CN115477743A - 一种含二硫键的聚乳酸及其制备方法和应用 - Google Patents
一种含二硫键的聚乳酸及其制备方法和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及医用高分子材料技术领域,具体涉及一种含二硫键的聚乳酸及其制备方法和应用。
背景技术
聚乳酸是以乳酸为主要原料聚合得到的聚酯类聚合物,其具有良好的生物相容性、可生物降解性、可调节性等,被广泛应用在生物医药领域(例如:用于药物递送和释放)。研究发现,通过在聚乳酸的分子链段中引入二硫化物可以使其具有两亲性,从而可以形成胶束来包封药物,且在还原性物质的作用下二硫键可以发生裂解,最终实现药物的释放。
目前,含二硫键的聚乳酸材料的制备方法主要包括以下几种:
1)利用胱胺、N,N'-双(丙稀酰)胱胺、2-羟乙基二硫化物等含二硫键的分子直接与聚乳酸大分子反应,用于连接聚乳酸与其他聚合物大分子、药物分子,或是作为交联剂,合成含有二硫键的聚乳酸功能材料(Cunningham A,Ko N R,Oh J K.Colloids and SurfacesB:Bio interfaces,2014,122,693-700;Gaspar V M,Bail P,Costa E C,de Melo-DiogoD,et al.Journal of Controlled Release,2015,213,175-191;Du X,Yin S P,Zhou F,etal.International Journal of Pharmaceutics,2018,550(1-2),1-13;Karandish F,Mamnoon B,Feng L,Hadar M K,et al.Molecules,2018,19(10):4122-4132);
2)利用二硫化物小分子(例如:二羟乙基二硫化物)与2-溴异丁酸、2-溴异丁酰溴、甲基丙烯酰氯等形成双端引发剂,利用羟基端引发丙交酯开环得到聚乳酸,利用溴端、氯端引发另一种功能性单体(或聚合物)的聚合,形成含有二硫键的聚乳酸功能材料(SourkohiB K,Cunningham A,Zhang Q,et al.Biomacromolecules,2011,12,3819-3825;Chan N,AnS Y,Oh J K.Polymer Chemistry,2014,55(5),1637-1649;Ko N R,Sabbatier G,Cunningham A,et al.Macromolecular Rapid Communications,2014,35(4):447-453;Zhou Q,Xu L,Liu F,et al.Polymer,2016,97,323-334;Jazani A M,Arezi N,Maruya-LiK,et al.ACS Omega,2018,3(8),8980-8991);
3)通过二硫键的交换反应,合成大分子引发剂引发丙交酯开环聚合,或是直接桥接两个大分子,形成含二硫键的聚乳酸材料(Fuoco T,Pappalardo D,Finne-WistrandA.Macromolecules,2017,50(18),7052-7061;Van Gheluwe L,Buchy E,Chourpa I,etal.Polymers,2020,12(10),2350)。
上述方法均是在亲水-疏水段中间或疏水段-药物分子的连接处引入二硫键,虽然得到的含二硫键的聚乳酸材料均可以形成胶束来包封药物,但功能比较单一,且上述合成过程存在反应条件苛刻(例如:避光、低温、合适的酸碱度等)、过程较长且涉及大量有机试剂的消耗、部分原料具有一定的毒性(例如:2-羟乙基二硫化物)、成本较高等问题,不利于含二硫键的聚乳酸材料的大规模应用(Shen W,Liu W G,Yang H L,et al.Biomaterials,2018,178:706-719)。
因此,通过操作简单、绿色环保、成本低的方法制备一种性能更加优异的含二硫键的聚乳酸具有十分重要的意义。
发明内容
本发明的目的在于提供一种含二硫键的聚乳酸及其制备方法和应用。
本发明所采取的技术方案是:
一种含二硫键的聚乳酸,其结构式为:
