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Self-assembly of triblock copolymers from cyclic esters as a tool for tuning their particles morphology Marta Socka, Marek Brzezi#ski, Adam Michalski, Anna Kacprzak, Tomasz Makowski, and Andrzej Duda Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b00440 • Publication Date (Web): 02 Mar 2018 Downloaded from http://pubs.acs.org on March 4, 2018

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Self-assembly of triblock copolymers from cyclic esters as a tool for tuning their particles morphology M. Socka*, M. Brzezinski, A. Michalski, A. Kacprzak, T. Makowski, A. Duda Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland * e-mail: [email protected]

Abstract

This paper presents the effect of end groups, chain structure and stereocomplexation on the micro- and nano-particles morphology and thermal properties of the supramolecular triblock copolyesters. Therefore, the series of the triblock copolymers composed of L,L- and D,D-lactide, trimethylene carbonate (TMC) and ɛ-caprolactone (CL) with isopropyl (iPr) or 2-ureido-4-[1H]pyrimidinone (UPy) end groups at both chain ends were synthesized. In addition, these copolymers were intermoleculary stereocomplexed by polylactide blocks with an opposite configuration of repeating units to promote their self-assembly in various organic solvents. The combination of two non-covalent interactions of the end groups and PLA enantiomeric chains leads to stronger interactions between macromolecules and allows for the alteration of their segmental mobility. The simple tuning of the copolymer microstructure and functionality induced the self-assembly of macromolecules at liquid-liquid interfaces, which leads consequence their phase separation in the form of particles with diameters ranging from 0.1 to 10 µm. This control is essential for their potential applications in the biomedical field in which biocompatible and well-defined micro- and nanoparticles are highly desirable.

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Keywords: biodegradable copolymers, supramolecular materials, stereocomplexes, selfassembly, micro- and nanoparticles Introduction Micro- and nano-particles of stereocomplexes composed of polylactide (PLA) and its copolymers with other aliphatic polyesters receive much attention due to their potential use in biomedical and pharmaceutical applications

1-4

. The synthetic route, most widely used for the

preparation of biodegradable and biocompatible copolyesters, is based on the sequential ringopening polymerization (ROP). However, this method of synthesis requires appropriate conditions for the elimination of even traces of impurities, and suppression of segmental exchange by transesterification 5. To overcome this limitation, we prepare triblock copolyesters of lactide (LA) external blocks with trimethylene carbonate (TMC) or ɛ-caprolactone (CL) internal blocks via coupling of the corresponding polyester (α,ω) diols and polyesters with monohydroxyl end groups using isophorone diisocyanate (IPDI) as the coupling agent. In addition, this method allows for tuning the length and sequence distribution of each segment

6

and unlike traditional ROP it allows for incorporation of desired functional groups on both sides of the chains. Therefore, we prepared two types of triblock copolymers functionalized with 2ureido-4-[1H]-pyrimidinone (UPy) which is able to form quadruple hydrogen bonds

7-10

and for

comparison isopropyl group which is not able to form hydrogen bonds. The first step to prepare UPy- functionalized triblock copolyesters was the synthesis of polylactide bearing UPy- end groups by ROP of both L,L- and D,D-LA using a UPy- functionalized initiator and stannous octoate as a catalyst

11-12

. The second step was the reaction of the obtained polymer with

isophorone diisocyanate. The applied conditions allow for the selective reaction of one of the isocyanate groups

13

and the second IPDI group is used for the further reaction with


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poly(trimethylene carbonate diol) (PTMC-diol) or polycaprolactone diol (PCL-diol) obtained by ROP

14-15

initiated by 1,5-pentanediol. For the comparison of the end group effect on the

properties of the prepared copolymers, ABA copolymers of LA (A) with TMC (B) or CL (B) with the external polylactide blocks and isopropyl- end groups were obtained. Typically, aliphatic poly(trimethylene carbonate) (PTMC) and polycaprolactone (PCL) have been used as components of di- and triblock copolymers with PLA to alter the brittle and rigid nature of PLA 15-20. The copolymerization of LA with TMC and CL allows for tuning of the PLA mechanical properties by varying the composition and the co-monomers block lengths Supramolecular polyesters copolymers of PLA-PCL (PVL)

22

21

20

.

and PCL with poly(δ-valerolactone)

functionalized with UPy- end groups were also investigated as thermoplastic

elastomers. However, these copolymers were prepared via post-polymerization method which does not ensure for complete functionalization with UPy- end groups. Therefore we applied UPy- functionalized initiator for the ROP of L,L- and D,D-LA, what allowed to attach UPy functionality at one terminus and hydroxyl- end group at the other

11, 23

, and subsequently to

couple UPy-functionalized PLAs with PTMC-diol and PCL-diol by applying IPDI. In contrary to previous reports

