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Copolymers from Unsaturated Macrolactones: Toward the Design of Cross-Linked Biodegradable Polyesters Inge van der Meulen,† Yingyuan Li,† Ronald Deumens,§ Elbert A. J. Joosten,§ Cor E. Koning,† and Andreas Heise*,†,‡ †
Eindhoven University of Technology; Laboratory of Polymer Chemistry, Den Dolech 2, P.O. Box 513, 5600 MB Eindhoven, The Netherlands ‡ Dublin City University, School of Chemical Sciences, Glasnevin, Dublin 9, Ireland § Department of Anesthesiology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands
bS Supporting Information ABSTRACT: The enzymatic synthesis of a series of random copolyesters by ring-opening polymerization of unsaturated macrolactones like globalide and ambrettolide with 1,5-dioxepan-2-one (DXO) and 4-methyl caprolactone (4MeCL) was investigated. 13C NMR diad analysis confirmed the randomness of all copolymers irrespective of the comonomer ratios. Thermal investigation showed that incorporating the comonomers lowered the melting points of the polymers as compared with the macrolactone homopolymers. The decrease was dependent on the comonomer ratio. The unsaturated copolymers were thermally cross-linked using dicumyl peroxide, which resulted in completely amorphous insoluble networks. It was found that 10% incorporation of the unsaturated macolactone was sufficient to obtain a gel content of 95 wt %. Preliminary degradation tests confirm that the cross-linked copolymers are enzymatically degradable and that the incorporation of hydrophilic comonomers like DXO enhances degradation.
’ INTRODUCTION Polyesters are widely used in different branches of industry, from packaging to biomedical materials, as they combine excellent properties with synthetic versatility.1,2 A relatively new class of polyesters is derived from cyclic ω-hydroxy fatty acids. Compared with the very common lactones such as ε-caprolactone, the chemical polymerization of these so-called macrolactones to high molecular weights is challenging but has been achieved by enzymatic ring-opening polymerization.3-6 From the materials perspective, the interest in polyesters derived from macrolactones stems from the excellent mechanical properties of the homopolymers,5,7 which has led to recent investigation of, for example, poly(pentadecalactone), in coating and fiber applications.6,8 We are interested in the application of polymers from unsaturated macrolactones such as Globalide and Ambrettolide for degradable biomedical devices. In a previous paper, we reported the synthesis of homopolymers from these monomers, which proved to be nontoxic.9 Unfortunately, all macrolactone homopolymers investigated by us were nondegradable under physiological conditions, owing to their semicrystalline morphology and high hydrophobicity. We hypothesized that both could be overcome by the introduction of more hydrophilic or crystallinitybreaking comonomers. The expected transition from a semicrystalline to an amorphous or low-melting material by copolyr 2011 American Chemical Society
merization requires a postsynthesis cross-linking step to be able to process the polymers into mechanically stable shapes for biomedical applications. The most common strategy to cross-link polyesters is by radical polymerization of telechelic R,ω-acrylated macromonomers of the polyester used.10-13 However, the polymer networks obtained in this process consist of polyacrylates with polyester cross-links with the drawback that after degradation a polyacrylate of substantial molecular weight will remain. Direct lateral cross-linking of polyesters would provide a clear advantage because nondegradable residues could be avoided. This requires substituted lactones with lateral cross-linkable functionalities, which are inert in the ring-opening polymerization step. Synthetic routes toward substituted lactones have been described in the literature but generally require tedious monomer synthesis or polymer analogous modification.14-17 For example, chlorine-substituted lactones were synthesized via Baeyer-Villiger oxidation of the corresponding ketone. Polymerization resulted in polyesters with chlorine functions, which were converted to azides and subsequently crosslinked by Huisgen’s cycloaddition with alkynes.18,19 A main chain unsaturation provides a much more straightforward functionality Received: January 18, 2011 Revised: January 26, 2011 Published: February 14, 2011 837
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Scheme 1. Copolymers from Unsaturated Macrolactones, Their Thermal Cross-Linking and Degradationa
a
Gl is a mixture of two constitutional isomers with the double bond at the 11 or 12 positions. For reasons of clarity, only one isomer is shown.
