantioselectivity in release process, naproxen should be sufficiently encapsulated in the particles. As mentioned above, the particles were prepared by suspension polymerization. To ensure a high drug loading, naproxen was added in the polymerization system. Because of the oil solubility, naproxen was mostly restricted in disperse phase together with monomers. After polymerization and solvent evaporation, the formed particles were loaded with naproxen. The drug loading efficiency was determined by UV−vis absorbance (316 nm) on leaching solution of the particles in EtOH. The drug loading efficiency was found to be 94% for P(PLLA2-co-R-CM), 93% for P(PLLA2-co-S-CM), 94% for P(PDLA2-co-R-CM), and 95% for P(PDLA2-co-S-CM). The chiral particles loaded with naproxen were used to perform the chiral drug release in two modes, i.e., single enantiomer release vs racemate release.38 The release processes in the present work were conducted in EtOH because it is a poor solvent for PLA and PCM chains; therefore, the chains in the particles can keep tightly packed in EtOH, avoiding the occurrence of burst
release. This is also in favor of exploring the enantioselectivity in the course of drug release. The single enantiomer release results are shown in Figure 6. For P(PLLA2-co-R-CM) (Figure 6A) and P(PDLA2-co-S-CM) (Figure 6D), S-naproxen released faster and more than Rnaproxen. The amount of S-naproxen released from P(PLLA2co-R-CM) is 1.7 times that of the R-isomer, and it is 1.5 times in the case of P(PDLA2-co-S-CM). But for P(PLLA2-co-S-CM) (Figure 6B) and P(PDLA2-co-R-CM) (Figure 6C), R-naproxen released only slightly faster and more than the other enantiomer, so the difference was almost negligible. The results imply that the two types of helical chirality could promote the enantioselectivity in PLLA+R-PCM and PDLA+S-PCM, obviously showing enantioselective discrimination in release process. However, PLLA+S-PCM and PDLA+R-PCM are quite different from the above two systems. The release results indicate that the chirality of the two helical components in PLLA+S-PCM and PDLA+R-PCM may partly counteract each other; therefore, the enantioselective discrimination was not obvious in the two cases. The racemate release results performed in EtOH are illustrated in Figure 7. The release amount of naproxen from the four particles is similar (Figure 7A,C). However, the enantiomeric excess (e.e.) of the four particles is remarkably different. The naproxen released from P(PLLA2-co-R-CM) (Figure 7B) and P(PDLA2-co-S-CM) (Figure 7D) both has positive e.e., meaning that the released naproxen was mainly consisting of S-naproxen. This is consistent with the single enantiomer release results of P(PLLA2-co-R-CM) in Figure 6A and P(PDLA2-co-S-CM) in Figure 6D. But for P(PLLA2-co-SCM) (Figure 7B) and P(PDLA2-co-R-CM) (Figure 7D), the released naproxen has negative e.e., which means that Rnaproxen was released faster than the other enantiomer. This is different from the single enantiomer release in Figure 6B,C. As F
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PCM are opposite in the CD signals sense, S-naproxen preferably released. Herein, we point out that since chiral interactions are frequently delicate and intricate, more studies on chiral materials and chiral interactions are still required to exactly understand the above rule. Despite the preliminary establishment of the rule, it is clear that chiral helical substituted polyacetylene has an effect on the enantioselectivity of PLA. Based on our earlier study dealing with the enantioselectivity of polylactide, PLLA- and PDLAbased particles both preferably released S-naproxen, and the e.e. was no more than 6% in EtOH.39 However, in the present work, due to the addition of chiral helical substituted polyacetylenes, the chiral particles’ preferential enantioselectivity is reversed in releasing naproxen enantiomers. Moreover, the e.e. in the present work surpassed 10% and the maximum e.e. was nearly 20%. A comparison of the two studies indicates that synergistic effects occur when chiral helical substituted polyacetylene and chiral helical polylactide work together harmoniously, obviously improving the enantioselectivity of PLA and even reversing the enantioselectivity of PLA. This work lays the foundation for further studying multichiral interactions and also provides a new idea for exploring drug release. Judiciously combining multichiral components in one entity is accordingly highly expected, from which interesting and unprecedented synergistic effects in chirality may be created.