21-22

, our goal was to use these different copolymer compositions with various

end groups to tune their interactions at the liquid-liquid interface to control the morphology of resulting micro- and nanoparticles. On top of that, we took an advantage from stereocomplexation between the enantiomeric PLLA and PDLA to create an additional factor for the alteration of phase separation in supramolecular copolyesters. Due to the biocompatibility and hydrolyzability of aliphatic copolyesters, an extensive research effort has been made to elucidate their utility as resorbable implants or a vehicles for controlled drug delivery 24-26. The control over the particles morphology is extremely important for their applications as drug-


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delivery systems, and for semi-crystalline polymers it can be enhanced by stereocomplexation 2728

. In this study, we reported a novel approach to attain a control over micro- and nanoparticles

of supramolecular copolymers by adjusting of the crystalline structure of copolymers. We achieved this goal by using a different comonomers repeating units composition, end group selection, stereocomplexation and a method of their preparation. Experimental Section Purification and handling of chemicals The L,L- and D,D-lactide (LA) (99%, Purac, Netherlands) was recrystallized from dry 2propanol and then further purified by sublimation in a vacuum (10–3 mbar, 85 °C) immediately before use. Trimethylene carbonate (TMC) (Boehringer Ingelheim, Germany, > 99%) was crystallized from dried THF: ethyl ether mixture (3:1) and sublimated (10-3 mbar, 45 oC). ɛCaprolactone (Aldrich, 99%) was stirred over CaH2 for several hours at room temperature and distilled under reduced pressure (~ 10-3 mbar, 90 °C) into ampoules covered with a Na mirror. The purified monomers were distributed into the glass ampules equipped with break-seals. 1,5pentanediol (Aldrich, 95%) and 2-propanol (POCh, Gliwice, Poland, p. a.) were dried with Na pellets and distributed by vacuum distillation into the thin-walled vials. 1-(5-hydroxypentyl)-3(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)urea (UPy-OH) was synthesized as it was described in our previous work

11

. Isophorone diisocyanate (Aldrich, 98%) was distilled under reduced

pressure and storage at low temperature (< 4 oC). Tin(II) octoate (2-ethylhexanoate, Sn(Oct)2, Aldrich, 95%] was purified by two consecutive high-vacuum distillations at 140 °C/3 × 10–3 mbar, stored under vacuum, and finally distributed into thin-walled vials or ampoules equipped with breakseals, which were sealed and stored at -12 °C. THF (POCH, Gliwice, Poland, 99%) was kept over KOH pellets for several days, filtered off, and refluxed over Na pellets for 4 ACS Paragon Plus Environment

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purification. After that it was distilled, degassed, and then stored over liquid Na/K alloy, thereby developing a blue color. All other reagents were purchased from Sigma Aldrich and used as received. Synthesis of the PLA, PTMC and PCL homopolymers Linear PTMC, PCL, and PLLA/PDLA homochiral polymers were synthesized according to known procedures 29-30 employing the mechanism of ROP. All polymerization experiments were performed using the standard high-vacuum technique. The monomers were polymerized in THF at 80 ºC with Sn(Oct)2 as a catalyst, triggered by 1,5-pentandiol, 2-propanol and a UPyfunctionalized initiator, as shown in Scheme S1 in Supporting Information. The resulting polymers were precipitated into methanol and dried under reduced pressure at room temperature. Synthesis of LA/TMC and LA/CL copolymers The coupling reactions of corresponding PTMCs or PCLs with PLAs were carried out through reaction with isophorone diisocyanate under a nitrogen atmosphere, in the presence of dibutyltin dilaurate (DBTL) as catalyst and chloroform as a solvent. Cycloaliphatic IPDI was chosen because it possesses two isocyanate groups with the unequal reactivity. Two different active isocyanate groups of IPDI allows for selective reaction in the two-step coupling procedure. Moreover, IPDI reveals much lover toxicity than commonly used hexamethylene diisocyanate (HDI) 31, and exhibits better solubility in many solvents. In addition, in a final step, IPDI can be easily removed from the resultant polymeric product by re-precipitation. As a representative example, triblock copolymer was synthesized by the following procedure: first a mixture containing monohydroxyl- terminated polylactide and diisocyanate in chloroform ([OH]/[-NCO] equal to 1:4) and catalytic amount of DBTL was stirred for 48 h at 50


