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Stereocomplex Film Using Triblock Copolymers of Polylactide and Poly(ethylene glycol) Retain Paxlitaxel on Substrates by Aqueous Inkjet System Hiroharu Ajiro, Ayaka Kuroda, Kai Kan, and Mitsuru Akashi Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.5b03169 • Publication Date (Web): 05 Sep 2015 Downloaded from http://pubs.acs.org on September 14, 2015

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Stereocomplex Film Using Triblock Copolymers of Polylactide and Poly(ethylene glycol) Retain Paxlitaxel on Substrates by Aqueous Inkjet System Hiroharu Ajiro,a,b,c,d,e,* Ayaka Kuroda,a Kai Kan,d,e and Mitsuru Akashia,b,f*. a

Department of Applied Chemistry, Osaka University, 2-1 Yamada-oka, Suita, 565-0871, Japan

b

The Center for Advanced Medical Engineering and Informatics, Osaka University, 2-2

Yamada-oka, Suita, Osaka, 565-0871, Japan c

JST PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan

d

Graduate School of Materials Science, Nara Institute of Science and Technology, 8916-5,

Takayama, Ikoma, Nara 630-0192, Japan e

Institute for Research Initiatives, Division for Research Strategy, Nara Institute of Science and

Technology, 8916-5, Takayama, Ikoma, Nara 630-0192, Japan

ACS Paragon Plus Environment

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Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, 565-0871,

Japan * These authors have contributed equally to the study.

ABSTRACT

The stereocomplex formation of poly(L,L-lactide) (PLLA) and poly(D,D-lactide) (PDLA) using an inkjet system was expanded to the amphiphilic copolymers, using poly(ethylene glycol) (PEG) as hydrophilic polymer. The diblock copolymers which are composed of PEG and PLLA (MPEG-co-PLLA) and PEG and PDLA (MPEG-co-PDLA) were employed for thin film preparation using an aqueous inkjet system. The solvent and temperature conditions were optimized for the stereocomplex formation between MPEG-co-PLLA and MPEG-co- PDLA. As a result, the stereocomplex was adequately formed in acetonitrile/water (1/1, v/v) at 40 ºC. The aqueous conditions improved the stereocomplex film preparation, which have suffered from clogging when using the organic solvents in previous work. The triblock copolymers, PLLA-coPEG-co-PLLA and PDLA-co-PEG-co-PDLA, were employed for square patterning with the inkjet system, which produced thin films. The amphiphilic polymer film was able to retain hydrophobic compounds inside. The present result contributed to the rapid film preparation by inkjet, retaining drugs with difficult solubility in water, such as paclitaxel within the films.


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Introduction. Layer-by-layer (LbL) assembly is widely known as a convenient approach to preparing thin films on substrate, by dipping into two different solutions alternatively, with interactions between the two polymers.1-3) One of the superior properties of the technique is an easy approach to obtaining thin films with nano-meter order uniformity. Recently, spray methods4-6) have been reported in order to improve the conventional LbL approach, which was relatively time consuming, because of the repeated cycles of dipping and washing. However, there is still significant loss of the polymer solution and washing solvents, which is a problem for larger scale manufacturing. On the other hand, the inkjet system has been reported to be an easy method for preparing thin films.7-14) This system enables the discharge of pico-liter order volumes automatically under computer control. The discharge rate is thousands of times a second and the target position can be adjusted at the micrometer level. Furthermore, the washing process is not necessary. Recently, the features of the inkjet system have been applied to LbL systems, such as in work with the extra-cellular matrix between cells,15) electronic circuits,16) and arrays.17,18) However, there is little information available regarding layer by layer systems using synthetic polymers and the inkjet system. To our knowledge, only three cases have been reported that focus on stereocomplex formation at present. There are polylactide (PLA) stereocomplex,19) poly(methyl methacrylate) stereocomplex,20) and the drug release profile from PLA stereocomplex prepared with organic solvents.21) During the research, it is always difficult to prepare PLA stereocomplexes using the inkjet system because of the vaporization of organic solvents at the nozzle, resulting in polymer precipitation and clogging at the tip. Furthermore, halogenated


