Degradable Thermoresponsive Polyesters by Atom Transfer Radical

Article pubs.acs.org/Macromolecules

Degradable Thermoresponsive Polyesters by Atom Transfer Radical Polyaddition and Click Chemistry Li-Jing Zhang, Bo-Tao Dong, Fu-Sheng Du, and Zi-Chen Li* Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Polymer Chemistry & Physics of Ministry of Education, Department of Polymer Science & Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China S Supporting Information *

ABSTRACT: Three types of linear polyesters containing monodisperse methoxy oligo(ethylene glycol)s (mOEG, x = 6, 7, or 8) side chains (P1-mOEG, P2-mOEG, and P3-mOEG) have been synthesized by atom transfer radical polyaddition and click chemistry. Degradable disulfide and ketal groups were incorporated into the polymer backbone of P2-mOEG and P3-mOEG respectively. All of these three series of mOEG-grafted polyesters are water-soluble and display reversible thermoresponsive properties with tunable cloud point (CP). Aqueous solution properties and thermo-induced phase transitions were studied by 1H NMR, turbidimetry, DLS, and fluorescence probe method. The results indicate that these polyesters mainly adopt single chain conformations in aqueous solution below CP. OEG length has a significant effect on the CP, the CP increases by ca. 10 °C when the repeating units of OEG side chains increase from 6 to 7, and by ca. 6 °C when they increase from 7 to 8. The main chain structures also affect the CP values, which decrease from P1-mOEG to P3-mOEG due to the increased hydrophobicity of the backbone. Degradation of the polymers was conducted under basic, reductive and mild acidic conditions, respectively. The degradation products also show thermoresponsive behaviors, but the CP values vary from the precursor polymers depending on the alteration of hydrophilic/hydrophobic balance and shielding effect of the OEG side chain.

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INTRODUCTION Thermoresponsive water-soluble polymers can undergo reversible phase transition in response to a small variation of the surrounding temperature. Polymers which show lower critical solution temperature (LCST) are soluble in water below a certain temperature but tend to collapse and become insoluble above the cloud point (CP). LCST-type polymers have found a variety of applications in biomedical science ranging from smart surfaces, biosensing and tissue engineering to intelligent drug/ gene delivery.1 Poly(N-substituted acrylamides) have been the most intensively studied thermoresponsive polymers with poly(N-isopropylacrylamide) (PNIPAM) as the representative example, whose phase transition is accompanied by the formation of inter- and/or intrachain hydrogen bonds (Hbonds) above its LCST.2 Another important LCST-type thermoresponsive polymer is that contains water-soluble and biocompatible poly(ethylene glycol) (PEG) or oligo(ethylene glycol) (OEG) segments either in the polymer main chain or on the side chains. These PEG-containing polymers are very promising since most of them show sharp and reversible phase transitions and the LCST can be easily tuned by varying the chain length of the PEG.3−10 Typical examples are linear poly(meth)acrylates,3−6 poly(vinyl ether)s,7 polystyrenics,8,9 and poly(norbornenyl esters)10 that containing OEG side chains or OEG-based hyperbranched, 11 dendritic,12 or dendronized13 polymers. © 2012 American Chemical Society

However, as most of the above polymers are based on carbon−carbon backbone, the nondegradability may limit their in vivo applications. To address this problem, degradable thermoresponsive polymers have been developed. Current methods for synthesizing these polymers can be characterized into two categories: (1) incorporation of labile moieties in the polymer main chain during polymerization,14−19 and (2) postmodification of degradable polymers in the side chains.20−23 For the first method, various polymerization approaches have been employed to anchor degradable linkages, such as ester or disulfide bonds into the polymer main chain. For example, ring-opening (co)polymerization of PEGfunctionalized lactides,16a lactones,16b or cyclic carbonates16c has been the most widely studied to produce thermoresponsive polyesters. However, some of these functional monomers are not easily accessible, and they are usually synthesized via multistep reactions with low yields. Degradable linkages have also been incorporated into the polymer backbones by radical copolymerization of oligo(ethylene glycol) methacrylate OEGMA and cyclic ketene17 or polycondensation of PEG di(meth)acrylates and dithiols.18 Compared with the first method, postfunctionalization provides a more versatile way. Received: August 1, 2012 Revised: October 13, 2012 Published: October 31, 2012 8580