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o

C, as shown in the Scheme S2 in the Supporting Information. The obtained isocyanate-

terminated PLA was precipitated into an excess of n-hexane, filtered and dried under vacuum. As a final step, the PLA with one available isocyanate group was used in DBTL- catalyzed reaction with the PTMC-diol or PCL-diol and this reaction was carried out at for 72 h at 50 oC in chloroform ([OH]/[-NCO] equal to 1:1), as is shown in Scheme S3 in the Supporting Information. Stereocomplex formation The equimolar amounts of PLLA-PTMC-PLLA and PDLA-PTMC-PDLA as well as PLLAPCL-PLLA and PDLA-PCL-PDLA copolymers were used for the preparation of the stereocomplexes. The samples of the copolymers with PLLA and PDLA blocks were dissolved separately in acetone and 1,4-dioxane. The solutions were mixed together and left for 24 h. The stereocomplexes in acetone spontaneously precipitated from the solution and supernatant was removed by decantation after 24 h, then the solid was washed with three portions of acetone and dried at room temperature under slight vacuum. However, the stereocomplexes from equimolar mixture of copolymers in 1,4-dioxane did not precipitate spontaneously as it was observed in our previous reports

32-33

, Therefore, we employed an inverse-nanoprecipitation and the cold

methanol was gradually added to induce the precipitation of stereocomplex. All samples were isolated and dried under vacuum. Measurements Proton Nuclear Magnetic Resonance Copolymers composition and microstructure were determined by NMR spectroscopy. 1

H NMR spectra were recorded in chloroform-d1 (CDCl3) using a Bruker Avance III 500 (11.7


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T) spectrometer operating at 500 MHz. The sample solutions were prepared by dissolving 15-30 mg of dried polymer in 1 mL of CDCl3.

Size exclusion chromatography (SEC) The number-average molecular weights (Mn) of copolymers were determined by SEC using an Agilent Pump 1100 Series (preceded by an Agilent G1379A Degaser), equipped with a set of two PLGel 5µ MIXED - C columns. A Wyatt Optilab Rex differential refractometer and a Dawn Eos (Wyatt Technology Corporation) laser photometer (MALS) were used as detectors. The measurements were conducted at 27 °C. The dn/dc increment of the refractive index of 0.035, 0.048 and 0.053 mL·g-1 were used for PLA, PTMC and PCL, respectively. Dichloromethane was used as eluent at a flow rate of 0.8 mL·min-1. Differential scanning calorimetry (DSC) DSC analyses were performed under nitrogen atmosphere at a heating and cooling rate of 2 °C·min– 1 and 10 °C·min–1 on a DSC 2920 Modulated TA Instrument. The measurements were performed from -50 °C to 200 °C for copolymers and -50 °C from to 250 °C for the stereocomplexes. Both temperature and heat flow were calibrated with indium. Fourier Transform Infrared Spectroscopy (FTIR) FTIR spectra were measured with a Nicolet 6700 spectrometer equipped with a DTGS detector. The technique of attenuated total reflectance (ATR) was used for the IR measurements. The spectra were obtained by adding 64 scans at a 2 cm-1 resolution. Scanning electron microscopy (SEM)


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The morphology of obtained micro- and nanospheres were followed by SEM. The images were taken with a JEOL JSH 5500 LV in high-vacuum mode at the accelerated voltage of 10 kV. Samples were coated with a gold conductive layer, about 20 nm thick using ion coating JEOL JFC 1200 apparatus. The electron micrographs were recorded with a resolution of 1024 × 768 pixels.

Atomic force microscopy (AFM) AFM images were recorded using a Nanosurf Flex Axiom with a C3000 controller (Nanosurf AG, Switzerland). The experiments were performed in Dynamic mode (amplitude modulation) intermittent contact mode (tapping mode). For the probes, commercially available rectangular silicon cantilevers (PPP-NCHR Nanosensors) with a nominal radius < 10 nm, asymmetric geometry, a spring constant of 42 N/m and a resonance frequency of 330 kHz were used. The images were recorded with a resolution of 512 × 512 data points. Image analysis was performed using SPIP Image Metrology software (Denmark). Results and discussion The goal of this work was to synthesize the aliphatic esters triblock copolymers with control over their functional groups and investigate the influence of their preparation method, functionalities, and stereocomplexation on the morphology of resulting particles. To achieve this aim, the copolymers consisting of PLLA or PDLA as the external blocks and the PTMC or PCL as the internal blocks were synthesized via coupling with IPDI. The polymer-polymer coupling reaction is well known

31, 34

and is a good alternative for the commonly used ring opening

sequential copolymerization. Therefore, we prepared UPy- functionalized PLLA and PDLA and then reacted their terminal hydroxyl groups with IPDI to form PLA decorated simultaneously 8 ACS Paragon Plus Environment

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with both UPy- and isocyanate- end groups. In the further synthesis, these polymers were used for coupling reactions with PTMC-diols and PCL-diols to form copolymers with ABA composition of PLA/PTMC and PLA/PCL blocks, as shown in Scheme 1.