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solvents are not compatible in biomedical applications despite their process. Discharge stabilization is necessary in order to expand the biomedical application. PLA is important for material applications, such as biomedical applications, due to its biocompatible and bioabsorbable properties. It is known that poly(L,L-lactide) (PLLA) and poly(D,D-lactide) (PDLA) form stereocomplexes under various conditions,22-24) improving melting points25-29) and mechanical strength.30-32) Therefore, nano-film preparation of PLA stereocomplexes is important, and the conventional LbL system has been investigated.33,34) The rapid inkjet system has also been applied to PLA stereocomplex formation.19) One of the possible applications of PLA stereocomplexation using the inkjet system is substrate coating for drug delivery systems,21) such as a drug-eluting stent. Actually, sirolimus35) and cyclosporine A36) were employed as drugs for the drug eluting from stent with PLA hydrolysis. The degradation behaviour of PLA copolymer with poly(trimethylene carbonate) has been reported by Li et al, suggesting possible applications for the drug eluting stent.37-39) There are many studies on block copolymers of polyethylene glycol (PEG) and PLA.40-45) Regarding stereocomplex formation using a copolymer of PEG and PLA, Fujiwara et al. investigated the stereocomplexation of PEG-co-PLLA and PEG-co-PDLA in aqueous media to induce gelation.46-48) Li et al., reported micelle formation with drug encapsulation by stereocomplexation.49,50) The formation of star-shaped polymers,51) mikoto-arm,52) electroactive copolymers (aniline),53) and so on have also been reported. The block copolymer was soluble in water, with stereocomplexation ability. However, nanofilm preparation with PEG-co-PLLA and PEG-co-PDLA has not been reported so far to the best of our knowledge. Thus, we selected the block copolymer of PEG and PLA for stable stereocomplex formation in an inkjet system.


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In this study, diblock copolymers, PEG-co-PLLA and PEG-co-PDLA were employed in aqueous media to optimize stereocomplex film preparation using the inkjet system. Triblock copolymers, PLLA-co-PEG-co-PLLA and PDLA-co-PEG-co-PDLA, were then utilized for drug eluting materials (Figure 1). The solvent conditions and temperature were optimized for effective stereocomplex formation. Paclitaxel was selected as a model drug, because of its low water solubility and its release behavior from the inkjet LbL films was also observed.

Figure 1. Chemical structures of PLAs and their copolymers in this study (a). Schematic illustration of alternative LbL approach to prepare stereocomplex film.

2. Materials and methods 2.1. Materials and measurements. The (L,L)-lactide and (D,D)-lactide were purchased from Musashino Chemical Laboratory, Ltd. (Japan, Tokyo). These monomers were recrystallized from hexane/ethyl acetate (8/2, v/v)


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before polymerization. Polyethylene glycol (PEG) and monomethyl poly(ethylene glycol) (MPEG) (Mn=5000) were purchased from NOF corporation (Japan, Tokyo). Tin (II) ethylhexanoate (Sn(Oct)2), were purchased from Tokyo Chemical Industry (Japan, Tokyo) and used without further purification. SEC was measured using a Tosoh System HLC-8120GPC. 1H NMR spectra were measured by JEOL JNM-GSX 400 (400MHz). FT-IR/ATR spectra were obtained by Perkin Elmer Spectrum 100. XRD was analysed using Rigaku RINT InPlane/ ultra X 18 SAXS-IP. DSC was measured by DSC6100 EXSTAR6000. HPLC was measured by Shimazu Liquid Chromatograph equipped with CBM-20A, Lc-20AD, SIL-20A, CTO-20A, SPD-20A, and RID-10A. 2.2. PLAs and copolymers. PLLA (Mn=8500, PDI=1.19, [α]D25=-148°) and PDLA (Mn=8300, PDI=1.20, [α]D25=+153°) were synthesized at 120 °C for 4 hr using Tin(II) ethylhexanoate as a catalyst as described elsewhere.54-57) MPEG-co-PLLA, PMEG-co-PDLA, PLLA-co-PEG-co-PLLA, and PDLA-co-PEG-co-PDLA were synthesized under the same condition using MPEG and PEG as initiators (Table 1). 2.3. Inkjet system. Polymer solutions were deposited on a substrate using an inkjet printer (Cluster Technology Co., Ltd.; frequency 1000 Hz, voltage 9 V). The inkjet printer was equipped with a single-nozzle drop-on-demand piezo electric print head (Pulse Injector), two-aligned with a lightemitting diode for visualization of the droplet ejection. Single droplets with volumes of 20 pL were deposited on demand from the nozzle, which had a diameter of 25 µm. The vertical separation between the nozzle and the substrate was typically 10 µm. The solvent of the droplet