for cross-linking because simple radical processes can be employed. However, few examples of this approach have been reported in the literature. One example of unsaturated polyesters was shown by Lou by ring-opening polymerization of 6,7-dihydro-2-(5H)-oxepinone without further investigation of cross-linking the material.20 Kobayashi investigated the enzymatic polymerization and subsequent cross-linking of vinyl-substituted macrolactones.21,22 We have shown that thermally induced radical cross-linking of PGl and PAm provides an easy route toward cross-linked polyesters.9 In this Article, we expand our previous approach by investigating copolymers from unsaturated macrolactones with the goal of increasing the biodegradability of the cross-linked materials. We first investigated the copolymerization with smaller biocompatible comonomers like 1,5-dioxepan-2-one (DXO) and 4-methyl caprolactone (4MeCL), respectively, and their influence on the polymer properties (Scheme 1). In the second part, we show that cross-linking of the polymer can be performed using dicumyl peroxide and that via this route, completely degradable crosslinked polyesters can be obtained in a simple way.
procedures. Dicumyl peroxide was purchased from Aldrich, and 4-hydroxybenzophenone was purchased from Fluka. Methods. Size exclusion chromatography (SEC) was performed on a Waters Alliance system equipped with a Waters 2695 separation module, a Waters 2414 refractive index detector (40 °C), a Waters 2487 dual absorbance detector, and a Polymer Laboratories PLgel guard column, followed by 2 PLgel 5 mm Mixed-C columns in series at 40 °C. Tetrahydrofuran (THF, Biosolve), stabilized with BHT, was used as eluent at a flow rate of 1 mL/min. The molecular weights were calculated against polystyrene standards (Polymer Laboratories, Mp = 580 Da up to M = 7.1 106 Da). All samples were filtered through a 0.2 μm PTFE filter (13 mm, PP housing, Alltech) before analysis. 1H and 13C NMR spectroscopy was performed on a VARIAN Mercury 400 MHz NMR in CDCl3. Data were acquired using VNMR software. Chemical shifts are reported in ppm relative to tetramethylsilane. Differential scanning calorimetry (DSC) was performed on a TA Q100 DSC. Approximately 5 mg of dried polymer was weighed in aluminum hermetic pans. Temperature profiles from -50 to 130 °C with a heating and cooling rate of 10 °C/min were applied. TA Universal Analysis software was used for data acquisition. Melting and crystallization temperatures were determined from the second heating run and the first cooling from the melt, respectively. IR measurements were performed on a PerkinElmer SpectrumOne FT-IR spectrometer using a universal ATR sampling accessory. Kinetic attenuated total reflection fourier transform infrared (ATR-FTIR) spectroscopy measurements were performed on a Bio-Rad Excalibur FTS3000MX infrared spectrometer using the golden gate setup. We recorded 32 scans per spectrum with a resolution of 4 cm-1. Data were acquired using Varian Resolutions Pro. The degree of randomness (R) of the copolymers was calculated from 13 C NMR spectra using the following set of equations27,28
’ EXPERIMENTAL SECTION Materials. Novozym 435 (Candida Antarctica Lipase B immobilized on cross-linked polyacrylate beads) was purchased from Novozymes A/S and dried following a literature procedure.23,24 Globalide and Ambrettolide were kind gifts of Symrise. Toluene was dried over aluminum oxide and stored over molecular sieves. All other solvents used were purchased from Biosolve and used without further purification. DXO25 and 4MeCL26 were synthesized following literature 838
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Figure 1. Left: 13C NMR spectrum of P(Gl-co-DXO) molar ratio 50:50 (entry 3, Table 1). Right: RCH2CdOOR region, peaks are assigned using the diad codes in Table 2. Gl is a mixture of two constitutional isomers with the double bond at the 11 or 12 position. For reasons of clarity, only one isomer is shown. PA=B ¼ PAB þ PBA
ð1Þ
PAX ¼
PA=B þ PAA 2
ð2Þ
PBX ¼
PA=B þ PBB 2
ð3Þ
PA=B 2PAX PBX
ð4Þ
R ¼
intervals, the buffer of one sample was removed, and the polymer was dried overnight, and the weight loss determined gravimetrically.