Scheme 1. Structures of triblock LA/TMC and LA/CL copolymers terminated with UPy- end groups. The progress of the coupling reactions was monitored by 1H NMR, as shown in Figure 1 and Figure S1 in Supporting Information. In the spectra of the final products, the disappearance of the signals at δ = 3.82, and 4.35 ppm was observed, ascribed to the PTMC, and PLA end groups, respectively 5. In addition, the appearance of characteristic resonance peaks of UPy N-H groups at δ = 10.2, 11.9, and 13.1 ppm in the final copolymer

11

demonstrated successful

preparation of triblock copolymers terminated with UPy- groups (Figure S2 in Supporting Information). Similarly, the formation of triblock UPy- terminated LA/CL copolymers was confirmed by 1H NMR (see Figure S3 in Supporting Information). The NMR spectra of LA/TMC and LA/CL copolymers with iPr- end groups can be found as Figure S4 in Supporting Information.


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Figure 1. 1H NMR spectra after each step of the UPy- terminated L,L-LA/TMC copolymer synthesis. The changes of NMR signals integration, which corresponds to reactive end groups (mark in green), proved almost quantitative coupling. Furthermore, the formation of the expected copolymer structures was confirmed by means of FTIR spectroscopy. In the FTIR spectra of the PLA/PTMC and PLA/PCL copolymers, signals characteristic for both co-monomers repeating units are observed, as shown in Figure 2. The confirmation of block copolymers formation was the absence of stretching of group N=C=O bands (2240 - 2270 cm-1) in all spectra of the final products, and the presence of the new bands at the region 1520 - 1590 cm-1 and 2850 - 3000 cm-1 assigned to deformation and stretching vibrations of urethane groups. While the confirmation of UPy- functionalized ABA copolymer formation was the presence of the characteristic vibrational bands at 1663, 1587, and 1522 cm-1 which are assigned to UPy motifs (Figure 2) 35. Similarly, the formation of triblock copolymers terminated with iPr- end groups was confirmed by FTIR (see Figure S5 in Supporting Information).


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Figure 2. FTIR spectra showing the formation of UPy- terminated L,L-LA/TMC (A) and L,LLA/CL (B) copolymers. Moreover, an expected shift of chromatographic peaks to the higher molar mass ranges after coupling reaction clearly indicated the copolymers formation, as shown in Figure S6 in Supporting Information. In the SEC analysis, the monomodal molar mass distributions with Đ ≤ 1.6 for copolymers terminated with both end groups was observed. In addition, for copolymers terminated with UPy- end groups chromatographic peaks are slightly shifted to higher molar masses. However, Mn values for UPy-terminated copolymers, obtained by SEC with MALS detector, are significantly higher than that of iPr- terminated copolymers, what indicates the aggregation of copolymers chains decorated with UPy moieties. This was confirmed previously by the presence of the high-molar fraction at elution volume in the range of 12 - 14 mL in SEC chromatograms of UPy- functionalized PLAs

11

. The determined molar masses of obtained

copolymers are in the range of 9 - 11 kg mol-1, as shown in Table 1 ( the molar mass of homopolymers are collected in Table S1 in the Supporting Information). Table 1. Comparison of the predicted (Mn(theor.)) and measured (Mn(GPC) and Mn(NMR)) molar masses of TMC/LA and CL/LA copolymers.


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M Copolymer

M

n

M

n

Entry

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a

(theor.) -1

n

(SEC, RI)

b

-1

(kg mol )

(kg mol )

M

(SEC,

n

c

MALS) -1

1

iPr-PLLA-PTMC-PLLA-iPr

10.0

13.2

(kg mol ) 13.2

2

iPr-PDLA-PTMC-PDLA-iPr

10.0

12.3

10.7

(NMR)d

Đe

-1

(kg mol ) 9.7

1.6

11.1

1.5

3

UPy-PLLA-PTMC-PLLA-UPy

10.0

15.9

22.8

11.2

1.3

4

UPy-PDLA-PTMC-PDLA-UPy

10.0

18.5

29.7

10.1

1.4

5

iPr-PLLA-PCL-PLLA-iPr

10.0

14.5

12.2

10.5

1.5

6

iPr-PDLA-PCL-PDLA-iPr

10.0

13.3

13.6

10.0

1.4

7

UPy-PLLA-PCL-PLLA-UPy

10.0

16.8

20.6

9.8

1.3

8

UPy-PDLA-PCL-PDLA-UPy

10.0

18.6

21.8

9.6

1.3

a

The number-average molar based on the starting concentrations of the comonomers. The number-average molar masses determined by SEC with an RI detector and calibration with polystyrene standards. c The number-average molar masses determined by SEC with a laser light scattering detector on the basis of the assumption that dn/dc = 0.035 mL·g-1 (PLA), 0.048 mL·g-1 (PTMC) and 0.053 mL·g-1 (PCL) respectively, calculated as an average value from two measurements obtained for PLA and PTMC, as well as PLA and PCL blocks. d The number-average molar masses determined from the ratio of the relative intensities of the main-chain and endgroup signals in the 1H NMR spectra. e Ð = Mw/Mn measured by SEC with RI detector. b

To investigate the influence of the composition and different end groups on the thermal properties of copolymers, differential scanning calorimetry (DSC) was employed. The thermograms of iPr- and UPy-functionalized are depicted in Figure 3. For the comparison, the thermograms of homopolymers are shown in Supporting Information (Figure S7).