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was evaporated from the surface at room temperature (1 step). The square film formation was achieved using a computer program, which 1,000 drops of PLLA-co-PEG-co-PLLA in 2 mm in line and vertically moved in 0.04 mm to move 1000 drops in 2 mm in line opposite way. After 50 times, it was counted as 1 step (total 50 000 drops), and the other PDLA- co-PEG- co-PDLA were deposited in the same condition on PLLA-co-PEG-co-PLLA deposited on the substrate. 2.4. Paclitaxel release The solution of PLLA-co-PEG-co-PLLA (10 mg/mL) and paclitaxel (0.2mg/mL) in acetonitrile/water (1/1, v/v) was prepared, as well as the solution of PDLA-co-PEG-co-PDLA (10 mg/mL) and paclitaxel (0.2 mg/mL) in acetonitrile/water (1/1, v/v). The solutions were charged to inkjet heads for alternative inkjet discharge to prepare two kinds of stereocomplex square films. As one sample condition, the square pattern of PLLA-co-PEG-co-PLLA/paclitaxel was discharged with 1 step as described in the abovementioned section (2.3. Inkjet system), the square pattern of PDLA-co-PEG-co-PDLA/paclitaxel was discharged with 1 step. Then, the 2 steps were counted as 1 cycle, and repeated for 1,000 cycles (Sample A). For the other sample condition, the square pattern of PLLA-co-PEG-co-PLLA/paclitaxel was discharged for 1,000 steps, and then the square pattern of PDLA-co-PEG-co-PDLA/paclitaxel was discharged for 1,000 steps, which was treated as 1 cycle (sample B). After forming stereocomplex films on a glass substrate, each film was dipped into 30 mL of phosphate buffered saline (PBS). Each 300 µL of supernatant was sampled for the analysis of the released amount of paclitaxel by HPLC system at the decided time interval. The released amount was estimated by a UV detector with a standard curve (Supporting Information, Figure S1).


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3. Results and discussion In a previous study, crystallinity of the stereocomplex has varied depending on the numbers of cycles with all other conditions held constant.21) We have therefore postulated that inkjet LbL conditions would have an influence on the amount of stereocomplex formation. Based on this idea, we have confirmed the behavior of stereocomplex formation using PLLA and PDLA with DSC analyses. The crystallinities of PLA stereocomplex showed almost the same values regardless of the cycle numbers, but the melting points were variable because of the different crystalline size (Supporting Information, Figure S2 and Table S1). The results were consistent with the previous study,21) implying that many cycles at LbL system lead to a greater chance of contact between PLLA and PDLA which contributes to the size and amount of stereocomplex formation when the same amount of polymer is used. In other words, the inkjet LbL system has the merit of being able to control stereocomplex formation by changing the number of cycles. However, one problem of inkjet systems is the evaporation of the organic solvent leading to clogging of the discharge head. This happens frequently resulting in unstable discharge and sometimes failure of LbL film creation. On the contrary, the aqueous solvent was much more stable during discharge using the current inkjet system. So, we expanded the PLA stereocomplex system in aqueous media, using a block copolymer with hydrophilic moiety. Herein we selected PEG as a block copolymer component because it is also a biocompatible polymer. The block copolymers used in this study are listed in Table 1.