’ RESULTS AND DISCUSSION Polymer Synthesis and Characterization. To investigate systematically the properties of the copolymers from unsaturated macrolactones, Gl and Am were copolymerized with 4MeCL and DXO in various ratios. The ability to homopolymerize enzymatically all individual monomers is known,9,30,31 but copolymers of these macrolactones were never previously investigated. All polymerizations were carried out in the same manner using Novozym 435 as a catalyst. For the molecular and physical characterization, preparative amounts of the copolymers were synthesized using the respective monomer combinations in toluene using water present in the enzyme as a nucleophile. Because of the unknown reactivity ratios of the monomers, all polymerizations were carried out over at least 24 h to ensure incorporation of both monomers and complete randomization of the copolymer. In general, all copolymers containing >50% Gl or Am were obtained as white powders, whereas copolymers containing 1 indicates a shorter sequence length).24,25 This suggests that despite the potentially different reactivity ratios of the monomers, all obtained copolymers are randomly distributed because of the rapid transesterification by Novozym 435. This is in agreement with a study by Gross on the enzymatic copolymerization of pentadecalactone with dioxanone.32 In Table 1, all melting (Tm) and crystallization points (Tc) of the copolymers with different compositions are listed. Homopolymers of DXO and 4MeCL are amorphous, and no melting point could be observed. All copolymers that are not completely amorphous reveal a single crystallization and melting process. Because of the amorphous character introduced by the comonomers DXO and 4MeCL, the melting enthalpies of the copolymers decrease upon increasing the amount of these comonomers (Figure 2). Moreover, with increasing the amount of these comonomers, the melting point of the copolymers decreased, for example, from 46.2 °C for the PGl homopolymer to 42.4 and 0.3 °C for the copolymers with 9 and 72% DXO, respectively. This is in agreement with a study by Albertsson stating that the incorporation of amorphous DXO will lower the melting and crystallization temperature.33 With the exception of copolymer 8 (75% 4MeCL), which is fully amorphous, all 4MeCL copolymers show melting transitions. The same trend was observed as for the DXO copolymers; namely, the incorporation of 4MeCL results in lowering of the melting and crystallization temperature. In general, the difference between Tm and Tc is very small for all polymers (ca. 20 °C), and in the thermograms of the cooling run (Figure 2, bottom) sharp peaks are observed. This confirms that crystallization in these materials
batch-to-batch variations. The polydispersity indices (PDIs) were all ∼2, as expected for enzymatic ROP under these conditions. P(Gl-co-4MeCL) was prepared using the same ratios as the P(Gl-co-DXO) set, and also in this series the incorporation ratio was in agreement with the monomer feed ratio (Table 1, entry 5-8). All molecular weights obtained from copolymerization of Gl with 4MeCL were ∼17 000 g/mol, with the exception of P(Gl-co-4MeCL) (25/75), for which only a mass of 6000 g/mol could be obtained. The randomness of all copolymers was derived from 13C NMR integrals (Table 2). The calculated diad content of A-B copolymers was compared with the theoretical diad content assuming a statistic random distribution. The signal from the carbon adjacent to the oxygen of the ester function (RCd OOCCR) between 70 and 60 ppm was used to calculate the diad ratios for 4MeCL copolymers. For the DXO containing copolymers, the ether carbon signal of this monomer interferes with the RCdOOCCR signals. Therefore, the diads for these polymers were calculated using the signal from the carbon next to the carbonyl (RCH2CdOOR) between 33 and 36 ppm (Figure 1). Signals from Gl-Gl repeating units (AA, 34.3 ppm) can be found next to the signals from DXO-DXO repeating units (BB, 34.8 ppm) in the spectrum. Gl-DXO (AB, 34.3 ppm) and DXO-Gl (BA, 35.0 ppm) diads can be found to be adjacent to the AA and BB peaks. It is noticeable that the diad ratios calculated from 13C NMR integration correspond very well with the theoretical values for a statistically random distribution in most cases, whereas for some, a deviation could be due to errors deriving from the NMR integration (Table 2). Nevertheless, the degree of randomness, R, is between 0.9 and 1.3, which is reasonably close to the expected value for fully random copolyesters, for which the distribution of the two different monomer 840
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Figure 2. DSC thermograms of the second heating run (top) and the cooling run (bottom) of copolymers of globalide (Gl) and DXO. The numbers in parentheses denote the copolymer composition.
