Degradation Behavior of Poly(Îµ-caprolactone)-b-poly(ethylene glycol

Biomacromolecules 2004, 5, 1756-1762

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Degradation Behavior of Poly(E-caprolactone)-b-poly(ethylene glycol)-b-poly(E-caprolactone) Micelles in Aqueous Solution Yong Hu,† Leyang Zhang,† Yi Cao,† Haixiong Ge,‡ Xiqun Jiang,*,†,§ and Changzheng Yang† Laboratory of Mesoscopic Chemistry and Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing 210093, People’s Republic of China, Department of Materials Science, Nanjing University, Nanjing 210093, People’s Republic of China, and Jiangsu Provincial Laboratory for Nanotechnology, Nanjing University, Nanjing 210093, People’s Republic of China Received March 16, 2004; Revised Manuscript Received June 2, 2004

Poly(-caprolactone)-b-poly(ethylene glycol)-b-poly(-caprolactone) triblock copolymers were synthesized by the ring-opening polymerization of -caprolactone in the presence of hydroxyl-terminated poly(ethylene glycol) with different molecular weights, using stannous octoate catalyst. Micelles prepared by the precipitation method with these triblock copolymers exhibit a core-shell structure. The degradation behaviors of these core-shell micelles in aqueous solution were investigated by FT-IR, 1H NMR, GPC, DLS, TEM, and AFM. It was found that the degradation behavior of micelles in aqueous solution was quite different from that of bulk materials. The size of the micelles increased in the initial degradation stages and decreased gradually when the degradation period was extended. The caprolactone/ethylene oxide (CL/EO) ratio in micelles measured by NMR also shows an increase at the initial degradation stage and a decrease at later stages. The morphology of these micelles became more and more irregular during the degradation period. We explain the observed behavior by a two-stage degradation mechanism with interfacial erosion between the cores and the shells followed by core erosion. Introduction Colloidal drug delivery systems including nanoparticles, microcapsules, and micelles have attracted increasing interest because they can effectively deliver drugs to a target site, thus increasing the therapeutic benefit and decreasing side effects of the drug.1-6 Among these colloid systems, nanoparticles, especially polymeric micelles, made of biodegradable and biocompatible amphiphilic block copolymers, such as poly(lactide)-poly(ethylene glycol) (PLA-PEG),7 poly(caprolactone)-poly(ethylene glycol) (PCL-PEG),8,9 and their copolymers (PCL-PLA-PEG),10 have been the subject of growing scientific attention in recent years. Generally, amphiphilic block copolymers can self-assemble to form nanosized micelles consisting of a hydrophilic outer shell and a hydrophobic inner core in aqueous media. Such micelles with core-shell structure can readily incorporate lipophilic drugs into their cores and release them in a controlled manner at a later stage, while the hydrophilic shell can provide stabilization for the micelles without the need for additional stabilizers, thus making them a potential carrier for drugs with poor water solubility.11 The size of these micelles is normally in the range of 10-200 nm, which is small enough to avoid filtration by the lung and spleen.12 In addition, if the hydrophilic shell is composed of flexible * Corresponding author. Fax: 86-25-83317761. E-mail: [email protected]. † Laboratory of Mesoscopic Chemistry and Department of Polymer Science & Engineering. ‡ Department of Materials Science. § Jiangsu Provincial Laboratory for Nanotechnology.