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Table 1. Block copolymers in this study.a Yield [EO]b [EO]c Mnd Mne PDIe Tm (%) [LA] [LA] ×103 ×103 (°C) 1 MPEG-co-PLLA 87 5.7 6.7 6.7 2.9 1.41 57 2 MPEG-co-PDLA 90 5.7 6.7 5.7 2.3 1.28 56 3 PLLA-co-PEG-co-PLLA 89 4.6 6.1 5.1 1.7 1.70 58 4 PDLA-co-PEG-co-PDLA 92 4.6 5.9 5.1 2.3 1.54 54 a Polymerization condition: Initiator=MPEG (run 1 and 2) and PEG (run 3 and 4). Catalyst=Tin (II) hexaoctanoate, 10 mol% to Initiator. Temperature=120°C. Time=4hr. b Mole ratio in feed. c Mole ratio in the obtained copolymer. d Determined by 1H NMR. eDetermined by SEC in THF.

Run

Polymer

At first, the stereocomplex formations of block copolymers with PEG were confirmed by the simple mixing procedure, using the combination of MPEG-co-PLLA/MPEG-co-PDLA and PLLA-co-PEG-co-PLLA/PDLA-co-PEG-co-PDLA. Each solution was combined and the

Figure 2. DSC traces at the first scan with mixture of MPEG-co-PLLA/MPEG-co-PDLA in chloroform (a), MPEG-co-PLLA/MPEG-co-PDLA in water/acetonitrile (1/1, v/v) (b), and PLLA-co-PEG-co-PLLA/PDLA-co-PEG-co-PDLA in water/acetonitrile (1/1, v/v) (c).


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precipitates were collected as stereocomplex. Figure 2 shows the results of DSC measurements. All of the samples exhibited melting points of around 40 ºC, suggesting PEG moieties. In the case of diblock copolymer, MPEG-co-PLLA and MPEG-co-PDLA, the melting point based on the stereocomplex around 210 ºC was not observed from either the organic solvent (Figure 2a) or aqueous media (Figure 2b). On the other hand, the melting points of the stereocomplex was confirmed under the condition with PLLA-co-PEG-co-PLLA/PDLA-co-PEG-co-PDLA in aqueous media, water/acetonitrile (1/1, v/v) around 210 ºC, implying the stereocomplex formation needs to be optimized for the inkjet system. Next, the solvent and temperature conditions of the inkjet LbL system for stereocomplex formation were varied with MPEG-co-PLLA and MPEG-co-PDLA. Each polymer solution at 10 mg/mL was loaded into the inkjet head. Then, a thousand drops of MPEG-co-PLLA solution was discharged onto the glass plate in one step, followed by a thousand drops of MPEG-co-PDLA solution on the same spot after 15 seconds. This cycle was repeated 500 times, and the obtained samples were analyzed by XRD (Figure 3) and FT-IR/ATR (Figure 4), together with the MPEGco-PLLA itself (Figure 3a and Figure 4a). Figure 3b shows an XRD image obtained using the inkjet system with a water solution at 75 ºC, which was the condition found to support gelation and stereocomplex formation of MPEG-PLLA and MPEG-PDLA in water.46) Compared to MPEG-PLLA (Figure 3a), the images showed overlapping peaks at 17º, which correspond to the homopolymers of PLLA and PDLA. The characteristic peak of the stereocomplex at 12º was not observed. On the other hand, the FT-IR/ATR spectrum of the film showed peaks at 1749 cm-1 and 1757 cm-1 (Figure 4b), while MPEG-co-PLLA only showed a peak at 1754 cm-1 (Figure 4a),


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Figure 3. XRD patterns of MPEG-co-PLLA (a), MPEG-co-PLLA/MPEG-co-PDLA prepared by inkjet system with water at 75 ºC (b), with water at 40 ºC (c), with water/acetonitrile (1/1, v/v) at 40 ºC (d), and the precipitation from the mixture of MPEG-co-PLLA and MPEG-co-PDLA solutions (e).

Figure 4. FT-IR/ATR spectra of MPEG-co-PLLA (a), MPEG-co-PLLA/MPEG-co-PDLA prepared by inkjet system with water at 75 ºC (b), with water at 40 ºC (c), with water/acetonitrile (1/1, v/v) at 40 ºC (d), and the precipitation from the mixture of MPEG-co-PLLA and MPEG-coPDLA solutions (e).


