Synthesis of Thermo-sensitive and Biocompatible Polyethylene Glycol Monomethyl Ether-Maleic Acid Polyester and Its Reversible Morphological Transition

QI Kun; ZOU Mengjun; LIAO Huazhen; ZHAO Yanzhi; LEI Fuhou; ZHOU Juying

doi:10.13718/j.cnki.xdzk.2021.11.012

2021 Volume 43 Issue 11

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QI Kun, ZOU Mengjun, LIAO Huazhen, et al. Synthesis of Thermo-sensitive and Biocompatible Polyethylene Glycol Monomethyl Ether-Maleic Acid Polyester and Its Reversible Morphological Transition[J]. Journal of Southwest University Natural Science Edition, 2021, 43(11): 93-101. doi: 10.13718/j.cnki.xdzk.2021.11.012

Citation:

QI Kun, ZOU Mengjun, LIAO Huazhen, et al. Synthesis of Thermo-sensitive and Biocompatible Polyethylene Glycol Monomethyl Ether-Maleic Acid Polyester and Its Reversible Morphological Transition[J]. Journal of Southwest University Natural Science Edition, 2021, 43(11): 93-101. doi: 10.13718/j.cnki.xdzk.2021.11.012

Synthesis of Thermo-sensitive and Biocompatible Polyethylene Glycol Monomethyl Ether-Maleic Acid Polyester and Its Reversible Morphological Transition

1.
School of Chemistry and Chemical Engineering, Guangxi University for Nationalities, Nanning 530006, China
2.
Key Laboratory of Chemistry and Engineering of Forest Products, State Ethnic Affairs Commission, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, Nanning 530006, China

More Information

Corresponding author: ZHOU Juying
Received Date: 18/11/2020
Available Online: 20/11/2021
MSC: O636.9

Abstract

Polyethylene glycol monomethyl ether-maleic acid polyester was prepared with the catalytic esterification method. The structure and molecular weight of polyethylene glycol monomethyl ether-maleic acid polyester were studied with infrared, nuclear magnetic, ultraviolet, GPC and other technologies. Polyethylene glycol monomethyl ether-maleic acid rosin acid polyester was found to be non-toxic and possess good thermal stability. Polyethylene glycol monomethyl ether-maleic rosin acid polyester chains aggregated into micelles and the size of micelles gradually increased during the process of heating the solution, and the size gradually decreased after the turning temperature. The aggregation and compaction morphology transition was reversible. In conclusion, the formation of polyethylene glycol monomethyl ether-maleic acid polyester micelles offers some new ideas for the design and development of thermo-sensitive carriers and green surfactants.
- thermo-sensitive,
- biocompatibility,
- reversible,
- morphological transition,
- polyethylene glycol monomethyl ether-maleic rosin acid polyester

References

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水溶性聚合物广泛应用在稳定剂、分散剂等领域^[1-2]. 美国食品药品监督管理局(FDA)认可的一类水溶性聚合物为聚乙二醇(PEG)，其具有相容性和水溶性好，且价廉等优良性能. 聚乙二醇及其衍生物在生物技术和药物传输等方面展现了较好的前景. 例如，聚乙二醇可运用于降低抗原性与免疫原性^[3]、沉淀蛋白^[4]、防止被酶和细胞降解等领域^[5].

聚乙二醇作为一种水溶性聚合物，常被用作共轭段与其他疏水聚合物共聚，其高的水合能力有利于调节材料的亲水性. 聚乙二醇基共聚物也是一种温度响应性聚合物，例如当其与聚(乙烯醚)、聚苯乙烯、聚(降冰片)和聚酯或聚(丙烯酸酯)形成共聚物时，在某些领域可取代传统的温度响应性的聚(n-异丙基丙烯酰胺). 聚乙二醇基共聚物^[6]在生理介质和水溶液中显示出低的临界转变温度，且高分子链具有可逆形态转变，通常应用于生物医学领域. 例如，紫杉醇负载于单甲氧基聚乙二醇(mPEG)-b-聚丙交酯胶束中，并在不损失细胞毒性的情况下可从胶束中释放^[7]. 聚谷氨酸-单甲氧基聚乙二醇纳米胶束可被应用于血液循环中^[8]. LIN D S等^[9]合成了甲氧基聚乙二醇单甲醚-聚己内酯-聚甲基丙烯酸二甲氨基乙酯三嵌段共聚物并研究了其自组装行为并用于载药和释药领域. 除上述mPEG共聚物外，其他共聚物如接枝壳寡糖共聚物(COS-g-PCL-b-mPEG) ^[10]，mPEG-壳聚糖双嵌段共聚物^[11]等也可用于药物载体领域.

松香是一种热塑性固体树脂，存在于天然松树的油脂中^[12]. 松香不溶于水，但通过引入亲水基团，松香衍生聚合物可以变成水溶性. 如以松香酰亚胺、马来酸酐加成物为基础的非离子表面活性剂可作为石油原油污泥分散剂^[13]. 两亲性聚乙二醇-聚脱氢松香甲基丙烯酸乙酯嵌段共聚物在阻碍肿瘤生长中表现出优越的性能^[14]. 两亲性松香基共聚物在亲水和疏水作用力下可发生多种高分子链形态转变. 固体酸催化法、酰氯酯化法和质子酸催化法是松香酯化共聚的常见方法^[15-16]. 我们实验室制备了两亲性脱氢松香酸-丁二酸聚酯并研究了其胶束化和在水中的分子链的形态转变过程^[17].