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Figure 3. DSC thermograms (the rate of heating and cooling: 2 °C·min-1) of iPr- and UPyterminated L,L-LA/TMC (A) and L,L-LA/CL (B) copolymers during first heating. Copolymers were precipitated from the solution into methanol. For two triblock enantiomeric copolymers with iPr- end groups one Tg value is observed at -14.3 °C for PLLA-PTMC-PLLA and at -15.3 °C for PDLA-PTMC-PDLA which is related to glass transition temperature of PTMC segments. In addition, the Tg of PLA segments are in the range 49-56 °C for PLA for both enantiomers. The existence of two distinct Tg in PLA-PTMCPLA copolymers proves that phase separation in these copolymers occurs 5. However, UPy- end capped copolymers show only one distinct Tg values in the range 47-54 °C which is related to PLA segments (the signals of PTMC can be hardly distinguished). Especially, it can be seen in the second heating run of DSC in Figure S8 Supporting Information. This can be attributed to two effects: plasticizing of PLA by TMC segments 5, 36-37 and the possible presence of extended 13 ACS Paragon Plus Environment

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defects such as PLA chain loops that can locally increase their mobility

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38

. Moreover, the

hydrogen bonding interactions of pendant groups in copolymers can enhanced the miscibility of both blocks

36

and this can also explain the existence of one Tg in UPy-functionalized

copolymers. For the PLA-PCL-PLA copolymers, the Tg of PLA segments cannot be observed because this transition is masked by the melting peak of PCL 39. The melting temperature of this copolymer is also affected by the presence of UPy- end groups. For PLA-PTMC-PLA copolymers decorated with UPy- end groups the melting temperature of PLA blocks is ~ 20 °C lower than for isopropoxy functionalized copolymers, in the first heating run. It is noteworthy that UPy moieties have a higher steric hindrance than isopropoxy functional groups, and therefore their influence is much stronger which leads to hindering the crystallization of the PLA segments in the copolymer (even during precipitation from the solution). This causes the formation of crystallites with lower perfection and in consequence lower melting temperature. This is attributed to the effect of UPy- end groups interactions which can decrease the diffusion ability of PLA segments, and as a consequence, prohibit the crystallization of PLA 40-41. Because PTMC block is amorphous only one melting peak of this copolymer is observed. The same trend is observed for PLA-PCL-PLA copolymers, however, the melting temperature of PCL is not altered by the presence of UPy- end groups, as shown in Table S2. It is worth noting, that thermal properties of copolymers differ slightly in the first heating run of DSC whether it contains PLLA or PDLA chains, however in the second heating run, after removal of residual thermal history, the thermal parameters are almost the same for iPr-functionalized copolymers, whereas UPy-functionalized copolymers exhibit lower degrees of crystallinity due to the effect of UPy end groups.


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In addition to the ability for supramolecular chain extension achieved by UPy- chain capping, we took additional advantage of dually associated stereocomplexes

1-4

, thereby

combining hydrogen-bonding interactions of enantiomeric PLLAS and PDLAs with the association of UPy- end groups between macromolecules. Moreover, by the alteration of comonomers repeating units in copolymers, we tuned the macromolecules rigidity. Based upon this approach of polymeric building-block assembly, we obtained PLA stereocomplexes in two different solvents: acetone and 1,4-dioxane. The equimolar mixtures of functionalized copolymers in 1,4-dioxane were precipitated into methanol, whereas a mixture in acetone was left in this solution at ambient temperature to precipitate. Subsequently, the resulting stereocomplexes were dried at vacuum and FTIR analysis was used to confirm the presence of stereocomplex assemblies. After stereocomplexation, a band appears at 909 cm-1, which is characteristic for the β-helix of stereocomplexes, whereas the band of the α-helix vibrations of enantiomeric PLAs at 921 cm-1 completely disappear 42, as shown in the Figure S9 in Supporting Information. To provide a further proof of stereocomplexation, DSC was used to investigate the thermal properties of stereocomplexed copolymers. Typically, the crystallinity and melting temperature of the supramolecular PLLA and PDLA copolymers increases significantly upon blending with the complementary enantiomeric PLA

