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Feb 14, 2018 - ization way.11−13 For example, chain-transfer reactions occurred during the ROP of monomer 1, ... as an analogue of poly(amino acids)...
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Well-Defined Poly(α-amino-δ-valerolactone) via Living Ring-Opening Polymerization Zhitao Hu, Yi Chen, Huahua Huang,* Lixin Liu, and Yongming Chen* Center for Functional Biomaterials, School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China S Supporting Information *

ABSTRACT: This article demonstrates the synthesis of a new kind of cationic poly(δ-valerolactone) with primary amino groups at α-positions (poly(α-NH2-VL)) via ring-opening polymerization (ROP) of α-NHBoc-valerolactone (α-NHBVL) followed by a simple deprotection reaction. The ROP of α-NHB-VL using benzyl alcohol as an initiator and DBU/TU (1,8-diazabicyclo[5.4.0]undec-7-ene/thiourea) as a catalytic system in THF at room temperature afforded poly(α-NHBVL) with narrow molecular weight distribution. The 1H NMR and MALDI-TOF MS analysis of poly(α-NHB-VL) indicated that each polymeric chain was capped by the initiator. Kinetic experiments confirmed the living nature of the DBU/TU-catalyzed ROP of α-NHB-VL in THF. The copolymerization result indicated that the polymerization activity of α-NHB-VL is comparable to that of ε-caprolactone (CL) and VL. In addition, block copolymers containing poly(α-NHB-VL) were successfully synthesized regardless of whether hydrophilic PEG or hydrophobic PCL was used as the macroinitiator. Moreover, water-soluble poly(αNH2-VL) was obtained by treatment with trifluoroacetic acid (TFA). It was found that poly(α-NH2-VL) degraded more slowly at pH 5.5 than at pH 7.4 through a hydrolysis kinetics study.

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INTRODUCTION Aliphatic polyesters are one of the most important biodegradable polymers and have been extensively used as sustainable materials and for applications in the biomedical field.1 Moreover, well-defined polyesters can be synthesized via living ring-opening polymerization (ROP) of lactides and lactones such as ε-caprolactone (CL) and δ-valerolactone (VL). However, due to their hydrophobic property, polyesters exhibit poor compatibility with other polymers and poor cell adhesion. Polyesters also lack functional groups along their polymeric chains. Considerable efforts have been made for the development of functional polyesters, especially cationic polyesters containing amino groups in a backbone or side chains. Cationic polyesters are of interest in a wide range of applications including, but not limited to, drug/gene delivery,2,3 antimicrobial agents,4 and tissue engineering. A number of cationic polyesters have been reported via ROP of either amino-functionalized lactones or lactones containing reactive groups for further postmodification.5 The postmodification method suffers from problems associated with complexity and incomplete transformation.6 In contrast, ROP of amino-functionalized monomers is an efficient methodology for the preparation of cationic polyesters.7 Nevertheless, only a few amino-functionalized lactones or lactides have been polymerized via ROP, as shown in Scheme 1.8−14 Moreover, because of the bulky functional lactones or lactides, most of the ROPs were not performed in a controlled or living polymerization way.11−13 For example, chain-transfer reactions occurred during the ROP of monomer 1, and thus the molecular weight © XXXX American Chemical Society

Scheme 1. Amino-Functionalized Monomers Used for the Synthesis of Polyesters in the Literature

and end group of the product were not well controlled.13 In addition, the amino group was generally introduced into the βor γ-positions of the polymeric backbone.14,15 Up to now, there has been no report on the synthesis of polyesters with amino groups at the α-positions via a living ROP. Actually, polyesters Received: November 24, 2017 Revised: February 14, 2018

A

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Macromolecules with primary amino groups at the α-positions can be regarded as an analogue of poly(amino acids) (PAAs), which may be more biocompatible. Moreover, the primary amines of polymers may not only transform to other functional groups such as secondary/tertiary amine, imine, and amide units via the postmodification method16,17 but also conjugate to drug/ protein molecule.18 Herein, we aim to develop a kind of new cationic poly(δvalerolactone) (PVL) with primary amino groups at the αpositions via a living ROP of α-NHBoc-valerolactone (α-NHBVL) as shown in Scheme 2. Poly(α-NHB-VL) homopolymers