polymers such as PEG and its derivatives, the outer shell can also help these micelles escape from the reticuloendothelial system (RES) after intravenous (iv) administration.13-15 Previous efforts have been made on the preparation method of micelles, control of the micelle size, modification of the micelles, the drug release behavior, and the biodistribution of micelles in body.16 However, only limited studies have focused on the stability and degradation of the micelles in aqueous solution although the degradability and stability in aqueous solution, which affect their drug encapsulation efficiency and drug release characteristics, are very important for the application of micelles. The biodegradability and stability of amphiphilic block copolymers films based on polyester and poly(ethylene glycol) have been extensively studied. Li et al. reported the degradability of PCL-PEG in a phosphate buffer solution containing pseudomonas lipase.17,18 They found that the hydrophilicity of PCL-PEG films was greatly improved compared with that of PCL homopolymer, but the content of PEG in the copolymer would not affect the degradability of the PCL segment. The hydrolytic degradation of PLA-PEO-PLA (PEO, poly(ethylene oxide)) triblock copolymers was investigated by Vert et al.19,20 They found that ester bonds of PLA-PLA and PLA-PEG were cleaved at similar rates under acidcatalyzed degradation. By taking advantage of the biodegradability of PCL, Wooley et al.21 and Jiang et al.22 successfully prepared hollow nanospheres by selective degradation of the polyester (PCL) core of core-shell structure micelles, but the degradation mechanism of PCL was not mentioned.

10.1021/bm049845j CCC: $27.50 © 2004 American Chemical Society Published on Web 07/30/2004

Degradation Behavior of PCL-PEG-PCL Micelles

Recently, Wu et al. developed a novel method to study the enzymatic biodegradation of nanoparticles consisting of PCL homopolymer and PCL-PEO diblock copolymer in aqueous medium by laser light scattering (LLS).23,24 They found that, in the presence of lipase, the PCL nanoparticles degraded 1000 times faster than PCL films and the biodegradation of the PEO-b-PCL nanoparticles took place in the PCL core in a one-by-one fashion. In this paper, we use the micelles of PCL-PEG-PCL triblock copolymers as a model to study their stability and degradation behavior in aqueous solution. In such micelles of triblock copolymers, both ends of the PEG blocks should be anchored at the core/shell interfaces and PEG chains will form loops at the surface of the micelles, which is different from the micelles of diblock copolymer where only one end of the PEG block is anchored at the core/shell interface and PEG chains form brushlike structures at the surface of the micelles. Because these micelles are usually prepared and maintained in aqueous solution, degradation of these triblock copolymer micelles was carried out in aqueous media at room temperature without enzyme. The changes in physicochemical properties are discussed from the results obtained by Fourier transform infrared spectra (FT-IR), proton nuclear magnetic resonance (1H NMR), gel permeation chromatography (GPC), transmission electron microscopy (TEM), dynamic light scattering (DLS), and atomic force microscopy (AFM). Experimental Section Materials. -Caprolactone (-CL) (Aldrich, USA) was purified by drying over CaH2 and distillation under reduced pressure. Dihydroxyl-terminated poly(ethylene glycol) (PEG), with molecular weights of 2000, 6000, and 10 000 g/mol (abbreviated as PEG2K, PEG6K, and PEG10K) were obtained from Jinling Petroleum Co., Jiangsu, China. Before use, these PEG polymers were purified by extraction with ethyl ether, followed by drying through azeotropic distillation in toluene. Stannous octoate (Aldrich, USA) was used as received. All other chemicals were of analytical grade and used without further purification. Polymerization. PCL-PEG-PCL triblock copolymers were synthesized by a ring-opening polymerization of -CL in the presence of PEG with stannous octoate as the catalyst, according to the literature8 with some modification. Briefly, a predetermined volume of -CL monomer was introduced into a polymerization tube containing 5 × 10-5 mol of degassed PEG and 1 × 10-5 mol of stannous octoate. The tube was connected to a vacuum line, heated to 50 °C, and evacuated for 2 h. Then this tube was sealed off and placed in an oven at 140 °C. After 48 h, the resulting copolymers were cooled, dissolved in CH2Cl2, and precipitated in an excess amount of methanol to removed residual -CL monomers and PEG homopolymer. The precipitate was filtered and washed several times with diethyl ether. The resulting product was dried in a vacuum oven at 40 °C for 3 days and stored in a desiccator under vacuum. Preparation of PCL-PEG-PCL Micelles. PCL-PEGPCL triblock copolymer micelles were prepared by a