43-45

. The Tm values of stereocomplexed

copolymers obtained in methanol are in the range ~ 180 - 207 °C in the first and second heating run of DSC, which is much higher than that of homocrystalites of PLA block in copolymers (~ 120 - 150 °C). The values of Tm and ∆Hm of stereocomplexes obtained via spontaneous precipitation in acetone are higher in comparison to inverse-nanoprecipitation, as shown in Table S3. It is clear that sedimentation plays an important role in controlling their regular folding in 15 ACS Paragon Plus Environment

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acetone which enhances their ability to crystallization. This demonstrates that after mixing of equimolar amounts of both enantiomeric copolymers, PLLA-PTMC-PLLA and PDLA-PTMCPDLA as well as PLLA-PCL-PLLA and PDLA-PCL-PDLA, melting peaks at temperatures characteristic for stereocomplexes were observed in the first and second heating run of DSC. It indicates that the stereocomplex formation is fully reversible

11, 28

. To elucidate the role of the

composition of obtained copolymers and the UPy- end groups, we also compared the crystallization behavior of the stereocomplexed copolymers of the corresponding PLA-PTMCPLA and PLA-PCL-PLA bearing the UPy- end groups with iPr- functionalized copolymers, as shown in Table S2. For the mixtures of enantiomeric polymers, the melting endotherm differs with the functionality and compositions of copolymers, as shown in Figure 4. The lower melting temperature was observed for the copolymer with UPy units, therefore, it can be concluded that UPy- end groups depress not only homocrystallization but also the stereocomplex crystallization of PLA blocks (see Figure 4), which is in contrast to previous observation by Pan et al. 43. They found that UPy- end groups enhanced the interactions between enantiomeric blocks and facilitated the crystallization of the formed stereocomplex 35, 43. In addition, the slightly higher melting temperature (Tm,sc) and melting enthalpies (∆Hm,sc) was observed for sc-UPy-PLA-PCL-PLA-UPy in comparison to sc-UPy-PLA-PTMC-PLA-UPy, as shown in Table S3. This is attributed to microphase separation process of stereocomplex PLA segments with semi-crystalline PCL blocks what could enhance the sc-PLA crystallization by the hetero-nucleation with PCL blocks. Thus, in the first and second heating run of DSC, both the melting endotherm of PCL and PLA stereocomplex was observed which proved the phase separation between these two comonomers blocks, as shown in Figure 4. In contrast, for the amorphous PTMC, due to the lack of nucleating activity of PTMC blocks, the lower Tm and ∆Hm 16 ACS Paragon Plus Environment

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of stereocomplexes is observed. It can be concluded that the crystallization of PCL segments with stereocomplexed PLA blocks causes the formation of stereocomplex crystallites with better perfection which additionally increases the melting temperature of UPy-PLA-PCL-PLA-UPy in comparison to UPy-PLA-PTMC-PLA-UPy. In addition, the lateral stacking of urethane groups can also have a strong influence on the self-assembly and phase-separation process 46-47

Figure 4. DSC thermograms of stereocomplexed particles composed of copolymers PLAPTMC-PLA (A) and PLA-PCL-PLA (B), terminated with iPr- and UPy- end groups. Scanning electron microscopy was chosen as a tool for the direct observation of the morphological differences between the particles of copolymers and stereocomplexes with varying composition. The PLA-PTMC-PLA copolymers functionalized with and iPr- and UPyend groups were prepared via the drop-wise addition of methanol to the copolymers solution in THF , whereas their stereocomplexes were precipitated from 1,4-dioxane into non-solvent. The iPr-PLA-PTMC-PLA-iPr copolymer assembled in flower aggregates with the size of 10 - 20 µm; these flowers grew from individual lamellae which due to the topological restriction of the neighboring lamellae, form branched and interpenetrating lamellae petals, as shown in Figure 5A. This morphology was also observed for UPy- functionalized 3-arm PLLA during the slow crystallization from solution

43

. In contrary, the UPy-PLA-PTMC-PLA-UPy copolymers self17 ACS Paragon Plus Environment

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Page 18 of 41

assembled into well-defined microspheres with the sizes of 0.2 to 4.0 µm which indicates the strong influence of the UPy units on the resulting morphology. We anticipate that strong intramolecular interactions of UPy units are essential for the formation of spherical particles. This interaction imparts the formation of polymer rich droplets what induces homogenous nucleation of PLLA chains near the droplet/solution interface leading to spherical particles with different sizes. To improve particle uniformity the stereocomplexation was applied

11

. The

interactions of the helical pairs of enantiomeric PLAs causes the additional physical crosslinking in solution what imparts faster crystallization rate of PLLA and PDLA. In addition, the UPy units can facilitate the anchoring of stereocomplexed copolymers at the 1,4dioxane/methanol interface by reducing the interfacial energy

48

. Therefore, the uniform

stereocomplexed particles are observed for UPy-PLA-PTMC-PLA-UPy, rather than for iPr-PLAPTMC-PLA-iPr for which this type of interactions is impossible. Interestingly, the size of the stereocomplex particles can be tuned by the presence of different functionality at the copolymers chains. The diameter of particles obtained from a solution of UPy-PLA-PTMC-PLA-UPy copolymers was approximately 0.5 µm, and it was smaller than the diameter of iPr-PLA-PTMCPLA-iPr, which was 1 - 2 µm. This can be attributed to the specific preorganization of macromolecules in the formed polymer-rich droplet due to effective cooperative interactions of enantiomeric PLA segments 27. This is induced by the UPy hydrogen bonds between copolymer precursors and retard the formation of larger polymer-rich droplets.