(PDI) = 1.07) were bought from Aladdin. Tetrakisacetonitrile copper(I) triflate ([Cu(CH3CN)4]OTf) and 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO) were purchased from Sigma-Aldrich. Ditert-butyl decarbonate (99%, Adamas-Beta), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 98%, J&K), dimethylaminopyridine (DMAP, TCI, 99%), dimethylformamide (DMF, 99.9%, INNO-CHEM), and anisole (99%, Acros) were purchased from different companies. Tetrahydrofuran (THF) and other solvents were analytical grade and offered by Guangzhou Chemical Reagent Factory. Unless otherwise noted, all commercial reagents and solvents were directly used. CL and VL were dried with CaH2 and distilled under reduced pressure. PCL18 (DP = 18, PDI = 1.15) was prepared according to the literature procedure.19 mPEG46 and PCL18 were dried by azeotropic distillation using toluene. BnOH, anisole, and THF were dried using CaCl2, CaH2, and Na, respectively, followed by distillation and storage over 4 Å molecular sieves. The α-NHBoc-VL and catalysts were dried in a vacuum prior to use. Thiourea (TU) was synthesized according to the literature procedure,20 and its 1H NMR data are offered in the Supporting Information. Instruments. 1H NMR spectra were measured on a Bruker AVANCE III 400 MHz instrument at room temperature (rt) with D2O or CDCl3 as the solvent. The element analysis (EA) data of the monomer were obtained on an Elementar Vario EL analyzer in C, H, and N test modes. Molecular weight and molecular weight distribution of the polymers were estimated by an Agilent Technologies 1260 Infinity containing a refractive index detector, and the flow rate was 1.0 mL/min. The PLgel columns for THF as an eluent included 5 μm 10E5A, 5 μm 10E4A, and 5 μm 10E3A, while the columns for DMF (containing 0.01 M LiBr) as an eluent included 10 μm MIXED-BLS, 5 μm MIXED-C, and 5 μm MIXED-D. The temperatures for THF and DMF were 40 and 50 °C, respectively. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDITOF MS) was carried out using a Bruker Ultraflextreme spectrometer in which dithranol was used as the matrix, and CF3COOK was used as the cationic reagent in the linear positive model. The pH and potential value were recorded on a pH meter with an E-201-C-Q9 composite electrode, and a two-point correction method was used to correct the instrument. Titration experiments were carried out using 40 mg of poly(α-NH2-VL)30 sample in 20 mL of ultrapure water. 0.02 M NaOH aqueous was used to adjust pH of the solution. Preparation of α-NHB-VL Monomer. α-NHB-VL monomer was synthesized according to the literature.21 Detailed synthetic experiments and characterization are given in the Supporting Information. Homopolymerization of α-NHB-VL. A typical homopolymerization procedure of entry 9 in Table 1 was as follows: Polymerization was carried out in a glovebox filled with nitrogen. To a stirred solution of α-NHB-VL (200 mg, 0.93 mmol) in 1 mL of THF was added DBU (23 mg, 0.15 mmol, 16 mol %) and TU (56 mg, 0.15 mmol, 16 mol

Scheme 2. Synthetic Route of Cationic PVL Containing Primary Amino Groups at the α-Positions

with controlled molecular weight and narrow polydispersity were prepared via an organocatalytic ROP of α-NHB-VL monomer under the optimized polymerization conditions. Then, water-soluble cationic poly(α-NH2-VL) was obtained via a simple deprotection reaction. The synthesis of well-defined poly(α-NHB-VL) copolyesters and block polymers is also demonstrated. This means that a type of polyester of unnatural amino acids, 2-amino-5-hydroxypentanoic acid, with controlled molecular weight, composition, charge density, and topological structure, can be synthesized with a living ROP methodology for potential biomedical applications.