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precipitation method. One hundred milligrams of copolymer was dissolved in 20 mL of acetone, and the solution was added dropwise into 50 mL of distilled water under moderate stirring at 25 °C to produce an aqueous suspension. The acetone in suspension was then removed under reduced pressure, and the final volume of the aqueous suspension was concentrated to 20 mL. The suspension was filtered with a microfilter of pore size 650 nm to remove the polymer aggregates and the larger micelle aggregates. The PCLPEG-PCL micelles containing PEG of molecular weight 2000, 6000, and 10 000 g/mol are named P2K, P6K, and P10K, respectively. Degradation of PCL-PEG-PCL Micelles. Five milliliter suspensions containing PCL-PEG-PCL micelles with concentration about 4 mg/mL and 0.01% (w/v) sodium azide (used to inhibit the growth of bacteria) were placed into 10 mL bottles. These bottles were then stored at room temperature. At determined intervals, samples were withdrawn from the bottles for analyses. Molecular Weight Measurement. The number-average molecular weight (Mn), weight-average molecular weight (Mw), and molecular weight distribution of the triblock copolymers were measured by gel permeation chromatography (GPC) (Waters 244) with tetrahydrofuran (THF) as eluent at a flow rate of 1 mL/min. Calibration was accomplished with monodispersed polystyrene standards with a molecular weight ranging from 800 to 124 000 g/mol. FT-IR. FT-IR measurements were carried out on a Bruker IFS66V vacuum-type spectrometer. Samples were obtained by lyophilizing the micelle suspension at -80 °C. The resulting powder was mixed with KBr and pressed into a plate for measurement. 1 H NMR. Samples were obtained as follows: The micelles were separated from the aqueous phase by ultracentrifugation (Ultra ProTM 80, Du Pont) at 50 000 rpm and 4 °C for 1 h. After being washed with distilled water three times, the sediment was frozen and lyophilized to obtain the dried micelle product. The 1H NMR spectra of these dried micelles in deuterated chloroform solution were collected using a Bruker MSL-300 spectrometer to determine the chemical structure and the molecular weight of the copolymer with tetramethylsilane as the internal standard. Wide-Angle X-ray Diffraction (WAXD). WAXD profiles of these copolymers were measured at room temperature on a Rigaku D/Max-Ra X-ray diffractometer employing Nifiltered Cu KR radiation (30 kV, 50 mA, 1.5418 Å) at room temperature. The scanning rate was 0.04°/s. Samples used were the same ones as used in the FT-IR measurement. Size Measurement of PCL-PEG-PCL Micelles. Mean diameter and size distribution of the prepared PCL-PEGPCL micelles were determined by the dynamic light scattering (DLS) method using a Brookheaven BI9000AT system (Brookheaven Instruments Corporation, USA). The analysis lasted 150 s at 25 °C with a detection angle of 90°. The zeta potential of the micelles was obtained with a Zetaplus instrument (Brookheaven Instruments Corporation, USA). Each sample of the micelle suspension was adjusted to a concentration of 0.05% (w/v) in filtered water or in 0.01 M NaCl solution in the case of zeta potential examination. All

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Hu et al. Table 1. Physicochemical Properties of Resulting PCL-PEG-PCL Triblock Copolymers sample

CL/EO (feed)a

CL/EO (product)b

Mnc (g/mol)

Mnd (g/mol)

Mw/Mnd

yield (%)

P2K P6K P10K

9.15 2.82 1.55

8.80 2.84 1.55

48 160 50 360 50 100

34 480 35 040 33 140

1.85 1.53 1.56

82.3 81.5 79.2

a Molar ratio in feed. b Molar ratio in resulting copolymer determined by 1H NMR. c Determined by 1H NMR. d Determined by GPC.

Figure 1.