本研究合成了聚乙二醇单甲醚-马来松香酸聚酯，得到了其临界胶束浓度，并探究了聚乙二醇单甲醚-马来松香酸聚酯在变温水溶液中的形态转变及形成胶束的行为，结果表明其具有温度响应性，可应用于温敏性载体及绿色表面活性剂.

1. 实验部分

1.1. 实验材料

甲氧基聚乙二醇购自阿拉丁(AR，M为1000)；4-二甲氨基吡啶购于上海雅本(AR，DMAP)；马来松香为广西林产化学与工程重点实验室自制(纯度可达到99%)；1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐购于三盛生物科技(AR，EDC)；MEM培养基来源于HYCLONE；T25培养瓶、96和24孔培养板均来源于CORNING；胰酶来源于生工生物；Cell Counting Kit-8来源于碧云天(C0042，CCK-8)；FBS来源于GIBCO；活细胞/死细胞染色试剂盒来源于贝博(BB-4126)；其他溶剂皆为分析纯.

1.2. 合成聚乙二醇单甲醚-马来松香酸聚酯

以干燥的250 mL单口烧瓶为反应容器，在氮气存在下加入3.05 g DMAP，2.23 g马来松香，12 g MPEG，加入二氯甲烷与搅拌子，使体系降温到0 ℃，保持温度为0 ℃的条件下加入4.6 g EDC，氮气氛围下反应30 min后，移走冰块，室温下继续反应2 d，透析10 d(透析袋分子量为2 000，溶剂为水和乙醇)后在50 ℃温度下旋转蒸干，产物为聚乙二醇单甲醚-马来松香酸聚酯.

1.3. 聚乙二醇单甲醚-马来松香酸聚酯的表征

使用美国Nicolet Magna公司IR-550(Ⅱ)型傅里叶红外光谱仪表征其特征基团与化学结构；¹H核磁光谱用德国Bruker公司AV600/400型核磁共振光谱仪测定；用日本岛津UV1800型紫外可见分光光度计测试聚乙二醇单甲醚-马来松香酸聚酯水溶液的紫外吸收光谱；用Waters公司Waters 1525型凝胶渗透色谱表征聚乙二醇单甲醚-马来松香酸聚酯分子量及其分布；利用德国NETZSCH公司STA449F3 Jupiter热重分析仪对材料的热性能进行分析，测试温度区间为25~700 ℃，升温速率控制在10 ℃/min.

1.4. 聚乙二醇单甲醚-马来松香酸聚酯细胞毒性表征

1.4.1. 细胞活性的测定

聚乙二醇单甲醚-马来松香酸聚酯的细胞毒性由CCK8实验表征. 当培养瓶内L929密度为100%时，消化并得到细胞悬液，计数，在96孔培养板内(4×10 ⁴个细胞/孔)连续培养24 h(5% CO₂、温度为37 ℃). 分别加入浓度为50，300，500 μmol/L的聚乙二醇单甲醚-马来松香酸聚酯，控制组加入灭菌水. 继续培养24 h后加入CCK8(10 μL)，1 h后室温下轻轻震荡10 min，然后以酶标仪(Perkinelmer，EnSpire)测定OD450值，各个样品平行测定5次.

1.4.2. Live/Dead细胞荧光染色实验

当培养瓶内L929相对密度为100%时，消化并得到细胞悬液，计数，96孔培养板内(1.5×10 ⁵个细胞/孔)培养24 h(5% CO₂、温度为37 ℃). 加入浓度为50，300，500 μmol/L的聚乙二醇单甲醚-马来松香酸聚酯，控制组加入灭菌水，在37 ℃、5% CO₂条件下培养24 h. 以1 500 r/min的转速离心5 min，轻轻除掉上清，冲洗后进行染色(calcein AM稀释浓度1 000倍，PI染料稀释浓度20 000倍)，采用分开染色方案也即calcein AM染色25 min，PI染色5 min. 用荧光显微镜(OLYMPUS，U-RFL-T)得到活细胞与死细胞图像，分别为黄绿色与红色.

1.5. 聚乙二醇单甲醚-马来松香酸聚酯温度响应性胶束形成及形态转变研究

利用BZY-2表面张力仪测定临界胶束浓度. 弹性光散射光谱与强度是通过用美国PE公司LS-55型的荧光分光光度计来测定的. 激发和发射狭缝均设置为2.5 nm^[18]. 可以进行升温与降温控制，升温与降温速率是1 ℃/min，每一温度测定3次.

3. 结论

本研究通过酯化的方法制备了具有温度响应性的聚乙二醇单甲醚-马来松香酸聚酯，对其进行了结构表征、热性能研究及细胞毒性研究. 考察了聚乙二醇单甲醚-马来松香酸聚酯各质量浓度溶液在变温条件下的高分子链及聚集胶束形态转变. 结果证明，聚乙二醇单甲醚-马来松香酸聚酯表现出温度响应性，形态转变具有温度可逆性. 聚乙二醇单甲醚-马来松香酸聚酯制备简便，具有良好的生物相容性与温度响应性，可应用于绿色表面活性剂及温度响应性载体.

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Synthesis of Thermo-sensitive and Biocompatible Polyethylene Glycol Monomethyl Ether-Maleic Acid Polyester and Its Reversible Morphological Transition