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EXPERIMENTAL SECTION

Materials. L-Glutamic acid (99%), 1-methylimidazole (99%), and 2,2′-bipyridine were purchased from Alfa Aesar. CL (98%), VL (98%), thionyl chloride (99.5%), cyclohexylamine (99.0%), 3,5-bis(trifluoromethyl)phenyl isothiocyanate (98.0%), 1,8-diazabicyclo[5.4.0]undec7-ene (DBU, 99%), lithium aluminum hydride (97%), benzyl alcohol (99.0%, BnOH), trifluoroacetic acid (TFA, 98%), and mPEG (Mw = 2000 g/mol, degree of polymerization (DP) = 46, polydispersity index

Table 1. Organocatalytic ROP of α-NHB-VL Monomera entry

solvent

[M]0/[I]0

catalystb (%)

time (h)

convc (%)

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

anisole anisole anisole THF THF THF THF THF THF THF THF THF

50 50 50 50 50 50 50 50 50 50 200 300

DMAP(5) TBD(5) DBU/TU (5) TBD(5) DBU(16) DBU/TU(4) DBU/TU(8) DBU/TU(12) DBU/TU(16) DBU/TU(20) DBU/TU(16) DBU/TU(16)

12 12 12 12 12 5 5 5 4.5 4.5 48 48

46 30 53 15 45 65 80 88 83 82 80

DPd

Mn,NMRe (kDa)

Mn,GPCf (kDa)

PDIf

23 33 40 44 42 164 240

4.9 5.3 5.7 1.6 4.8 7.0 8.6 9.4 9.0 35.2 51.6

1.0 4.1 1.0 0.7 3.7 4.5 5.5 8.0 6.9 14.5 16.4

1.10g 1.25g 1.33g 1.23g 1.12 1.13 1.14 1.10 1.12 1.28 1.28

a

Condition: BnOH was used as the initiator at rt. Entries 1−5: [M]0 = 0.4 M; entries 6−10: [M]0 = 0.46 M; entries 11 and 12: [M]0 = 0.92 M. Molar percentage relative to monomer. cCalculated by 1H NMR. dDP = conversion of monomer × ([M]0/[I]0). eMn,NMR = DP × Mmonomer + MBnOH. fMeasured by GPC in THF using polystyrene (PS) standards as calibration. gThe GPC curves show two or multiple peaks. b

B

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Macromolecules %). BnOH (2 μL, 0.019 mmol) was then added to the solution. After stirring at rt for 4.5 h, the polymerization was quenched by adding benzoic acid, and the mixture was precipitated into 15 mL of diethyl ether/petroleum ether (v/v = 1:2) three times. The purified polymer was dried for 24 h under vacuum. Yield: 80%. Copolymerization of α-NHB-VL and CL (or VL). To a stirred solution of α-NHB-VL (50 mg, 0.23 mmol) and CL (27 mg, 0.23 mmol) in 0.5 mL of THF was added DBU (11 mg, 0.074 mmol, 16 mol %) and TU (27 mg, 0.074 mmol, 16 mol %). BnOH (1 μL, 0.0092 mmol) was then added to the solution. After stirring at rt for 12 h, the polymerization was quenched by adding benzoic acid. The precipitation and drying procedures were the same as the homopolymerization of α-NHB-VL, and the yield of PCL-co-poly(αNHB-VL) was 70%. Using an analogous procedure, a copolymer PVLco-poly(α-NHB-VL) was also prepared with a yield of 70%. Synthesis of Block Polymers. Three kinds of block polymers were prepared with a similar homopolymerization procedure, except for the initiator. mPEG46 (56 mg, 0.028 mmol) was added as an macroinitiator to prepare PEG-b-poly(α-NHB-VL), PCL18 (39 mg, 0.018 mmol) was used to prepare PCL-b-poly(α-NHB-VL), and poly(α-NHB-VL)15 (20 mg, 0.0058 mmol) was added to synthesize poly(α-NHB-VL)-b-PVL. Deprotection Reaction of Poly(α-NHB-VL). After the polymerization of α-NHB-VL (200 mg) the mixture was concentrated. DCM (2.0 mL) and TFA (2.5 mL) were then added. After stirring for 2 h at rt, 20 mL of diethyl ether was used to precipitate poly(α-NH2-VL). The precipitation was repeated another two times with TFA as a good solvent. After drying under vacuum for 24 h, the polymer was obtained with a yield of 80%. Hydrolysis Experiment of Poly(α-NH2-VL). A poly(α-NH2-VL) sample (90 mg) was dissolved into 10 mL of PBS solution (0.02 mol/ L, pH = 5.5 or 7.4) and incubated at 37 °C. During the hydrolysis experiment, small portions of the solution (0.5 mL) were removed, freeze-dried, and analyzed by 1H NMR to monitor the degree of degradation.