1H

NMR spectrum of P6K triblock copolymer.

analyses were run in triplicate, and the results are reported as the average values. Morphology Observation of PCL-PEG-PCL Micelles. Morphological examination of the micelles was conducted using a JEOL (Japan) JEM-100S transmission electron microscope (TEM). One drop of micelle suspension was placed on a copper mesh covered with nitrocellulose membrane and dried in air before being negative stained with phosphotungstic sodium solution (1% w/v). Atomic force microscopy (AFM) (SPI3800, Seiko Instruments Inc., Japan) was used to study the surface morphology of the micelles. One drop of properly diluted micelle suspension was placed on the surface of a clean silicon wafer and dried under nitrogen flow at room temperature. The AFM observations were performed with a 20-µm scanner in tapping mode. Results and Discussion Characterization of PCL-PEG-PCL Triblock Copolymers. A series of PCL-PEG-PCL triblock copolymers with various lengths of PEG blocks were synthesized by ringopening polymerization of -CL monomer in the presence of PEG using stannous octoate as the catalyst. Generally, PCL homopolymer is a hydrophobic semicrystalline polymer, contributing to a long degradation period (about 2 years) in vivo.25 The introduction of PEG into a PCL chain can greatly increase the hydrophilicity and reduce the degradation time. To gain insight into the chemical structure of the various PCL-PEG-PCL copolymers, 1H NMR measurements were performed. Figure 1 shows the typical 1H NMR spectrum of P6K copolymer. The sharp singlet peak at 3.62 ppm is attributed to the methylene protons of the oxyethylene unit of PEG, and the other four signals at 4.03, 2.28, 1.61, and 1.36 ppm are assigned to the methylene protons of the oxycarboxy-1,5-pentamethylene unit derived from the PCL segment as marked in Figure 1. The physicochemical properties of the resulting PCLPEG-PCL triblock copolymers are summarized in Table 1. The caprolactone/ethylene oxide (CP/EO) molar ratio of the products was determined from the integrations of methylene bands on the 1H NMR spectra. The molecular weights of PCL-PEG-PCL copolymers measured by NMR were also calculated according to the equation M hn)M h n,PEG + 114DPPCL where DPPCL ) (M h n,PEG/44)(CL/EO).

As shown in Table 1, the compositions of the copolymers are rather close to those of the feed, and the yield is around 80% for all three copolymers after purification. This result indicates that almost all the monomers are converted to the copolymer. Nevertheless, the Mn values calculated from 1H NMR spectra are higher than GPC values since GPC data are relative values based on polystyrene standards. Figure 2A shows the FT-IR spectrum of P6K copolymer. The strong absorption at 1728 cm-1 corresponds to the stretching mode of CdO from PCL segment. The peaks at the 1186 and 1242 cm-1 are due to the stretch C-O-C and C-O. These three peaks indicate the ester groups in the copolymer. The peak at 2943 cm-1 belongs to the absorption of C-H stretch of CH2 from PCL blocks, while the peak at 2865 cm-1 corresponds to the C-H stretching band of PEO. It is worth noting that we do not find the absorption peaks around 960 and 870 cm-1, which were known to be characteristic of the crystalline phase of PEG,20 suggesting that no PEG crystals form in the copolymers, while the peak at 772 cm-1 suggests the presence of some crystalline PCL, which is useful in the later discussion about the PCL-PEGPCL micelle degradation process. In addition, we do not find any absorption peak in the range from 3200 to 3500 cm-1, which indicates that there are no or very few free hydroxyl groups in P6K copolymer. Figure 2B is the WAXD results of the prepared PCLPEG-PCL triblock copolymer. Obviously, there are only two major peaks at about 21.3° and 23.5° of 2θ, which corresponded to the characteristic PCL crystalline peaks.26 These results confirmed the PCL crystal in these copolymers. Morphology and Size of PCL-PEG-PCL Micelles. Amphiphilic block copolymers can usually form core-shell type micelles in aqueous solution,11 due to their amphiphilic characteristic. In our case, we used the precipitation method to obtain PCL-PEG-PCL micelles. Figure 3 shows the TEM photographs of P2K, P6K, and P10K micelles, respectively. It can be seen that most of the micelles have a spherical shape with a bright core and dark shell. The bright core should correspond to the PCL block and dark shell to the PEG block. The average diameter of P2K micelles is around 100 nm, and the other two samples are less than 100 nm in the dry state. The particle size and polydispersity (PD) in aqueous solution were determined by DLS and are displayed in Table 2 and Figure 4. Generally, for amphiphilic block copolymer micelles, increasing the length ratio of the hydrophobic block to the hydrophilic one would increase the micelle size.27 From Table 2, it is found that the diameter of the micelles indeed increases with the decrease of the length of the hydrophilic block. Further examination of Figure 4 reveals that P2K,