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Figure 5. SEM micrographs illustrating the morphology of PLA-PTMC-PLA copolymers and its stereocomplexes (copolymers with Mn ~ 10 kg mol-1) obtained in methanol. In the case of copolymers of PLA-PCL-PLA, the formed particles have exhibited spherical morphology neither for individual copolymers nor for stereocomplexes, as shown in Figure 6. This is an additional proof that the phase-separation occur between the PLA and PCL and in the microscale, it causes the formation of petal-like morphology. The competition between crystallization of PCL and PLA blocks retards the formation of spherical particles because the radial growth of polymer lamellae is mainly induced by heterogeneous nucleation. At the early stages of phase separation in the polymer solution, the randomly oriented and the well-distributed interface is formed either by spinodal decomposition or by nucleation

49

. The

particles are prepared via the drop-wise addition of copolymers to a poor solvent, therefore this method of preparation enhances the nucleation in the concentrated phase of polymers which prefers to occur at the diffuse interface. Subsequently, the crystallites are generated along the curvature of the spherical surface of the segregated polymers domains and crystals are randomly oriented. This process has enthalpic rather than entropic origin, similar to polymer immiscible


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blends 50. The microphase separation leads to non-equilibrium morphologies and in this process, the phase separation preceded the crystallization of copolymer blocks

51-52

, therefore the

spherical morphology is not formed. In addition, even a faster crystallization caused by the stereocomplexation did not impart the spherical shape of the particles what proves that block segregation strength disrupts the stereocomplexation process and stereocomplexed crystals with lower perfection are probably formed.

Figure 6. SEM micrographs illustrating the morphology of PLA-PCL-PLA copolymers and its stereocomplexes (copolymers with Mn ~ 10 kg mol-1) obtained in methanol. Furthermore, to elucidate the influence the stereocomplex preparation method on the shape and dimension of forming particles we compare the morphology of particles obtained by spontaneous precipitation in acetone and those prepared via the drop-wise addition of methanol to a solution of copolymers in 1,4-dioxane. As was expected, the more uniform particles with the size of ~ 400 nm were obtained by spontaneous precipitation of UPy- functionalized copolymers 53

. Thus, the spontaneous pre-organization of PLA macromolecules containing UPy- end groups

in acetone is apparently a factor promoting the formation of uniform spherical nanospheres 20 ACS Paragon Plus Environment

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during precipitation of the stereocomplexed UPy-PLA-PTMC-PLA-UPy copolymers (see Figure S10 in Supporting Information). We anticipate that the nucleation and growth is a dominant mechanism leading to their formation 33. To prove our concept that the nucleation and growth is a mechanism of stereocomplexed nanoparticles formation, we conducted the AFM analysis to elucidate the nanostructure of particles obtained via spontaneous precipitation in acetone. The AFM images indicate that stereocomplex

nanoparticles

are

formed

via

aggregation

of

stereocomplex

species

(nanogranules) having nanometric size. The measured size of nanogranules of stereocomplexed copolymers with UPy functionalities is ~ 52 nm, (see Figure S11 in Supporting Information) which is close to the values observed for PEG-PLA and PLA-PEG-PLA stereocomplex nanoparticles deposited on silicon surface

54

. In our case, the morphology can be attributed to

phase inversion process in which the UPy-terminated PLA stereocomplex becomes the continuous phase that surrounds the PTMC or PCL phase 55-56, as shown in Figure 7b and Figure S12 in Supporting Information. In addition, strongly associated UPy- end groups can be the soft polar interface between sc-PLA crystallites

57

. In contrast to the results obtained for sc-UPy-

PLA-PTMC-PLA-UPy, spontaneous precipitation of sc-iPr-PLA-PTMC-PLA-iPr particles leads to the randomly associated nanogranules formation due to the lack of their end groups interactions, as shown in Figure 7a. In addition to UPy- end groups interactions, the swelling of block copolymers in acetone is also important in this process

58-59

. As a result, the immiscibility of the PTMC or PCL and

stereocomplexed blocks induces the internal phase separation on the nanoscale, producing multicompartment nanogranules 60-61 The mechanism of the similar process was described by us before

33

and may be summarized as follow: all nanogranules nucleate at the same time to form


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nanoaggregates, which then grow and after reaching the critical size, precipitate in the form of uniform nanoparticles.