mentioned above, in the two cases of PLLA+S-PCM and PDLA +R-PCM, the chirality of each combination counteracted each other, leading to unobvious enantioselective discrimination. However, the release amount of R-naproxen was still slightly higher than S-naproxen in Figure 6B,C, implying that the chirality of the two helical components was not completely offset. In single enantiomer release, the particles were loaded with only one enantiomer (R- or S-naproxen), so there was no competition between the two enantiomers in the course of release. Theoretically, a loaded enantiomer interacted with the chiral helical polymer chains in its release path. The other enantiomer loaded in the same particle also had a similar experience. Therefore, the enantioselective discrimination was hard to exhibit in single enantiomer release when the chiral interaction was weak. However, in the racemate release mode, the particles were loaded with equal amount of R- and Snaproxen, so competition occurs in the racemate release. Namely, once one enantiomer preferentially interacted with the chiral helical polymer chains, the other enantiomer would have less opportunity. Therefore, enantioselective discrimination readily took place in racemate release. Additionally, Figure 7 demonstrates that naproxen released from P(PLLA2-co-R-CM) and P(PDLA2-co-S-CM) reached the maximum e.e. much earlier than that from P(PLLA2-co-S-CM) and P(PDLA2-co-RCM), also suggesting the weak enantioselectivity of P(PLLA2co-S-CM) and P(PDLA2-co-R-CM) particles. To explore in depth the relationship between chirality of each helical polymer and the preferentially released naproxen, CD signals of the helical polymers and the preferably released enantiomers are summarized in Figure 8. Herein we find a quite
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CONCLUSIONS Chiral helical polylactides bearing polymerizable alkynyl group were successfully prepared. The polylactides were employed as macromers to copolymerize with chiral alkynyl monomer through suspension polymerization, fabricating the tailored chiral particles consisting of helical polylactide and helical substituted polyacetylene. Terminal hydroxyl groups in polylactide chains performed the emulsification effect, leading to pores in the final particles. The particles were used to load chiral naproxen drug to conduct enantioselective release experiments. The particles consisting of PLLA+R-PCM and PDLA+S-PCM both preferably released S-naproxen, while the particles consisting of PDLA+R-PCM and PLLA+S-PCM preferably released R-naproxen in racemate release. The polyacetylene chain segments can improve the enantioselectivity of polylactide. The work demonstrates that the enantioselectivity of chiral materials can be adjusted by combining with other chiral components, providing new ideas for developing new chiral materials.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b00580. Synthesis procedure and additional spectroscopies (PDF)
Figure 8. Relationship between CD signals of the two helical polymers and the preferentially released naproxen.