Figure 2. (A) FT-IR spectrum of P6K triblock copolymer. (B) WAXD profiles of P2K (a), P6K (b), and P10K (c) triblock copolymers. Table 2. Mean Diameters of PCL-PEG-PCL Micelles sample

diameter (nm)

polydispersity

P2K P6K P10K

124.7 ( 1.6 106.8 ( 1.0 96.2 ( 0.2

0.119 ( 0.008 0.136 ( 0.018 0.251 ( 0.022

Figure 4. Size distribution of P2K (A), P6K (B), and P10K (C) micelles measured by DLS.

Figure 3. TEM images of P2K (A), P6K (B), and P10K (C) micelles.

P6K, and P10K micelles exhibit a unimodal size distribution, but the polydispersity in size increases with the increase of PEG block length. Degradation Behavior of PCL-PEG-PCL Micelles. It is well-known that bulk PCL homopolymer has a degrada-

tion time of more than 2 years under physiological conditions without the aid of enzymes. However, for PCL nanoparticles and micelles, because of their larger surface area, their degradation characteristics can be quite different from those of the bulk materials. Figure 5 shows the size changes of PCL-PEG-PCL micelles as a function of standing period in aqueous solution. Interestingly, for all PCL-PEG-PCL micelles used, the size of the micelles increases continuously during the first 20 days and then gradually drops off with

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Figure 5. Size changes of PCL-PEG-PCL micelles with different PEG block lengths as a function of standing period in aqueous solution. Figure 7. GPC traces of P6K micelles with different standing periods in aqueous solution: (a) 0, (b) 60, and (c) 150 days. Table 3. Molecular Weight of P6K Micelles at Different Standing Periods in Aqueous Solution

Figure 6. FT-IR spectra of P6K micelles at standing period in aqueous solution: 0, 60, and 150 days.

extended time. We think that both the increase and the decrease in the size of micelles during the experimental period are related to the degradation of PCL-PEG-PCL micelles. To further address this issue, we selected one of the three copolymers, P6K, to study the degradability of its micelles in aqueous solution at room temperature. Figure 6 shows the FT-IR spectra of P6K micelles with different standing periods in aqueous solution: 0, 60, and 150 days. From Figure 6, it can be seen that there is a CdO absorption from PCL segment at 1728 cm-1 in all three traces. Interestingly, the peak intensity at 772 cm-1 associated with the PCL crystals decreases continuously as the degradation time increases. After 150 days of degradation, the PCL crystal peak at 772 cm-1 almost disappears. This result illustrates that the PCL crystalline structure is gradually destroyed during the degradation process. With the degradation time of 150 days, a new broad absorption peak appears at 3445 cm-1. We assign this peak to the -OH and -COOH groups in PCL chain ends arisen from the degradation and the PCL chain cleavage. However, no shift in the carbonyl stretch to lower wavenumber, the signature of the presence of carboxylic acid groups in the degraded micelles, was detected in FT-IR measurement, even at degradation for 150 days. This is because the relative amount of the carboxylic acid groups in the degraded micelles is not enough and the signal of the carboxylic acid groups is overlapped by the peak of the ester groups in copolymer chains. This has been confirmed in our previous work, where the shift in the carbonyl stretch to lower wavenumber was also not detectable in oligocaprolactone initiated by citric acid with PCL molecular weight of about 1000 g/mol.28

time (day)

Mn (g/mol)

Mw (g/mol)