ification reactions had occurred. Following this, THF was used. Polymerization catalyzed by TBD was still poorly controlled, which was related to the strong basicity of TBD (entry 4, Table 1). However, polymerization using the DBU/TU catalytic system in THF provided a poly(α-NHB-VL) polymer whose GPC curve exhibited a symmetrical unimodal peak as shown in Figure 1. Μoreover, when the molar loading of DBU/TU vs

Figure 1. GPC curves of poly(α-NHB-VL) products of entries 6−9 in Table 1 with THF as an eluent using PS standards for calibration.

monomer was increased up to 16%, the conversion of α-NHBVL was as high as 88% (entry 9, Table 1), which was estimated by the 1H NMR spectra of the polymerization mixtures before purification. Also, poly(α-NHB-VL) of high molecular weight was simply obtained by increasing the feed ratio of monomer to initiator (entries 11 and 12). Polymerization of α-NHB-VL with the feed ratio of [monomer] to [initiator] = 300:1 for 48 h offered a product of a high Mn,NMR of 51.6 kDa and a small PDI of 1.28 (entry 12). Herein, it is worth mentioning that the polymerization of α-NHB-VL catalyzed by only DBU without the TU cocatalyst offered a polymer of low yield and broad polydispersity (entry 5), which is similar to the result of the DBU-catalyzed ROP of VL.23 This indicated that the addition of TU together with DBU is necessary to efficiently activate αNHB-VL through electrophilic attack by TU via hydrogen bonding. Structural Characterization of Poly(α-NHB-VL). The chemical structure of poly(α-NHB-VL) was confirmed by 1H NMR. Figure 2 shows a typical 1H NMR spectrum of poly(αNHB-VL)44 of entry 9 in Table 1. The strong peaks of the CH2CH2 and CH3 protons of the repeating unit appear in the upfield region of 1.0−2.0 ppm, while other strong peaks at 5.31,

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RESULTS AND DISCUSSION Synthesis of Monomer. In recent years, great progress has been achieved in the preparation of functional lactones of high chemo-/regioselectivity through the oxidative lactonization of diols, which promotes the development of functional polyesters.22 According to recent literature about aerobic oxidative lactonization of diols using Cu/2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) as a catalyst,21 the α-NHB-VL monomer was synthesized via lactonization of β-NH-Bocpentadiol as shown in Scheme S1. The β-NH-Boc-pentadiol was prepared via the esterification, reduction, and N-protection of L-glutamic acid, meaning that the monomer and corresponding polyester are derived from a natural amino acid. The structure and purity of the monomer were confirmed by 1H NMR (Figure S1) and EA. ROP of α-NHB-VL. Organocatalytic ROPs have been commonly used in the preparation of polyesters, which are highly desirable for biomaterials due to the absence of metal catalysts. First, three catalytic systems including DMAP, TBD, and DBU/TU were chosen to investigate the ROP of α-NHBVL monomer. The polymerization reaction was carried out using BnOH as the initiator and anisole as the solvent at rt. The polymer was purified by precipitation from petroleum ether and diethyl ether (v/v = 2/1). The polymerization results are collected in Table 1. It was found that DMAP cannot polymerize α-NHB-VL due to it being a weak Brϕnsted base (entry 1, Table 1). α-NHB-VL was polymerized using either the TBD or DBU/TU system in anisole, but the GPC curves of the products showed two or more peaks (Figure S2), indicating that serious transester-