interesting phenomenon. For PLLA+S-PCM and PDLA+RPCM, in which PLLA and S-PCM both had positive CD signals and PDLA and R-PCM both had negative CD signals, the two combinations both preferably released R-naproxen. For PLLA +R-PCM and PDLA+S-PCM, in which the senses of the CD signals of PLA and PCM in each combination were opposite, Snaproxen preferably released. Accordingly, a rule can be established that when PLA and PCM have the same sense in CD signals, R-naproxen preferably released, and when PLA and
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AUTHOR INFORMATION
Corresponding Author
*(J.D.) Tel +86-10-6443-5128; Fax +86-10-6443-5128; e-mail
[email protected]. ORCID
Jianping Deng: 0000-0002-1442-5881 G
DOI: 10.1021/acs.macromol.8b00580 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules Notes
(17) Hongen, T.; Taniguchi, T.; Nomura, S.; Kadokawa, J.; Monde, K. In Depth Study on Solution-State Structure of Poly(lactic acid) by Vibrational Circular Dichroism. Macromolecules 2014, 47, 5313−5319. (18) Kobayashi, J.; Asahi, T.; Ichiki, M.; Oikawa, A.; Suzuki, H.; Watanabe, T.; Fukada, E.; Shikinami, Y. Structural and Optical Properties of Poly Lactic Acids. J. Appl. Phys. 1995, 77, 2957−2973. (19) Wen, T.; Wang, H.-F.; Li, M.-C.; Ho, R.-M. Homochiral Evolution in Self-Assembled Chiral Polymers and Block Copolymers. Acc. Chem. Res. 2017, 50, 1011−1021. (20) Wang, H.-F.; Chiang, C.-H.; Hsu, W.-C.; Wen, T.; Chuang, W.T.; Lotz, B.; Li, M.-C.; Ho, R.-M. Handedness of Twisted Lamella in Banded Spherulite of Chiral Polylactides and Their Blends. Macromolecules 2017, 50, 5466−5475. (21) Kan, K.; Fujiki, M.; Akashi, M.; Ajiro, H. Near-Ultraviolet Circular Dichroism of Achiral Phenolic Termini Induced by Nonchromophoric Poly(L,L-lactide) and Poly(D,D-lactide). ACS Macro Lett. 2016, 5, 1014−1018. (22) Zhang, C.; Liu, F.; Geng, Q.; Zhang, S.; Shen, X.; Kakuchi, R.; Misaka, H.; Kakuchi, T.; Satoh, T.; Sakai, R. Synthesis of a Novel OneHanded Helical Poly(phenylacetylene) Bearing Poly(L-Lactide) Side Chains. Eur. Polym. J. 2011, 47, 1923−1930. (23) Zhang, Z.-H.; Qiao, C.-Y.; Zhang, J.; Zhang, W.-M.; Yin, J.; Wu, Z.-Q. Synthesis of Unimolecular Micelles with Incorporated Hyperbranched Boltorn H30 Polyester modified with Hyperbranched Helical Poly(phenyl isocyanide) Chains and Their Enantioselective Crystallization Performance. Macromol. Rapid Commun. 2017, 38, 1700315. (24) Chen, J.-L.; Su, M.; Jiang, Z.-Q.; Liu, N.; Yin, J.; Zhu, Y.-Y.; Wu, Z.-Q. Facile Synthesis of Stereoregular Helical Poly(phenyl isocyanide)s and Poly(phenyl isocyanide)-block-Poly(L-lactic acid) Copolymers Using Alkylethynylpalladium(II) Complexes as Initiators. Polym. Chem. 2015, 6, 4784−4793. (25) Yashima, E.; Ousaka, N.; Taura, D.; Shimomura, K.; Ikai, T.; Maeda, K. Supramolecular Helical Systems: Helical Assemblies of Small Molecules, Foldamers, and Polymers with Chiral Amplification and Their Functions. Chem. Rev. 2016, 116, 13752−13990. (26) Shen, J.; Okamoto, Y. Efficient Separation of Enantiomers Using Stereoregular Chiral Polymers. Chem. Rev. 2016, 116, 1094−1138. (27) Freire, F.; Quiñoá, E.; Riguera, R. Supramolecular