dx.doi.org/10.1021/ma3016213 | Macromolecules 2012, 45, 8580−8587

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Scheme 1. Synthetic Route of Biodegradable Thermoresponsive Polyestersa

Regents and conditions: (a) Cu/CuBr2/BPMOA in anisole, 0 °C, 48 or 72 h; (b) NaN3 in DMF, −20 °C, 48 h; (c) mOEG propargyl ether (x = 6, 7, 8), CuBr/PMDETA in THF, room temperature, 4 h. BPMOA = N,N-bis(2-pyridylmethyl) octylamine; PMDETA = N,N,N′, N′, N″pentamethyldiethylenetriamine. a

Introduction of pendent OEG or amide groups onto a hydrophobic degradable polymer backbone can be a general method. Representatives are modification of poly(dichlorophosphazene) with PEG and amino acid,20 anchoring PEG on the polyglycolide,21 and grafting of NIPAM onto poly(amino ester)s.22 In some cases, the backbone may suffer from degradation during postmodification when vigorous conditions are used. However, this drawback can be overcome by using the effective coupling methods, especially the coppercatalyzed click chemistry.23,24 Here, we report a facile method to synthesize thermoresponsive degradable polymers by atom transfer radical polyaddition and click chemistry. On the basis of our previous reports,25 we prepared three polyesters (P1, P2, and P3) by atom transfer radical polyaddition between three bis(bromoisobutyrate) type monomers (A1, A2, and A3) and a bis(styrenic) type monomer (B). These monomers are easily accessible with high yields. Additional degradable disulfide and ketal groups were incorporated into the polymer backbone for the P2 and P3 series, respectively. The pendent bromo groups of the polyester are very reactive and can be substituted with azido groups under mild conditions. Subsequently, click chemistry with three propargyl-functionalized monodisperse methoxy oligo(ethylene glycol)s (mOEG, x = 6, 7, or 8) produces three families of degradable polymers (Scheme 1). We investigated the aqueous solution properties of these polymers with several means, and found they were all LCSTtype thermoresponsive polymers, whose cloud points can be tuned by changing the polymer main chain structure, molecular weight of the polymers as well as the length of OEG. Furthermore, the labile linkages, like ester, disulfide and ketal groups, make these polymers degradable under basic, reductive or mild acidic conditions, and the thermoresponsive properties of the degradation products were also studied.

Table 1. Characterization of Polymer−Br, Polymer−N3, and the Fractions of Polymer−N3

a

polymer sample

Mna

Mpa

Mw/Mna

yield (%)

P1−Br P1−N3 P1-f1 P1-f2 P1-f3 P1-f4 P2−Br P2−N3 P2-f1 P2-f2 P2-f3 P2-f4 P3−Br P3−N3 P3-f1 P3-f2 P3-f3 P3-f4 P3-f5

8000 7900 3800 8200 20 300 37 700 8000 7900 4500 7300 17 200 42 500 10 300 10 100 3800 9600 28 100 84 800 165 800

8400 9200 4600 10 800 21 600 36 000 10 500 11 400 5200 9800 19 300 45 400   3900 13 700 36 600 103 200 220 800

3.29 2.93 1.28 1.28 1.18 1.37 2.63 2.69 1.28 1.30 1.23 1.41 4.72 4.67 1.33 1.47 1.32 1.26 1.19

95.8 82.0 26.5 17.8 16.8 11.1 97.0 71.3 17.8 14.3 13.4 10.7 92.4 62.1 16.6 9.5 10.3 13.7 11.2