Figure 7. AFM height and phase images of sc-iPr-PLA-PTMC-PLA-iPr (A) and sc-UPy-PLAPTMC-PLA-UPy (B) revealing the nanogranular nature of the nanospheres surface and 3D image with phase contrast of two different blocks of the stereocomplexed copolymers. Conclusions In summary, a simple and efficient method to prepare triblock copolymers of PLA and PTMC or PCL with two different functional groups was successfully achieved. Introduction of the UPy moiety to the copolymers allows for the strong hydrogen bonding into PLA-PTMC-PLA and PLA-PLC-PLA copolymers, respectively leading to form supramolecular aggregates. The interfacial energy between block copolymers as well as phase separation was controlled via the composition of polymeric blocks, end groups, stereocomplexation and method of their preparation. As a result, we can tune the thermal properties of prepared polymeric materials and control the phase separation not only at microscale but also in nanoscale. Both the flower-shape and spherical particles can be obtained by varying the preparation method, composition, and


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functional end groups of triblock copolymers. This allows for the creation of a “library” of materials from which particles with controllable morphology are formed in a convenient way. In addition, the presence of the UPy moieties as the stimuli-responsive groups in the final microand nanoparticles, and also biocompatibility and biodegradability building copolymer blocks, allow these materials to be potentially used as drug carriers.

Supporting Information: Additional information is available via the Internet at http://acs.pubs.org/.

Acknowledgements: Dr. M. Socka acknowledges support from the National Centre for Research and Development (NCBiR); Project LACMAN PBS2/A1/12/2013. Dr. M. Brzezinski acknowledges support from the National Science Center Poland Grant No. DEC- 2016/23/D/ST5/02458. References: (1)

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block copolymers in nanoparticles. Angew. Chem., Int. Ed. 2008, 47 (42), 8044-8046.


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Self-assembly of triblock copolymers from cyclic esters as a tool for tuning their particles morphology M. Socka*, M. Brzezinski, A. Michalski, A. Kacprzak, T. Makowski, A. Duda

The series of the triblock copolymers composed of L,L- and D,D-lactide (LA), trimethylene carbonate (TMC) and ɛ-caprolactone (CL) with isopropyl (iPr) and 2-ureido-4-[1H]pyrimidinone (UPy) end groups were synthesized. These copolymers are intermolecular stereocomplexed by polylactide blocks to promote their self-assembly in organic solvents. Control over particles morphology can be achieved by simply tuning the interactions between polymer chains, which leads to their phase separation in the form of uniform nanoparticles.


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79x47mm (300 x 300 DPI)

ACS Paragon Plus Environment

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Scheme 1. Structures of triblock LA/TMC and LA/CL copolymers terminated with UPy- end groups. 48x13mm (300 x 300 DPI)


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Figure 1. 1H NMR spectra after each step of the UPy- terminated L,L-LA/TMC copolymer synthesis. The changes of NMR signals integration, which corresponds to reactive end groups (mark in green), proved almost quantitative coupling. 85x57mm (300 x 300 DPI)


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Figure 2. FTIR spectra showing the formation of UPy- terminated L,L-LA/TMC (A) and L,L-LA/CL (B) copolymers. 129x56mm (300 x 300 DPI)


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Figure 3. DSC thermograms (the rate of heating and cooling: 2 °C·min-1) of iPr- and UPy-terminated L,LLA/TMC (A) and L,L-LA/CL (B) copolymers during first heating. Copolymers were precipitated from the solution into methanol. 129x93mm (300 x 300 DPI)


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Figure 4. DSC thermograms of stereocomplexed particles composed of copolymers PLA-PTMC-PLA (A) and PLA-PCL-PLA (B), terminated with iPr- and UPy- end groups. 74x30mm (300 x 300 DPI)


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Figure 5. SEM micrographs illustrating the morphology of PLA-PTMC-PLA copolymers and its stereocomplexes (copolymers with Mn ~ 10 kg mol-1) obtained in methanol. 170x78mm (300 x 300 DPI)


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Figure 6. SEM micrographs illustrating the morphology of PLA-PCL-PLA copolymers and its stereocomplexes (copolymers with Mn ~ 10 kg mol-1) obtained in methanol. 170x76mm (300 x 300 DPI)


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Figure 7. AFM height and phase images of sc-iPr-PLA-PTMC-PLA-iPr (A) and sc-UPy-PLA-PTMC-PLA-UPy (B) revealing the nanogranular nature of the nanospheres surface and 3D image with phase contrast of two different blocks of the stereocomplexed copolymers. 170x101mm (300 x 300 DPI)


Self-Assembly of Triblock Copolymers from Cyclic ... - ACS Publications

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