Assemblies from Poly(phenylacetylene)s. Chem. Rev. 2016, 116, 1242−1271. (28) Li, W.; Huang, H.; Li, Y.; Deng, J. Particles of Polyacetylene and Its Derivatives: Preparation and Applications. Polym. Chem. 2014, 5, 1107−1118. (29) Siriwardane, D. A.; Kulikov, O.; Rokhlenko, Y.; Perananthan, S.; Novak, B. M. Stereocomplexation of Helical Polycarbodiimides Synthesized from Achiral Monomers Bearing Isopropyl Pendants. Macromolecules 2017, 50, 9162−9172. (30) Yang, B.; Raza, S.; Li, S.; Deng, J. Ring Opening Precipitation Polymerization for Preparing Polylactide Particles with Tunable Size and Porous Structure and Their Application as Chiral Material. Polymer 2017, 127, 214−219. (31) Liang, J.; Deng, J. A Chiral Interpenetrating Polymer Network Constructed by Helical Substituted Polyacetylenes and Used for Glucose Adsorption. Polym. Chem. 2017, 8, 1426−1434. (32) Liang, J.; Deng, J. Chiral Porous Hybrid Particles Constructed by Helical Substituted Polyacetylene Covalently Bonded Organosilica for Enantioselective Release. J. Mater. Chem. B 2016, 4, 6437−6445. (33) Liang, J.; Wu, Y.; Deng, J. Construction of Molecularly Imprinted Polymer Microspheres by Using Helical Substituted Polyacetylene and Application in Enantio-Differentiating Release and Adsorption. ACS Appl. Mater. Interfaces 2016, 8, 12494−12503. (34) Schrock, R. R.; Osborn, J. A. π-Bonded Complexes of the Tetraphenylborate Ion with Rhodium (I) and Iiridium (I). Inorg. Chem. 1970, 9, 2339−2343. (35) Lin, J.; Huang, H.; Wang, M.; Deng, J. Optically Active Hollow Nanoparticles Constructed by Chirally Helical Substituted Polyacetylene. Polym. Chem. 2016, 7, 1675−1681. (36) Alba, A.; du Boullay, O. T.; Martin-Vaca, B.; Bourissou, D. Direct Ring-Opening of Lactide with Amines: Application to the
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21474007 and 21774009). REFERENCES
(1) Ray, S. S. Polylactide-Based Bionanocomposites: A Promising Class of Hybrid Materials. Acc. Chem. Res. 2012, 45, 1710−1720. (2) Poh, P. S. P.; Chhaya, M. P.; Wunner, F. M.; De-Juan-Pardo, E. M.; Schilling, A. F.; Schantz, J.-T.; van Griensven, M.; Hutmacher, D. W. Polylactides in Additive Biomanufacturing. Adv. Drug Delivery Rev. 2016, 107, 228−246. (3) Bawa, K. K.; Oh, J. K. Stimulus-Responsive Degradable Polylactide-Based Block Copolymer Nanoassemblies for Controlled/ Enhanced Drug Delivery. Mol. Pharmaceutics 2017, 14, 2460−2474. (4) Lee, J. S.; Han, P.; Song, E.; Kim, D.; Lee, H.; Labowsky, M.; Taavitsainen, J.; Ylä-Herttuala, S.; Hytö nen, J.; Gü lcher, M.; Perampaladas, K.; Sinusas, A. J.; Martin, J.; Mathur, A.; Fahmy, T. M. Magnetically Coated Bioabsorbable Stents for Renormalization of Arterial Vessel Walls after Stent Implantation. Nano Lett. 2018, 18, 272−281. (5) Liu, X.; Li, Y.; Tan, X.; Rao, R.; Ren, Y.; Liu, L.; Yang, X.; Liu, W. Multifunctional Hybrid Micelles with Tunable Active Targeting and Acid/Phosphatase-Stimulated Drug Release for Enhanced Tumor Suppression. Biomaterials 2018, 157, 136−148. (6) Hao, S.; Meng, J.; Zhang, Y.; Liu, J.; Nie, X.; Wu, F.; Yang, Y.; Wang, C.; Gu, N.; Xu, H. Macrophage Phenotypic Mechanomodulation of Enhancing Bone