Determined by GPC in THF with polystyrene standards.

structures were confirmed by 1H NMR spectra (Figure S1A and Figure S2, Supporting Information). Then, the bromo-groups were transformed into azido-groups by the substitution reactions at low temperature. Figure 1 presents the GPC traces of the polymers before and after substitution reactions, demonstrating that polymer backbone did not degrade during the reaction. 1H NMR spectra (Figure S1B and Figure S3, Supporting Information) also confirmed the quantitative transformation. Elimination reaction is an inevitable side reaction along with the substitution reaction, which generates HBr and a double bond conjugated to the phenyl group in the polymer backbone. The signals of the double bond (−CH CH−) appeared at 6.49 ppm.26 The ratio of the elimination reaction (re) can be estimated by the integration of peak s and peak e (re = s/2/(s/2 + e)). The calculated values were 1.59%, 1.66%, and 1.05% for P1−N 3 , P2−N 3 , and P3−N 3 , respectively.

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RESULTS AND DISCUSSION Synthesis of Degradable Thermoresponsive Polyesters. We used our reported method to synthesize these polymers (Scheme 1).25 Briefly, atom transfer radical polyaddtion of three monomers (A1, A2 and A3) and monomer B afford three linear polyesters with pendent bromo-groups (P1−Br, P2−Br, and P3−Br) in high yields, their molecular weights were over 8000 (Table 1), and their 8581


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can be considered as two mOEG chains per repeating unit for all of the three series of polymers. Molecular weights of the grafted polymers were characterized by GPC in THF (Figure 3 and Table 2). Mn of the mOEG grafted polymers was not in consistent with the expected values and the differences increased with the increase of molecular weight of the starting polymer. For example, the measured Mn of P1-f1-mOEG6 (5.6 × 103 g/mol) is only slightly lower than the value calculated from Mn of P1-f1 and the grafting density of mOEG6 (7.7 × 103 g/mol). However, for P1-f4-mOEG6, the GPC-based molecular weight (13.2 × 103 g/mol) is much less than the calculated one (76.2 × 103 g/mol) and even lower than that of P1-f4 (37.7 × 103 g/mol), as shown in Figure 3. A similar phenomena was also observed by Baker et al., showing that a lower molecular weight after grafting of mOEG onto PLA-co-PPGL indicated by GPC in THF.21 Using a GPC system equipped with a light scattering detector, they determined that the molecular weight was indeed higher than that of the starting copolymers and slightly larger than the theoretical value. In the present case, we suspected that THF might not be a good solvent for OEG. Aggregation of the OEG side chains might exist in THF, which significantly decreases the hydrodynamic radius and thus the apparent molecular weight. We then carried out GPC measurements of P1-f4 and P1-f4-mOEG6 in DMF, a good solvent for both OEG and the polymer backbone.27 The GPC traces (Figure S5, Supporting Information) showed a similar retention time of the two polymers, indicating the same apparent molecular weight other than a higher one. Since branched polymers have more compact structures than the linear analogues with identical molecular weight,28 the hydrodynamic radius of the polymer decreased after grafting, which suggested that the above result is reasonable. Overall, we concluded that there was no chain degradation during the click reaction. Polymer Degradation. Degradation of the mOEG grafting polymers was followed by GPC. Ester degradation of P1mOEG6 was conducted under basic condition, and Figure 4A presents the GPC traces of the polymer before and after degradation. Clearly, the molecular weight of the polymer significantly decreased after degradation, confirming hydrolysis of the ester bonds in the polymer backbone. Disulfide bonds undergo scission in the presence of redox stimuli.29 Ketal bonds

Figure 1. GPC traces of P1−Br, P1−N3, and the four fractions of P1− N3.