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which are assigned as a carbonyl stretching. This peak shift is known to be associated with stereocomplex formation,57,58) and the same tendency was observed around 3000 cm-1 (Figure 4a and 4b). One of the reasons for the poor efficiency in forming stereocomplex at 75 ºC is the high temperature, which was above the melting point of both MPEG-co-PLLA and MPEG-co-PDLA (Table 1, run 1 and run 2). Therefore, the temperature was set to 40 ºC, which was below the melting point of both polymers. However, stereocomplex formation did not improve, as shown in both the XRD (Figure 3c) and FT-IR/ATR (Figure 4c) images. When processing at 40 ºC, it was necessary to wait 30 seconds after each step for 500 cycles to allow for water evaporation. This delay might have influenced stereocomplex formation. In order to accelerate polymer-polymer interaction, the use of acetonitrile, which is known as a theta solvent for PLA in spite of possible toxicity unless the solvent is removed, was considered. MPEG-co-PLLA and MPEG-co-PDLA solutions at 10 mg/mL in acetonitrile/water (1/1, v/v) were examined. An apparent peak at 12 º was observed by XRD (Figure 3d), implying stereocomplex formation. The FT-IR/ATR image also showed a peak shift to 1749 cm-1 (Figure 4d). Therefore, the optimized condition for the inkjet LbL system using MPEG-coPLLA/MPEG-co-PDLA was selected as 10 mg/mL in acetonitrile/water=1/1 (v/v) at 40 ºC in this study. The optimized solvent and temperature conditions were also applied to the system with PLLA-co-PEG-co-PLLA and PDLA-co-PEG-co-PDLA (Figure 5). The nanofilm prepared with the triblock polymers resulted in the same peak on XRD (Figure 5a) corresponding to


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Figure 5. XRD pattern (a) and FT-IR/ATR spectrum (b) of PLLA-co-PEG-co-PLLA/PDLA-coPEG-co-PDLA prepared by inkjet with water/acetonitrile (1/1, v/v) at 40 ºC.

stereocomplex structure, and a peak shift for the carbonyl stretching adsorption at 1749 cm-1 on the FT-IR/ATR spectrum (Figure 5b). Since the optimized condition was confirmed for stereocomplex formation on the inkjet LbL system, it was applied to triblock copolymers for three dimensional network construction using aqueous media. To study the mixture of PLLA-co-PEG-co-PLLA and PDLA-co-PEG-co-PDLA, they were simply mixed in acetonitrile/water (1/1, /v) and dried at 40 ºC. Then, the solution was added to a large amount of water, resulting in gel formation (Figure 6a). The swelling ratio was estimated as 5 using a TGA scan (Supporting Information, Figure S3). The gel formation indicates stereocomplex formation between PLLA-co-PEG-PLLA/PDLA-co-PEG-co-PDLA, which plays a role of crosslinking points.46) So, the optimized condition in an inkjet system would produce the stable nanofilm in water, possessing hydrophobic sites. Finally, the drug eluting behavior was


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tested, using the triblock copolymers. We selected paclitaxel as a model for drugs with poor water solubility.

Figure 6. Photo of PLLA-co-PEG-co-PLLA/PDLA-co-PEG-co-PDLA gel prepared by mixing solutions (a). Line trace of inkjet pattern for covering area (2 mm×2 mm) (b). Photos of inkjet LbL films prepared by 1 step for PLLA-co-PEG-co-PLLA/PDLA-co-PEG-co-PDLA with 1000 cycles (c) by 1000 steps for PLLA-co-PEG-co-PLLA/PDLA-co-PEG-co-PDLA with 1 cycle (d).