Figure 2. 1H NMR spectrum (400 MHz, CDCl3) of poly(α-NHBVL)44 (entry 9, Table 1). C

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loading of catalyst vs monomer and a feed ratio of [monomer] to [initiator] = 30:1 at rt was monitored by 1H NMR. Figure 4A shows a first-order relationship between the polymerization time and monomer conversion, meaning that the consumption rate of α-NHB-VL monomer was constant throughout the polymerization. Also, the molecular weight of poly(α-NHB-VL) linearly increased with the polymerization time (Figure 4B). These results indicate that the DBU/TU-catalyzed ROP of αNHB-VL in THF follows a living polymerization mechanism. Copolymerization of α-NHB-VL with CL or VL. Copolyesters of different lactones are highly desirable materials in biomedical applications due to their tuning properties such as charge density, thermal stability, and hydrolysis rate. CL and VL were chosen to be copolymerized with α-NHB-VL. It was found that the random copolymers PCL-co-poly(α-NHB-VL) and PVL-co-poly(α-NHB-VL) of a narrow monodispersity were prepared under the conditions of 16% molar loading of DBU/ TU vs monomer and a feed ratio of [α-NHB-VL]:[CL or VL]: [BnOH] = 23:23:1 in THF at rt (Figure 5). Moreover,

4.27, and 4.14 ppm belong to the NH, COCH, and OCH2 protons, respectively. A weak yet clear peak at 7.35 ppm is assigned to the protons of the terminal phenyl group while another weak peak at 3.45 ppm is attributed to the CH2 adjacent to another terminal OH group. The structure of poly(α-NHB-VL) was also confirmed by the 1H−1H COSY spectrum (Figure S3). The structure of poly(α-NHB-VL) was further characterized by MALDI-TOF MS. As shown in Figure 3, the mass spectrum

Figure 3. MALDI-TOF mass spectrum of poly(α-NHB-VL)23 (entry 6, Table 1).

of the product contains a main series of peaks whose data conform to poly(α-NHB-VL) containing a benzyl group at one end and an OH group at the other end. For example, the observed value, m/z = 1867, agrees with the theory value of poly(α-NHB-VL) at DP of 8 [108(Minitiator) + 215(Mmonomer) × 8 + 39(MK+) = 1867]. Additionally, there are a minor series of peaks attributed to the polymer where one tert-butyl group was cleaved during the MALDI-TOF MS test. This result confirmed that ROP catalyzed by the DBU/TU system is only initiated by BnOH without any side reactions. Therefore, all the results based on GPC, 1H NMR, and MALDI-TOF preliminarily indicated that DBU/TU-catalyzed ROP of α-NHB-VL in THF proceeds in a controlled polymerization manner. Kinetics Study of ROP of α-NHB-VL. Kinetics experiments were performed to confirm the living ROP of α-NHBVL catalyzed by DBU/TU in THF. Conversion of α-NHB-VL with time under the polymerization conditions of 16% molar

Figure 5. GPC curves of (A) PCL-co-poly(α-NHB-VL) and (B) PVLco-poly(α-NHB-VL) with DMF as an eluent using PEO standards for calibration.

estimated by the 1H NMR spectra of the copolymerization mixtures before purification, the conversions of CL and αNHB-VL reached 89% and 70%, respectively. For copolymerization of VL and α-NHB-VL, the conversions of VL and αNHB-VL were as high as 98% and 84%, respectively. Herein, it is worth mentioning that the polymerization of α-NHB-VL

Figure 4. Plots of (A) ln([M]0/[M]) as a function of time and (B) molecular weight as a function of time for the polymerization of α-NHB-VL at rt where the molar loading of DBU/TU vs monomer = 16%, [M]0:[I]0 = 30:1, and [M] = 0.75 mol/L. D