Since atom transfer radical polyadditions undergo stepgrowth mechanism, they produce polymers with broad polydispersities. To further investigate the effects of molecular weights on the polymer properties, P1−N3, P2−N3, and P3− N3 were fractionated before the click reactions. Fractionation can be easily performed in cold mixtures of THF and petroleum ether. A typical GPC traces of P1−N3, and the four fractions are shown in Figure 1, and the data for fractions of P2−N3 (four fractions) and P3−N3 (five fractions) are summarized in Table 1. The fractions cover a broad range of molecular weights of the polymers and they all have relatively narrow polydispersities. Three mOEG propargyl ethers with 6, 7, or 8 ethylene glycol units were synthesized and introduced to the backbone of the three series of polymers by click reaction. All of the mOEG grafting polymers are listed in Table 2. 1H NMR spectra (Figure S1C, Supporting Information and Figure 2) showed that the resonances at 4.73 ppm (CH−N3) completely disappeared, and new peaks at 8.04 ppm (H of the triazole) and 3.28−3.62 ppm (H of mOEG) appeared; at the same time, peak a and d shifted to low field after the reaction. IR absorption (Figure S4, Supporting Information) of the azide at 2106 cm−1 disappeared completely after the click reaction, confirming the quantitative reaction. Since the ratio of the double bond in the polymer backbone generated from the elimination reaction is very low, the grafting density of mOEG

Table 2. Characterization and Properties of the mOEG-grafted Polymers entry

polymer sample

Mna

Mw/Mna

Mn, calb

CP (°C)c

temperature range (°C)d

1 2 3 4 5 6 7 8 9 10 11 12

P1-f2-mOEG6 P1-f2-mOEG7 P1-f2-mOEG8 P1-f1-mOEG6 P1-f3-mOEG6 P1-f4-mOEG6 P2-f3-mOEG6 P2-f3-mOEG7 P2-f3-mOEG8 P3-f3-mOEG6 P3-f3-mOEG6&7(1:1) P3-f3-mOEG7

10 400 9900 8500 5600 11 300 13 200 7500 9000 8800 14 000 13 400 14 700

1.22 1.19 1.21 1.17 1.20 1.22 1.44 1.33 1.43 1.16 1.36 1.24

16 600 17 700 18 800 7700 41 000 76 200 32 600 34 600 36 700 53 000 54 600 56 200

40.6 52.0 58.5 41.6 40.7 39.6 36.9 45.9 52.2 31.2 37.5 43.3

1.9 1.6 1.7 1.6 1.9 2.1 1.6 1.9 2.2 3.2 1.9 3.9

a

Determined by GPC in THF with polystyrene standards. bCalculated from the Mn of the polymers before click reaction (measured by GPC) and the density of azide groups, with the assumption that all the azido groups underwent cycloaddition reactions. cDefined as the temperature when the transmittance was 50% during the heating process with a polymer concentration of 1.0 mg/mL. dTemperature difference between 90 and 10% transmittance during the heating process. 8582


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Figure 2. 1H NMR spectra of (A) P2-f3-mOEG6 and (B) P3-f3-mOEG6 in acetone-d6.