To cover the appropriate area on the substrate for drug eluting, square patterning was achieved using the inkjet system (Figure 6b). Following the results of different cycle numbers of inkjet conditions (Supporting Information, Figure S2 and Table S1), it was observed that the cycle numbers influenced the crosslinking structure of PLLA-co-PEG-co-PLLA/PDLA-co-PEGco-PDLA. Thus, two different cycle numbers of inkjet conditions were selected. For the inkjet LbL film preparation, the blend solutions of PLLA-co-PEG-co-PLLA/paclitaxel and PDLA-coPEG-co-PDLA/paclitaxel were used. The inkjet LbL films were prepared in 1 step for PLLA-coPEG-co-PLLA/PDLA-co-PEG-co-PDLA using 1000 cycles (Figure 6c), and in 1000 steps for PLLA-co-PEG-co-PLLA/PDLA-co-PEG-co-PDLA using 1 cycle (Figure 6d). Both conditions gave the similar stereocomplex films. The two obtained stereocomplex films on glass plates (Figure 6c and 6d) were immersed in PBS solutions, and the aliquot of supernatant was analyzed by HPLC to determine the released


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amount of paclitaxel. The results are shown in Figure 7. The 60-70 % of paclitaxel in both stereocomplex films was released over 1hr, and the values maintained after 5 hr. The slight rapid release was recognized from the inkjet LbL film prepared by 1 step for PLLA-co-PEG-coPLLA/PDLA-co-PEG-co-PDLA with 1000 cycles (Figure 7a), although there was no significant difference. Under both conditions, the stereocomplex films were formed, which could be used to retain paclitaxel for long term release over 5 hr (Figure 7). As demonstrated in this study, PLA stereocomplex formation was utilized for inkjet LbL films in aqueous media by the use of copolymers with PEG, resulting in the hydrophobic sites including for drug release control.

Figure 7. Paclitaxel release form the inkjet LbL films prepared by 1 step for PLLA-co-PEG-coPLLA/PDLA-co-PEG-co-PDLA with 1000 cycles (Sample A) (a) by 1000 steps for PLLA-coPEG-co-PLLA/PDLA-co-PEG-co-PDLA with 1 cycle (Sample B) (b).

Conclusions The stereocomplex formation using diblock copolymer of MPEG-co-PLLA and MPEGco-PDLA was achieved in water/acetonitrile (1/1, v/v) solution at 40 °C using an inkjet system. The stereocomplex formed by alternative deposition of copolymers were analyzed by IR and XRD. The aqueous media of PLA stereocomplex formation enables the stable discharge of


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polymers. The stereocomplex films of PLLA-co-PEG-co-PLLA/PDLA-co-PEG-PDLA were also successfully prepared by inkjet LbL system in aqueous media. The square patterning was achieved using an inkjet program for stereocomplex film of PLLA-co-PEG-co-PLLA/PDLA-coPEG-PDLA. The hydrophobic compound, paclitaxel, was incorporated into the stereocomplex film. The present system demonstrated its potential for possible application in biomaterials for drug eluting materials.

Supporting Information. Standard curve of HPLC analysis for paclitaxel release. DSC traces of PLLA/PDLA stereocomplex. Thermal properties of stereocomplex prepared by various method. 1

H NMR spectra, XRD patterns, FT-IR/ATR spectra, and TGA analysis on the mixture of

PLLA-co-PEG-co-PLLA and PDLA-co-PEG-co-PDLA. This material is available free of charge via the Internet at http://pubs.acs.org.

Corresponding Author *Hiroharu Ajiro. E-mail: [email protected], TEL: +81-(0)743-72-5508, FAX: +81-(0)743-725509. * Mitsuru Akashi. E-mail: [email protected], TEL: +81-(0)6-6105-5247, FAX: +81-(0)66879-9712. Author Contributions ‡*These authors contributed equally.


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ACKNOWLEDGMENT This work is partially supported by “Development of manufacturing technology for functional tissues and organs employing three-dimensional biofabrication” funded by New Energy and Industrial Technology Development Organization (NEDO) and Japan Agency for Medical Research and Development (AMED). This work was partly supported by a Grant-in-Aid for Scientific Research (S) from the Ministry of Education, Culture, Sports, Science and Technology (23225004). The present study is also partly supported by JST PRESTO “Molecular Technology” with Prof. T.K.


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