Regeneration by Superparamagnetic Scaffold upon Magnetization. Biomaterials 2017, 140, 16−25. (7) Shalgunov, V.; Zaytseva-Zotova, D.; Zintchenko, A.; Levada, T.; Shilov, Y.; Andreyev, D.; Dzhumashev, D.; Metelkin, E.; Urusova, A.; Demin, O.; McDonnell, K.; Troiano, G.; Zale, S.; Safarova, E. Comprehensive Study of the Drug Delivery Properties of Poly(Llactide)-Poly(Ethylene glycol) Nanoparticles in Rats and TumorBearing Mice. J. Controlled Release 2017, 261, 31−42. (8) Maudens, P.; Seemayer, C. A.; Thauvin, C.; Gabay, C.; Jordan, O.; Allémann, E. Nanocrystal−Polymer Particles: Extended Delivery Carriers for Osteoarthritis Treatment. Small 2018, 14, 1703108. (9) Chelladurai, R.; Debnath, K.; Jana, N. R.; Basu, J. K. Nanoscale Heterogeneities Drive Enhanced Binding and Anomalous Diffusion of Nanoparticles in Model Biomembranes. Langmuir 2018, 34, 1691− 1699. (10) Guo, X.; Wang, L.; Duval, K.; Fan, J.; Zhou, S.; Chen, Z. Dimeric Drug Polymeric Micelles with Acid-Active Tumor Targeting and FRET-Traceable Drug Release. Adv. Mater. 2018, 30, 1705436. (11) Kricheldorf, H. R.; Boettcher, C.; Tönnes, K.-U. Polylactones: 23. Polymerization of Racemic and Meso D,L-Lactide with Various Organotin CatalystsStereochemical Aspects. Polymer 1992, 33, 2817−2824. (12) Gupta, A. P.; Kumar, V. New Emerging Trends in Synthetic Biodegradable Polymers−Polylactide: A Critique. Eur. Polym. J. 2007, 43, 4053−4074. (13) Alemán, C.; Lotz, B.; Puiggali, J. Crystal Structure of the α-Form of Poly(L-lactide). Macromolecules 2001, 34, 4795−4801. (14) Pandey, S. K.; Patel, D. K.; Thakur, R.; Mishra, D. P.; Maiti, P. D.; Haldar, C. Anticancer Evaluation of Quercetin Embedded PLA Nanoparticles Synthesized by Emulsified Nanoprecipitation. Int. J. Biol. Macromol. 2015, 75, 521−529. (15) Chen, Y.; Zhang, Z.-H.; Han, X.; Yin, J.; Wu, Z.-Q. Oxidation and Acid Milieu-Disintegratable Nanovectors with Rapid CellPenetrating Helical Polymer Chains for Programmed Drug Release and Synergistic Chemo-Photothermal Therapy. Macromolecules 2016, 49, 7718−7727. (16) Du, K.; Shi, X.; Gan, Z. Rapid Biomimetic Mineralization of Hydroxyapatite-g-PDLLA Hybrid Microspheres. Langmuir 2013, 29, 15293−15301. H
DOI: 10.1021/acs.macromol.8b00580 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules Organo-Catalyzed Preparation of Amide End-Capped PLA and to the Removal of Residual Lactide from PLA Samples. Polym. Chem. 2015, 6, 989−997. (37) Zhang, Z.; Marson, R. L.; Ge, Z.; Glotzer, S. C.; Ma, P. X. Simultaneous Nano- and Microscale Control of Nanofibrous Microspheres Self-Assembled from Star-Shaped Polymers. Adv. Mater. 2015, 27, 3947−3952. (38) Xie, P.; Liu, X.; Cheng, R.; Wu, Y.; Deng, J. pH-Sensitive Chiral Hydrogels Consisting of Poly(N-acryloyl-L-alanine) and β-Cyclodextrin: Preparation and Enantiodifferentiating Adsorption And Release Ability. Ind. Eng. Chem. Res. 2014, 53, 8069−8078. (39) Liang, J.; Yang, B.; Deng, J. Polylactide-Based Chiral Particles with Enantio-Differentiating Release Ability. Chem. Eng. J. 2018, 344, 262−269.
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DOI: 10.1021/acs.macromol.8b00580 Macromolecules XXXX, XXX, XXX−XXX