parts B and C) showed a prominent decrease of molecular weight, indicating that the disulfide and ketal groups have been degraded. However, a small portion of dimers and trimers may exit due to the mild degradation conditions, as revealed by the shoulder peak at 23−26.5 min in the GPC traces. Thermoresponsive Properties of the mOEG-Grafted Polymers. Grafting mOEG chains increased the hydrophilicity of the polyesters, providing the polymer with water-soluble and thermoresponsive properties. Generally speaking, the key factor that governs the thermoresponsive property of a polymer is the inherent hydrophilic/hydrophobic balance in a polymer structure. H-bonds formed between the ether oxygens of OEG chains and water molecules offer water solubility of the polymers;31 at the same time, this hydrophilicity is counterbalanced by the hydrophobicity of the main chain. All of the mOEG-grafted polymers listed in Table 2 are soluble in water and show LCST upon heating. To demonstrate whether the amphiphilic polymers aggregate in dilute aqueous solution at lower temperature,32 we first measured the solution properties of these polymers below LCST. 1H NMR spectra of polymer P1-f2-mOEG6 in D2O and acetone-d6 were recorded and compared (Figure 5). In acetone-d6, all the peaks are clear and sharp, and the integration ratios are consistent with the theoretical values, indicating that the polymers dissolve uniformly and molecularly in acetone. In D2O, the proton signals of the mOEG side chains were only slightly broadened, but the signals of the main chains were significantly broadened, with the decreased integration ratio of the signals of the backbone to the mOEG chains. From these results, we speculate that the hydrophobic main chain might tend to aggregate in aqueous solution. Then we investigated the conformation of the polymer under similar conditions by DLS. Figure 6 presents the volume and size distributions of P1-f2mOEG6. The intensity distribution indicated that two components coexisted, with the diameter ranging from 4 to 130 nm; however, the volume distribution demonstrated that only one component with an average diameter of 5.5 nm

Figure 3. GPC traces of polymers (P1 series) before and after click reaction in THF.

Figure 4. GPC traces of mOEG-grafted polymers before (solid line) and after (dashed line) degradation.

are relatively stable at pH 7.4 (physiological pH) but degrade more quickly at pH 5.0−6.0 (environment of lysosomes).30 Therefore, reductive degradation of P2-mOEG6 was carried out in aqueous solution in the presence of DTT (5 mM); and acidic degradation of P3-mOEG6 was conducted in phosphate buffer (pH 5.0, 100 mM). Both of the GPC traces (Figure 4, 8583


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Figure 5. 1H NMR spectra of P1-f2-mOEG6 in (A) acetone-d6 and (B) D2O at 25 °C (polymer concentration: 1 mg/mL).

basis of these results, we conclude that the mOEG-grafted polymers dissolve unimolecularly in aqueous solution at 25 °C, with only a slight aggregation of the hydrophobic main chain. Phase transition behaviors of these polymers in aqueous solution were then studied by turbidimetric methods. Figure 7 shows the optical transmittance of the polymer solutions (1.0 mg/mL) as a function of temperature in a heating process. The transmittance decreased sharply at a specific temperature, and CP of each sample was measured. The values are varied with different parameters and summarized in Table 2. First, increase of the length of mOEG can increase the CP for the same polymer backbone. For example, in the case of P1 series, CP increased from 41.2 °C for P1-f2-mOEG6 to 52.0 °C for P1-f2mOEG7, and to 58.5 °C for P1-f2-mOEG8. The increment of CP from P1-f2-mOEG6 to P1-f2-mOEG7 was higher than that from P1-f2-mOEG7 to P1-f2-mOEG8, which probably because the former resulted in a higher increment of the hydrophilic group ratio. The P2 and P3 series of polymers followed the same trend. This feature also adds one advantage to tune the

Figure 6. Volume and intensity size distribution of aqueous solution of P1-f2-mOEG6 (1.0 mg/mL) at 25 °C measured by DLS.

existed in the solution. DLS measurements of the other polymers (Figure S6, Supporting Information) showed that the average diameters were less than 10 nm, indicating that these polymers mainly adopt unimolecular conformations.5,33 On the

Figure 7. Transmittance versus temperature plots of (A) P1-mOEG, (B) P2-mOEG, and (C) P3-mOEG upon heating processes, λ = 650 nm. Polymer concentration: 1.0 mg/mL. 8584