is fast. Glass-transition temperatures could not be measured because of the limit of the DSC equipment (-60 °C). Cross-Linking of Copolymers. It was previously shown that PGl and PAm can be cross-linked using a thermal cross-linker such as dicumyl peroxide.9 Upon mixing this curing agent with the polymer in the melt and heating to 150 °C, completely crosslinked networks were obtained. Because the dilution of double bonds by copolymerization might have an adverse effect on the network formation, we first investigated the minimum amount of cross-linkable comonomer (Gl or Am) needed to obtain a fully cross-linked material. This study was carried out on a series of copolymers from Gl and ε-caprolactone (CL) (Table 3). This
set of copolymers was chosen as a model system because of the ready availability of CL. These copolymers show an identical polymerization behavior and trends as the DXO and 4MeCL copolymer sets, and all polymers were obtained as random copolymers, as evident from diad analysis. Moreover, the molecular weights are comparable to the ones obtained from the DXO and 4MeCL copolymers (Table 1). The amount of globalide in the P(Gl-co-CL) was varied between 10 and 50 mol percent. For the cross-linking, all copolymers were melted, mixed with dicumyl-peroxide in the melt, and cured at 150 °C for 30 min. Afterward, the cured materials were cooled to room temperature, and the amount of cross-links in the material were 841
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Table 3. Double-Bond Conversion and Gel Content of Cross-Linking Copolymers Containing Globalide and Caprolactone
a
entry
feed Gl/CL [mole%/mol %]
ratio Gl/CL [mole%/mol %]a
Mn [g/mol]b
PDIb
reacted CdC bonds [mole %]c
gel content [wt%]
17
50/50
47/53
20 000
3.3
n.d.
99
18
40/60
40/60
21 000
3.0
13
97
19
30/70
32/68
23 000
2.4
16
98
20
20/80
22/78
18 000
2.8
33
96
21
10/90
10/90
16 000
2.4
58
95
Determined with 1H NMR. b Determined by SEC in tetrahydrofuran. c Determined by IR.
estimated by IR-spectroscopy from the decrease in the signal of the trans-unsaturated carbon-carbon bond at ∼970 cm-1. A clear trend could be seen in the percentage of cross-linked monomer residues in the polymer. The lower the amount of cross-linkable comonomer (Gl), the higher the percentage of reacted double bonds, for example, 58% for P(Gl-co-CL) (10/ 90) and 13% for P(Gl-co-CL) (40/60). This is probably a consequence of the increased network rigidity with higher doublebond density even at low double-bond conversion. This reduces the mobility of the polymer chains and the cross-linking reaction stops. When the amount of Gl is lower, the network becomes less dense, and this facilitates a continuous and more complete crosslinking of the unsaturated bonds in the network. The lower absolute amount of double bonds is thus compensated for by higher cross-linking efficiency. This results in a relatively constant cross-linking density throughout all copolymer compositions in the range of 5 to 6%. The gel content of the cross-linked copolymers was determined by Soxhlet extraction in chloroform. Whereas there is a slight decrease in the gel content with decreasing amount of Gl in the copolymer, it remained >95% for all investigated copolymers (Table 3). The results show that even 10 mol % of Gl is sufficient to obtain a fully cross-linked material. This means that at least 90% of any comonomer can be incorporated without losing the ability to cross-link the system. Considering that in the literature it was described that comonomers like DXO could only be incorporated up to 20 mol % in linear copolymers because of the unfavorable influence on the melting point,34 this presents a real advantage when designing degradable polymers for medical applications because it allows the incorporation of a higher amount of hydrophilic comonomer. This is desirable because it can enhance the hydrophilicity and thus degradation properties of the polymeric materials significantly. By cross-linking, the material can be tuned to meet the desired properties without taking the melting point and crystallinity into account. This opens various possibilities for degradable biocompatible polymers. Enzymatic Degradation of Copolymers. In our previous work, the degradation of cured homopolymers of PAm and PGl was studied.9 It was concluded that no degradation could take place because of the highly hydrophobic and crystalline character of the polymers. It was hypothesized that upon the incorporation of hydrophilic and noncrystalline comonomers like 4MeCL or DXO the enzymatic degradability could be enhanced. In a preliminary study, the influence of the comonomer on the polymer degradation was investigated using P(Am-co-DXO) (25/75), P(Am-co-DXO) (50/50), and P(Gl-co-4MeCL) (53/47). All polymers were cross-linked using dicumyl peroxide at 150 °C, and the obtained films were cut into pieces of ∼1 cm2 (∼100 mg) and placed in test tubes with 4 mL of PBS buffer containing Pseudomonas cepacia lipase in a shaker at 37 °C. It is noticeable
Figure 3. Poly(Gl-co-4MeCl) (75:25) before (left) and after (right) thermal cross-linking with dicumyl peroxide.