Mw/Mn

0 60 150

35 040 10 700 1 330

53 600 38 800 17 200

1.53 3.63 12.93

To observe the changes in molecular weight of PCLPEG-PCL triblock copolymers in degraded micelles, GPC measurements were carried out after dissolution of the lyophilized powers of P6K micelles with THF. Figure 7 shows the GPC traces of P6K micelles after degradation for 0, 60, and 150 days. Obviously, for as-prepared sample P6K micelles, it shows a narrow and symmetrical GPC curve, while samples that were degraded for 60 days and 150 days display broad and asymmetric peaks with long tails in the GPC curves. The molecular weight and molecular weight distribution of these three samples are listed in Table 3. It can be seen that, with longer degradation times, the molecular weight of P6K in the micelles decreases and the molecular weight distribution broadens. Combining the results of FTIR and GPC measurements, we can conclude that, with the hydrolysis effect, P6K chains in the micelles degrade and the PCL crystallinity is disrupted in the degradation process. The morphology of P6K micelles at different standing periods in aqueous solution was monitored by AFM in tapping mode and is displayed in Figure 8. Figure 8A shows the AFM image of the as-prepared sample P6K micelles. It was found that these micelles have a nice spherical morphology with a smooth surface. The diameter of micelles is determined to be about 60 nm, which is much smaller than the result determined by DLS. This difference can be attributed to the difference between the dried and hydrated states. As the standing period is extended to 60 and 90 days, the morphology of the P6K micelles becomes more irregular, and the appearance of those micelles becomes blurred (Figure 8B to 8C). After 150 days, it is hard to find any P6K micelles in the AFM image as shown in Figure 8D. These results indicate that, during the degradation process, the morphology of P6K micelles changes significantly. 1H NMR was used to detect the changes in the chemical structure of P6K micelles in the degradation process. Figure 9 displays the results showing the variation of the CL/EO ratio of the micelles as a function of standing period in


Figure 8. Top-view AFM images of P6K micelles with standing periods in aqueous solution: (A) 0, (B) 60, (C) 90, and (D) 150 days.

aqueous solution. From Figure 9a, it can be seen that there is no new peak appearing in the 1H NMR spectrum between the as-prepared sample and the sample that was degraded for 60 days. However, for the sample that was degraded for 150 days, the new small peaks assigned to the methylene protons of degraded PCL-connecting carboxyl end group at 2.18 ppm and the methylene protons of degraded PCLconnecting hydroxyl end group at 3.2 ppm appear in the 1H NMR spectrum (indicated by the arrows in Figure 9a). Figure 9b presents the variation of the molar ratio of the caprolactone unit to the ethylene oxide unit of P6K micelles with degradation time of 0, 20, 60, 90, and 150 days. It can be seen that the ratio shows an increase during the first 20 days and then a linear decrease with extended standing period. This result suggests that the degradation mechanism of micelles is quite different from that of bulk materials. For PCL-PEG bulk materials, the molar ratio of the caprolactone unit to the ethylene oxide unit continually increased during the whole degradation period due to the cleavage of ester bond between PEG block and PCL block, resulting in the PEG segment detachment from the copolymer backbone to the solution.29 In our case, at the beginning of degradation,


the hydrolysis of ester bond of P6K micelles should mainly occur at the interface region between the core and the shell. Thus, the partial ester bonds on the surface of PCL core, including the PCL-PEG and PCL-PCL ester bonds, were first cleaved. The partial scission of the PCL-PEG ester bond caused some PEG segments to leave the P6K micelles when the ester-bond scission occurred on both sides of PEG block, and some PEG blocks to become brushes when the ester-bond cleavage took place on one side of PEG block. Moreover, the partial scission of PCL-PEG ester bond also produced some carboxylic acid groups in the surface of PCL core, as shown by zeta potentials of -22.08, -9.72, and -3.6 mV for P2K, P6K, and P10K micelles, respectively, in the first 60 days. On the other hand, at this stage, the partial scission of PCL-PCL ester bonds would not lead to weight loss of the PCL core since the cleaved parts of PCL still had a large enough molecular weight. Therefore, the CL/ EO ratio in micelles increased at this stage. When the degradation time is extended, there will be many caves or channels in the PCL core because of the detachment of PEG segments and the hydrolysis of PCL segments. More ester bonds in the PCL segments can get access to water through these caves or channels, and thus PCL segments in the core can be hydrolyzed easily. Ester bonds in the cores composed of the PCL blocks are further broken, and CL oligomers are produced. These formed CL oligomers with low molecular weight can easily diffuse into the aqueous solution from the core of P6K micelles. Thus, a behavior with a linear decrease in CL/EO ratio was observed at this stage, as shown in Figure 9B. This behavior implies that both degradation reactions involving the PCL-PEG and PCL-PCL ester bonds are zero-order reactions in the degradation kinetics, and the degradation rate of PCL ester bond is much faster than that of PCL-PEG ester bond at this stage. Presently, taking into account the above-described experimental results, the following degradation mechanism is proposed for the PCL-PEG-PCL micelles as illustrated schematically in Figure 10. First, PCL-PEG-PCL triblock copolymers form core-shell micelles with an outer shell composed of PEG blocks and an inner core of PCL blocks in aqueous solution via the precipitation method (Figure 10A,B). Since PEG segments are highly hydrated, water can cross the PEG shell freely and contact the surface region of PCL core, resulting in the swelling of PCL-PEG-PCL