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for P2, and to 43.3 °C for P3. This is because the hydrophobicity of the polymer main chain increases in the order of P1 < P2 < P3. P2 and P3 have longer chain length of the hydrophobic spacer in the repeating unit than that in P1, while the two methyl groups in P3 make it even more hydrophobic than P2.5 Thermoresponsive Behaviors after Degradation. The LCST behaviors can be modulated by degradation, taking the advantages of the variation of hydrophilic/hydrophobic balance34 or molecular-weight dependent LCST behavior.35 The three series of polymers were degraded under basic, reductive, and acid conditions respectively, the structures of the degradation products are shown in Scheme 2. In our case, the degradation products of P1 series showed a pH-sensitive LCST behavior (Figure S10A, Supporting Information). The carboxylic acid groups formed after cleavage of the ester bonds alter the hydrophilicity of the degradation products through protonation and deprotonation.36 For P1-f2-mOEG7, the degradation products displayed no CP at pH 7.4 and 5.8, but at pH 3.3, a broad CP was observed at 51.2 °C, and it further decreased to 27.4 °C at pH 1.5, both were lower than the precursor polymer (CP=52.0 °C). For P2 series, degradation of the disulfide linkages resulted in a decreased CP (ca. 5 °C); whereas an increase of CP (ca. 3 °C) was observed for P3 series after the ketal linkage degradation (Figure S10, parts B and C (Supporting Information), and Table 3). As shown in Scheme 2, two thiol groups were formed at the ends of the repeating units after the scission of the disulfide bonds in P2-mOEG, while two hydroxyl groups were formed after the breakage of the ketal bonds in P3-mOEG. First, we speculated that the hydrophilicity decreased for P2-mOEG and increased for P3mOEG after degradation. The polarity changeof the polymers before and after degradation was then characterized by fluorescence method using pyrene as a probe. The excitation and emission spectra of Py are sensitive to the polarity of the microenvironment where it locates. The [0, 0] band in the excitation spectrum of pyrene red-shifts when the hydrophobicity of the environment increases (ca. 333 nm in water and ca. 339 nm in polystyrene film).37 For P2-mOEG, I338/I333 increased by ca. 0.10 after reductive degradation, indicating a slight increase of hydrophobicity. By contrast, in the case of P3 series, I338/I333 decreased by ca. 0.45 after acid degradation, demonstrating a significant increase of hydrophilicity (Table 3). The above results supported our hypothesis, but the variation of I338/I333 was not in consistent with the variation of CP values when comparing the two series. For P2-mOEG, the increase of hydrophobicity is small, but the decrease of CP is much pronounced. This discrepancy is probably attributed to the absence of shielding effect38 after degradation. In these polymers, the hydrophobic main chain is shielded by the hydrophilic PEG side chains, which reduces the interchain entanglement caused by the hydrophobic interaction and favors the solubility. However, the hydrophobic groups were exposed to the surrounding water environment in the degradation product. The increased tendency of aggregation accelerates the dehydration upon heating, and consequently, leading to a decrease of CP. Therefore, the variation of LCST behaviors after degradation probably results from two cooperative factors, namely the change of hydrophilic/hydrophobic balance and shielding effect of OEG.

CP by using a mixture of mOEG with different chain lengths. For example, mOEG6 and mOEG7 with a molar ratio of 1:1 were grafted onto the backbone of P3-f3. The obtained polymer has a CP of 37.5 °C, similar to the average CP value of P3-f3mOEG6 and P3-f3-mOEG7 (37.2 °C). The transmittance vs temperature plots of P1-f2-mOEG6 was also recorded in a cooling process (Figure S7,Supporting Information). No hysteresis was observed, indicating the absence of interchain H-bonds3,4 or large chain entanglements in the aggregates5 above CP. Then, the effect of polymer concentration on CP was studied with P1-f2-mOEG6 as an example (Figure S8 (Supporting Information), Figure 8, and Table 2). We found that CP

Figure 8. Dependence of CP of P1-f2-mOEG6 aqueous solution on the polymer concentration.

decreased remarkably with the increase of polymer concentration and became constant above a concentration of 5.0 mg/ mL. But the effect of molecular weight (MW) of polymers is small, CP only decreased by 2 °C as the MW (Mn cal) decreased from 76200 to 7700 for the P1-mOEG6 series (Figure S9 (Supporting Information) and Figure 9). These results are consistent with the previous reports,4a,b demonstrating that the phase behavior of OEG-based polymer was relatively insensitive to molecular weight of polymers.