DOI: 10.1021/acs.macromol.7b02489 Macromolecules XXXX, XXX, XXX−XXX

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These results indicated that each polymeric chain of poly(αNHB-VL) was terminated by the OH group which possessed further polymerization ability. Next, ROP experiments of αNHB-VL were carried out using hydrophilic mPEG46 and hydrophobic PCL18 macroinitiators, respectively. The resulting block copolymers mPEG-b-poly(α-NHB-VL) and PCL-bpoly(α-NHB-VL) were also characterized by 1H NMR (Figures S6 and S7) and GPC (Figures S8 and S9), which confirmed that the DBU/TU-catalyzed ROP of α-NHB-VL still proceeded in a controlled polymerization nature even if using the macroinitiator. Deprotection of Poly(α-NHB-VL). Cationic polyester is an attractive biomaterial used as a drug/gene delivery nanocarrier or antibacterial material. The deprotection of poly(α-NHB-VL) can be achieved via a simple and classical procedure under acidic condition. Poly(α-NHB-VL)164 as a representative polymer was reacted with TFA (∼35 × molar excess per Boc group) in dichloromethane at rt for 2 h. All Boc groups were removed since the peak assigned to the Boc proton at 1.46 ppm was not observable in the 1H NMR spectrum (Figure 8),

with lactide cannot produce a copolymer, which is similar to the result of polymerization of lactide with other lactones using DBU/TU, due to the very high polymerization rate of lactide. The structures of the random copolymers were confirmed by 1 H NMR. In the 1H NMR spectrum of PCL-co-poly(α-NHBVL) (Figure 6), the resonance peaks of the repeating units of

Figure 6. 1H NMR spectrum (400 MHz, CDCl3) of PCL-co-poly(αNHB-VL).

PCL and poly(α-NHB-VL) are clearly observed. Additionally, it was found that the molar content of the α-NHB-VL unit in the copolymer was 44%, which was only a little lower than the molar content of CL unit (56%), calculated by the typical peak area of their units. A similar result was also obtained in the copolymer PVL-co-poly(α-NHB-VL) with a molar content of α-NHB-VL of 46% (Figure S4). This indicated that the polymerization activity of α-NHB-VL is comparable to that of CL and VL in the DBU/TU-catalyzed ROP system, even if there is a bulky Boc unit existing in the α position of α-NHBVL. Block Copolymer Containing Poly(α-NHB-VL). The living nature of the DBU/TU-catalyzed ROP of α-NHB-VL offered an opportunity to prepare block copolymer containing poly(α-NHB-VL). First, poly(α-NHB-VL)16 was used as a macroinitiator to initiate a ROP of VL, and it was found that the GPC curve of the resulting poly(α-NHB-VL)-b-PVL moved to a higher molecular weight while the distribution remained narrow (Figure 7). The block copolymer composing of PVL and poly(α-NHB-VL) was confirmed by 1H NMR (Figure S5).

Figure 8. 1H NMR spectrum (400 MHz, D2O) of poly(α-NH2-VL)164.

indicating that a water-soluble poly(α-NH2-VL)164 was obtained. Meanwhile, no evident degradation of poly(α-NH2VL)164 was detected by 1H NMR, as the amines in the backbone were protonated, reducing their nucleophilicity. This indicated that a cationic PVL with a −NH3+ group at the αposition is relatively stable. To further confirm the structure of poly(α-NH2-VL), poly(α-NHB-VL)37 of relatively low molecular weight was also reacted with TFA, and its product poly(αNH2-VL)37 was analyzed by MALDI-TOF. As shown in Figure 9, the mass spectrum only contains a series of peaks whose data

Figure 7. GPC curves of (A) poly(α-NHB-VL)16 and (B) block copolymer poly(α-NHB-VL)16-b-PVL20 with DMF as an eluent using PEO standards for calibration.