Figure 9. 1H NMR characterization of P6K micelles with different standing times in aqueous solution. (a) 1H NMR spectra: 0, 60, and 150 days. (b) CL/EO ratio as a function of standing times in aqueous solution.

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The morphology of these micelles changed from a uniform spherical shape to an irregular and blurred shape. The PCL crystals are disrupted during the degradation stage, and the molar ratio of the caprolactone unit to the ethylene oxide unit measured by 1H NMR shows an increase during the initial stage and a decrease at later stages. The observed degradation behavior of PCL-PEG-PCL micelles is quite different from that of bulk materials and can be explained by a two-stage degradation mechanism: interfacial erosion between the cores and shells, followed by core erosion. Acknowledgment. This work has been supported by the Natural Science Foundation of China (No. 20374026). References and Notes Figure 10. Schematic representation of hydrolysis degradation mechanism of PCL-PEG-PCL micelles in aqueous media.

micelles. On the other hand, water cannot freely penetrate the inner part of the PCL core due to the strong hydrophobic and crystallizable character of the PCL block. Thus, the hydrolytic degradation of ester bond first takes place at the interface between the PCL core and PEG shell, resulting in the partial cleavage of ester bonds of PCL-PCL and PCLPEG on the surface of the PCL core. Some of the PEG chains with both chain ends detached from the core/shell interface of the micelles would diffuse into the aqueous solution, while PEG chains with only one detached end remain in the micelles and form a polymer brush. In this stage, the size of the micelles increases slightly due to the swell of the PCLPEG-PCL micelles and the brush formation of some PEG chains (Figure 10C). With increasing degradation time, some caves and channels in the PCL cores would appear because of the detachment of the partial PEG chains and the partial degradation of the PCL segments. At this stage, water can permeate the inner part of the PCL core through the formed caves and channels, which leads to the occurrence of an accelerated degradation of PCL cores with random scission of ester bond in PCL chains (Figure 10D). The degradation of micelles at this stage results in a decrease in both the micelle size and CL/EO ratio in micelles, the destruction of PCL crystals, and the occurrence of hydrolyzed chains that retain -OH and -COOH end groups. Therefore, the degradation of PCL-PEG-PCL micelles in aqueous solution can be divided into two stages: One is the interfacial erosion stage, during which the degradation mainly occurs at the interface region between the PEG shell and PCL core, and another is the core erosion stage, where the degradation mainly occurs in the PCL core. Conclusions In this work, PCL-PEG-PCL micelles with a core-shell structure were prepared by the precipitation method and the degradation behavior of the micelles in aqueous solution was investigated by FT-IR, GPC, 1H NMR, AFM, and DLS techniques. These micelles have a mean diameter less than 130 nm and a spherical shape. It was found that that these micelles are unstable in aqueous solution. The size of the micelles increases in the initial degradation stage and decreases gradually when the degradation time is extended.

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BM049845J

Degradation Behavior of Poly(Îµ-caprolactone)-b-poly(ethylene glycol

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