Figure 9. Dependence of CP of P1-mOEG6 aqueous solution on the molecular weight. Polymer concentration: 1.0 mg/mL.

The main chain structure of the polymer also affects the CP. When comparing the three series of polymers with the same OEG length and comparable molecular weights, we found that the CP decreases in the order of P1 > P2 > P3. For example, with mOEG6 as the side chains, CP decreases from 40.6 °C for P1 to 36.9 °C for P2, and to 31.2 °C for P3; with mOEG7 as the side chains, CP decreases from 52.0 °C for P1 to 45.9 °C 8585


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Scheme 2. Main Degradation Products of P1-mOEG (A), P2-mOEG (B), and P3-mOEG (C)

polymers. It is anticipated that this new class of biodegradable thermoresponsive polyesters hold promise for potential use in drug delivery applications. Moreover, this method offers possibilities to conjugate other functionalities, such as peptides, biomolecules, or fluorescent groups, to the backbone of the polyesters together with OEG for more applications.

Table 3. Solutions Properties before and after Degradation for P2-mOEG and P3-mOEG before degradation polymer sample P2-f3mOEG6 P2-f3mOEG7 P2-f3mOEG8 P3-f3mOEG6 P3-f3mOEG7

after degradation

CP (°C)a

I338/ I333b

CP′ (°C)a

I338′/ I333′c

ΔCP (°C)d

ΔI338/ I333d

36.9

1.49

31.1

1.60

−5.8

0.11

45.9

1.46

40.6

1.60

−5.3

0.14

52.2

1.41

46.6

1.51

−5.6

0.10

31.2

1.65

35.3

1.20

4.1

−0.45

43.2

1.55

45.9

1.10

2.7

−0.45

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ASSOCIATED CONTENT

S Supporting Information *

Experimental Section, more 1H NMR of the monomers and polymers, IR spectra, GPC in DMF, more DLS results, and more results of turbidimetric measurements. This material is available free of charge via the Internet at http://pubs.acs.org.

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a

AUTHOR INFORMATION

Corresponding Author

Defined as the temperature when the transmittance was 50% during the heating process with a polymer concentration of 1.0 mg/mL. b Obtained by excitation spectra of pyrene in aqueous solution of P2mOEG and phosphate buffer (pH 7.4, 10 mM) of P3-mOEG. Polymer concentration: 1.0 mg/mL. cObtained by excitation spectra of pyrene in aqueous solution of P2-mOEG and phosphate buffer (pH 5.0, 10 mM) of P3-mOEG after degradation under the same conditions as the CP measurements. Polymer concentration: 1.0 mg/mL. dThe differences between the corresponding values before and after degradation.

*E-mail: [email protected]. Telephone: +86-10-6275-5543. Fax: +86-10-6275-1708. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is financially supported by National Natural Science Foundation of China (Nos. 20534010, 21074002, and 21090351) and National Basic Research Program of China (No. 2011CB201402).

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CONCLUSIONS We demonstrated a simple method to synthesize biodegradable thermoresponsive mOEG-grafted polyesters by atom transfer radical polyaddition of two difunctional monomers and the postclick modification. This approach has an advantage that it allows facile incorporation of a broad range of cleavable groups in the polymer main chain. These mOEG-grafted polyesters are water-soluble and show reversible phase transition behaviors upon heating or cooling. The nature of the main chain structure and the OEG length can be adjusted to tailor the cloud points (CP). In addition, these polymers can be easily degraded under basic, reductive, and acidic conditions, respectively. The degradation has a significant effect on the thermoresponsive behaviors: a pH-sensitive CP for P1 series, a decreased CP for P2 series, and an increased CP for P3 series. The degradability of these polymers and the corresponding change of CP with degradation may expand the applications of thermoresponsive

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