Figure 9. MALDI-TOF mass spectrum of poly(α-NH2-VL)37. E

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Figure 10. (A) Titration curves of pH and zeta potential vs volume of NaOH solution (0.02 M) and (B) zeta potential vs pH curve for an aqueous solution of poly(α-NH2-VL)30.

conform to poly(α-NH3+-VL) without Boc unit. At the same time, GPC curve of poly(α-NH2-VL)37 exhibited a symmetrical unimodal peak (Figure S10). These results indicate that there is no degradation during deprotection, and poly(α-NH2-VL) is stable when the amines in the backbone are protonated. Potentiometric Titration of Poly(α-NH2-VL). The pKa value is a key parameter of pH-sensitive materials for biomedical applications. A standard acid−base titration experiment was carried out to determine the pKa value of poly(αNH2-VL)30. Figure 10A shows a titration curve of poly(α-NH2VL)30 in dilute aqueous solution ([NH2] = 8.4 mmol/L), where the x-axis represents the volume of NaOH solution. The pKa of poly(α-NH2-VL)30 can be obtained from the titration curve as the pH of the solution with a 50% protonation degree of amine groups within the polymer,24 and thus the pKa value of poly(αNH2-VL)30 is 5.68. This means that poly(α-NH2-VL)30 will become hydrophobic when the pH of the solution exceeds 5.68. However, no macroscopic precipitation was observed during the whole experiment (Figure S11). Additionally, as shown in the curve of zeta potential vs pH (Figure 10B), a positive zeta potential at pH less than 7.07 was observed. Hydrolysis of Poly(α-NH2-VL). In order to investigate the biodegradation of cationic poly(α-NH2-VL) material in normal tissue and acidic intracellular microenvironments (e.g., endosome and lysosome), degradation of poly(α-NH2-VL) was monitored at buffered pH values of 7.4 and 5.5 at 37 °C. Small portions of samples were taken at appropriate times, freezedried, and examined by 1H NMR. As shown in the 1H NMR spectra of the degraded samples of poly(α-NH2-VL)44 (Figure S12), the peak at 3.50 ppm assigned to −CH2OH become larger while the peaks in the range of 4.0−4.3 ppm ascribed to the repeating units become smaller as the degradation proceeded. Figure 11 shows the degradation degree of poly(α-NH2-VL)44 as a function of time, which was estimated by 1H NMR. It was found that poly(α-NH2-VL)44 degraded faster at pH 7.4 than at pH 5.5. Poly(α-NH2-VL)164 of a high Mn also displayed similar degradation behavior (Figures S13 and S14). These results are consistent with the pH-degradation profiles of other amino-functionalized polyesters.25 It is reasonable that the amine groups without protonation can react with the ester units of the backbone to contribute to a more rapid degradation at higher pH.

Figure 11. Degradation of poly(α-NH2-VL)44 at 37 °C pH 5.5 and 7.4. The degradation degree is calculated by 1H NMR, and the estimated equation is offered in the Supporting Information.

protected monomer α-NHBoc-VL. By optimizing the conditions, it was found that the DBU/TU catalyzed ROP of αNHBoc-VL in THF proceeded in a living polymerization manner. Moreover, the polymerization activity of α-NHB-VL is comparable to that of CL and VL. Thus, well-defined homo-/ copolyesters as well as block copolymers containing poly(αNHBoc-VL) were successfully prepared via living ROP. Moreover, a water-soluble and relatively stable poly(α-NH2VL) was obtained by treatment with TFA. As far as we know, this is the first example where functional polyester with primary amino groups at the α-positions (an analogue of PAA) can be prepared via a living ROP methodology. Therefore, this methodology offers an opportunity to synthesize PAA analogues with controlled molecular weight and tunable properties for biomedical applications.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.7b02489. Experimental procedures, EA data, GPC curves, 1H NMR, and 1H−1H COSY spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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*(H.H.H.) E-mail: [email protected]. *(Y.M.C.) E-mail: [email protected].

CONCLUSION We demonstrated the synthesis of a new amino-functionalized polyester, poly(α-NH2-VL), via ROP of the corresponding

ORCID

Yongming Chen: 0000-0003-2843-5543 F

DOI: 10.1021/acs.macromol.7b02489 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

We gratefully acknowledge the financial support from Natural Science Foundation of China (No. 51533009), Guangdong Innovative and Entrepreneurial Research Team Program (No. 2013S086), and Natural Science Foundation of Guangdong Province (No. 2014A030312018).

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DOI: 10.1021/acs.macromol.7b02489 Macromolecules XXXX, XXX, XXX−XXX