Figure 4. Enzymatic degradation of selected cross-linked copolymers in PBF buffer at 37 °C in the presence of Pseudomonas cepacia lipase. Cumulative mass loss as a function of degradation time: b, P(Am-coDXO) (25/75); 9, P(Gl-co-4MeCL) (53/47); 2, P(Am-co-DXO) (50/50).
that all polymers became amorphous upon cross-linking (Figure 3). Degradation was followed during a period of 14-18 weeks, during which the medium and enzyme were replaced weekly. As can be seen in Figure 4, a mass loss of ∼30 wt % was detected for P(Gl-co4MeCL) after 130 days. A similar trend was obtained for the polymer containing 50% DXO, P(Am-co-DXO). A more significant degradation occurred when the DXO concentration in the copolymer was increased. Degradation of P(Am-co-DXO) (25/75) reaches >90 wt % after 100 days. The difference in degradation speed can be explained by the higher hydrophilicity of the latter copolymer due to the incorporation of DXO repeating units. These 842
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preliminary results clearly show that the degradation can be tuned by altering the ratio and nature of the copolymer as hypothesized. However, more systematic degradation studies are required to derive additional quantitative degradation data, in particular, concerning the analysis of the degradation products and the change of the mechanical properties, as has been shown for other cross-linked polymers.35-37
(6) de Geus, M.; van der Meulen, I.; Goderis, B.; Van Hecke, K.; Dorschu, M.; van der Werff, H.; Koning, C. E.; Heise, A. Polym. Chem. 2010, 1, 525. (7) Gazzano, M.; Malta, V.; Focarete, M. L.; Scandola, M.; Gross, R. A. J. Polym. Sci., Part B: Polym. Phys. 2003, 41, 1009. (8) Simpson, N.; Takwa, M.; Hult, K.; Johansson, M.; Martinelle, M.; Malmstrom, E. Macromolecules 2008, 41, 3613. (9) van der Meulen, I.; de Geus, M.; Antheunis, H.; Deumens, R.; Joosten, E. A. J.; Koning, C. E.; Heise, A. Biomacromolecules 2008, 9, 3404. (10) Aoyagi, T.; Miyata, F.; Nagase, Y. J. Controlled Release 1994, 32, 87. (11) Takwa, M.; Simpson, N.; Malmstrom, E.; Hult, K.; Martinelle, M. Macromol. Rapid Commun. 2006, 27, 1932. (12) Yan Xiao, Cummins, D.; Palmans, A. R. A.; Koning, C. E.; Heise, A. Soft Matter 2008, 4, 593. (13) Thatiparti, T. R.; Tammishetti, S.; Nivasu, M. V. J. Biomed. Mater. Res., Part B 2009, 111. (14) Madelaine, C.; Valerio, V.; Maulide, N. Angew. Chem., Int. Ed. 2010, 49, 1583. (15) Cossy, J.; Rasamison, C.; Pardo, D. G. J. Org. Chem. 2001, 66, 7195. (16) Pounder, R. J.; Dove, A. P. Polym. Chem. 2010, 1, 260. (17) Jerome, C.; Lecomte, P. Adv. Drug Delivery Rev. 2008, 60, 1056. (18) Lenoir, S.; Riva, R.; Lou, X.; Detrembleur, C.; Jer^ome, R.; Lecomte, P. Macromolecules 2004, 37, 4055. (19) Riva, R.; Schmeits, S.; Jer^ome, C.; Jer^ome, R.; Lecomte, P. Macromolecules 2007, 40, 796. (20) Lou, X.; Detrembleur, C.; Lecomte, P.; Jerome, R. Macromolecules 2001, 34, 5806. (21) Uyama, H.; Kobayashi, S.; Morita, M.; Habaue, S.; Okamoto, Y. Macromolecules 2001, 34, 6554. (22) Habaue, S.; Asai, M.; Morita, M.; Okamoto, Y.; Uyama, H.; Kobayashi, S. Polymer 2003, 44, 5195. (23) de Geus, M.; Peeters, J.; Wolffs, M.; Hermans, T.; Palmans, A. R. A.; Koning, C. E.; Heise, A. Macromolecules 2005, 38, 4220. (24) de Geus, M.; Schormans, L.; Palmans, A. R. A.; Koning, C. E.; Heise, A. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 4290. (25) Mathisen, T.; Masus, K.; Albertsson, A.-C. Macromolecules 1989, 22, 3842. (26) Vangeyte, P.; Jer^ome, R. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 1132. (27) Yamadera, R.; Murano, M. J. Polym. Sci., Part A-1: Polym. Chem. 1967, 5, 2259. (28) Jansen, M. A. G. Modification of Poly(butylene terephtalate) by Incorporation of Comonomers in the Solid State. Ph.D. Thesis, Eindhoven University of Technology, The Netherlands, 2005. (29) Ebata, H.; Toshima, K.; Matsumura, S. Macromol. Biosci. 2007, 7, 798. (30) Mathisen, T.; Albertsson, A.-C. Macromolecules 1989, 22, 3838. (31) Al-Azemi, T. F.; Kondaveti, L.; Bisht, K. S. Macromolecules 2002, 35, 3380. (32) Zhaozhong, Jiang; Azim, H.; Gross, R. A. Biomacromolecules 2007, 8, 2262. (33) Andronova, N.; Finne, A.; Albertsson, A.-C. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 2412. (34) Albertsson, A.-C.; Gruvegard, M. Polymer 1995, 36, 1009. (35) Hakkarainen, M.; Albertsson, A.-C. Adv. Polym. Sci. 2008, 211, 85. (36) H€oglund, A.; Hakkarainen, M.; Kowalczuk, M.; Adamus, G.; Albertsson, A.-C. J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 4617. (37) Melchels, F. P. W.; Velders, A. H.; Feijen, J.; Grijpma, D. W. Macromolecules 2010, 43, 8570.
’ CONCLUSIONS Biodegradable random copolyesters were made via enzymatic ring-opening polymerization from unsaturated macrolactones with DXO and 4MeCL. Thermal investigation showed that the melting point was lowered upon incorporating the comonomers and that the decrease was dependent on the comonomer ratio. Because of the presence of main chain double bonds from the unsaturated macrolactones, all copolymers could be cross-linked, which resulted in completely amorphous insoluble networks. It was found that 10% incorporation of the unsaturated macolactone was sufficient to obtain a gel content of 95 wt %. Preliminary degradation tests confirm that the cross-linked copolymers are enzymatically degradable and that the incorporation of hydrophilic comonomers like DXO enhances degradation. The results presented here open the possibility of designing new materials based on bioderived functional macrolactones. Whereas incorporation of comonomers allows for modification of the polymer properties like hydrophilicity, crystallinity, and so on, the possibility for direct cross-linking via the main-chain double-bonds can be utilized to stabilize the polymers in the preferred shapes for the desired applications. ’ ASSOCIATED CONTENT S b 13
Supporting Information. GPC traces of copolymers and C NMR spectra of copolymers with diad signal integration. This material is available free of charge via the Internet at http:// pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ ACKNOWLEDGMENT This work forms part of the research program of the Dutch Polymer Institute (DPI, project number 608). We thank Symrise for their kind gift of the macrolactone monomers. A.H. is an SFI Stokes Senior Lecturer (07/SK/B1241). ’ REFERENCES (1) Griffith, G. Acta Mater. 2000, 48, 263. (2) Polymers for Biomedical Applications; Kulshrestha, A. S., Mahapatro, A., Eds.; ACS Symposium Series 977; American Chemical Society: Washington, DC, 2008. (3) Namekawa, S; Suda, S.; Uyama, H.; Kobayashi, S. Int. J. Biol. Macromol. 1999, 25, 145. (4) Bisht, K. S.; Henderson, L. A.; Gross, R. A. Macromolecules 1997, 30, 2705. (5) Focarete, M. L.; Scandola, M.; Kumar, A.; Gross, R. A. J. Polym. Sci., Part B: Polym. Phys. 2001, 39, 1721. 843
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