优选的,所述含二硫键的聚乳酸的重均分子量为2100Da~2800Da。
一种如上所述的含二硫键的聚乳酸的制备方法包括以下步骤:
1)将乳酸单体预聚,得到预聚物;
2)将预聚物、胱胺单体和催化剂混合进行熔融聚合,即得含二硫键的聚乳酸。
优选的,一种如上所述的含二硫键的聚乳酸的制备方法包括以下步骤:
1)将乳酸单体预聚,得到预聚物;
2)将预聚物、胱胺单体和催化剂混合进行熔融聚合,再用有机溶剂溶解产物,再加水进行沉析,再将沉析出来的固体分离出来进行干燥,即得含二硫键的聚乳酸。
优选的,所述乳酸单体、胱胺单体的摩尔比为1~120:1。
进一步优选的,所述乳酸单体、胱胺单体的摩尔比为10~50:1。
优选的,步骤1)所述预聚在真空度为1kPa~10kPa、温度为100℃~180℃的条件下进行,聚合时间为3h~10h。
优选的,步骤1)所述乳酸单体进行过常压脱水处理。
优选的,所述常压脱水处理在100℃~170℃下进行,脱水时间为1h~10h。
优选的,步骤2)所述催化剂为ZnCl2、SnCl2、对甲苯磺酸、ZnO、SnO中的至少一种。
优选的,步骤2)所述催化剂的添加量为预聚物质量的0.02%~4%。
优选的,步骤2)所述熔融聚合在真空度为1kPa~10kPa、温度为100℃~180℃的条件下进行,聚合时间为3h~10h。
优选的,步骤2)所述有机溶剂为甲醇、乙醇、四氢呋喃、三氯甲烷中的至少一种。
优选的,步骤2)所述干燥在真空度为1kPa~10kPa、温度为30℃~45℃的条件下进行。
一种如上所述的含二硫键的聚乳酸在制备药物载体、药物或伤口敷料中的应用。
本发明的有益效果是:本发明的含二硫键的聚乳酸在聚乳酸的聚酯主链中引入了二硫键,其在可以形成两亲性胶束的同时还便于实现二硫交换反应,嫁接较为复杂的功能性分子或药物分子,且其制备方法具有操作简单、绿色环保、成本低等优点,适合进行大规模生产应用。
具体来说:
1)本发明的含二硫键的聚乳酸具有良好的可还原性,在还原性物质(例如:二硫苏糖醇)的作用下可以很好地实现大分子中的二硫键的还原、断裂;
2)本发明的含二硫键的聚乳酸是在聚乳酸的聚酯主链中引入二硫键,不同于现有的在亲水-疏水段中间或疏水段-药物分子的连接处引入二硫键而得到的含二硫键的聚乳酸,其不仅可以满足形成两亲性胶束的要求,而且还有利于实现二硫交换反应,嫁接较为复杂的功能性分子或药物分子,拓展了聚乳酸材料的应用;
3)本发明的含二硫键的聚乳酸是由乳酸和胱胺共聚得到,且通过调整投料比便可以灵活调节其理化性质;
4)本发明的含二硫键的聚乳酸在制备时采用的是廉价易得的生物基乳酸单体和无毒害作用的胱胺(二硫源),并不需要使用价格高昂的试剂,也不需要使用定制的合成设备,工艺简单且容易控制,产物提纯操作简便,产率高。
附图说明
图1为实施例3中的PLAC30的1H NMR图。
图2为实施例3中的PLAC30的FT-IR图。
图3为实施例1~5中的PLAC10、PLAC20、PLAC30、PLAC40和PLAC50的分子量及其分布的测试结果图。
图4为实施例1~5中的PLAC10、PLAC20、PLAC30、PLAC40和PLAC50的热性能测试结果图。
图5为实施例1~5中的PLAC10、PLAC20、PLAC30、PLAC40和PLAC50的结晶性能测试结果图。
图6为实施例3中的PLAC30的可还原性测试结果图。
具体实施方式
下面结合具体实施例对本发明作进一步的解释和说明。
实施例1:
一种含二硫键的聚乳酸,其制备方法包括以下步骤:
1)将4.5g(50mmol)的乳酸(LA)单体加入反应瓶,开启搅拌,常压下160℃脱水4h,再用循环水真空泵抽真空,在真空度为5kPa、温度为160℃的条件下聚合4h,得到预聚物;
2)将0.76g(5mmol)的胱胺(Cys)单体和0.1g的SnO加入步骤1)中的反应瓶,用旋片式真空油泵抽真空,在真空度为8kPa、温度为140℃的条件下聚合4h,再用甲醇溶解产物,再加去离子水进行沉析和洗涤,过滤,将滤得的固体放入真空干燥箱中45℃干燥24h,即得含二硫键的聚乳酸(记为PLAC10)。
实施例2:
一种含二硫键的聚乳酸,其制备方法包括以下步骤:
1)将4.5g(50mmol)的乳酸单体加入反应瓶,开启搅拌,常压下160℃脱水4h,再用循环水真空泵抽真空,在真空度为5kPa、温度为160℃的条件下聚合4h,得到预聚物;
2)将0.38g(2.5mmol)的胱胺单体和0.1g的SnO加入步骤1)中的反应瓶,用旋片式真空油泵抽真空,在真空度为10kPa、温度为130℃的条件下聚合3h,再用甲醇溶解产物,再加去离子水进行沉析和洗涤,过滤,将滤得的固体放入真空干燥箱中45℃干燥24h,即得含二硫键的聚乳酸(记为PLAC20)。
实施例3:
一种含二硫键的聚乳酸,其制备方法包括以下步骤:
1)将4.5g(50mmol)的乳酸单体加入反应瓶,开启搅拌,常压下160℃脱水4h,再用循环水真空泵抽真空,在真空度为7kPa、温度为160℃的条件下聚合5h,得到预聚物;
2)将0.25g(1.6mmol)的胱胺单体和0.1g的SnO加入步骤1)中的反应瓶,用旋片式真空油泵抽真空,在真空度为10kPa、温度为130℃的条件下聚合4h,再用甲醇溶解产物,再加去离子水进行沉析和洗涤,过滤,将滤得的固体放入真空干燥箱中45℃干燥24h,即得含二硫键的聚乳酸(记为PLAC30)。
实施例4:
一种含二硫键的聚乳酸,其制备方法包括以下步骤:
1)将4.5g(50mmol)的乳酸单体加入反应瓶,开启搅拌,常压下150℃脱水4h,再用循环水真空泵抽真空,在真空度为5kPa、温度为150℃的条件下聚合4h,得到预聚物;
2)将0.18g(1.2mmol)的胱胺单体和0.09g的SnO加入步骤1)中的反应瓶,用旋片式真空油泵抽真空,在真空度为10kPa、温度为140℃的条件下聚合4h,再用甲醇溶解产物,再加去离子水进行沉析和洗涤,过滤,将滤得的固体放入真空干燥箱中45℃干燥24h,即得含二硫键的聚乳酸(记为PLAC40)。
实施例5:
一种含二硫键的聚乳酸,其制备方法包括以下步骤:
1)将4.5g(50mmol)的乳酸单体加入反应瓶,开启搅拌,常压下160℃脱水4h,再用循环水真空泵抽真空,在真空度为5kPa、温度为160℃的条件下聚合6h,得到预聚物;
2)将0.15g(1mmol)的胱胺单体和0.1g的SnO加入步骤1)中的反应瓶,用旋片式真空油泵抽真空,在真空度为10kPa、温度为140℃的条件下聚合3h,再用甲醇溶解产物,再加去离子水进行沉析和洗涤,过滤,将滤得的固体放入真空干燥箱中45℃干燥24h,即得含二硫键的聚乳酸(记为PLAC50)。
性能测试:
1)实施例3中的PLAC30的核磁共振氢谱(1H NMR,δ,ppm)图如图1(使用氘代三氯甲烷CDCl3作为溶剂)所示,红外光谱(FT-IR,KBr,v,cm-1)图如图2所示。
由图1可知:1.47ppm~1.52ppm范围内的峰对应聚乳酸链段末端的-CH 3(Ha′),1.54ppm~1.61ppm范围内的峰对应乳酸单元中的-CH 3(Ha),2.84ppm~2.89ppm范围内的峰对应Cys单元中的CH 2(Hc),3.58ppm~3.62ppm范围内的峰对应Cys单元中的-NHCH 2-(Hd),4.37ppm~4.41ppm范围内的峰对应聚乳酸链段末端的-CH-(Hb),5.16ppm~5.20ppm范围内的峰对应聚乳酸单元中的-CH-(Hb′)。
由图2可知:3540cm-1处为O-H基团伸缩振动峰,3350cm-1处为PLAC30中-NH-基团伸缩振动吸收峰,2995cm-1和2951cm-1处为乳酸单元中饱和C-H基团的伸缩振动吸收峰,1755cm-1处为乳酸单元中C=O基团的强伸缩振动吸收峰,1638cm-1和1545cm-1处分别为PLAC30中酰胺结构的N-H伸缩振动和弯曲振动吸收峰,1450cm-1和1387cm-1处为PLAC30中饱和C-H的弯曲振动吸收峰,1185cm-1、1130cm-1和1085cm-1处为乳酸单元中C-O-C基团的强伸缩振动吸收峰,687cm-1处为胱胺单元中的S-S伸缩振动吸收峰,综上可知,PLAC30由于接入了二硫键,出现了酰胺结构的N-H伸缩振动和弯曲振动吸收峰,以及S-S伸缩振动吸收峰,证实了所得产物的结构如预期。
2)对实施例1~5中的PLAC10、PLAC20、PLAC30、PLAC40和PLAC50(对应的n(LA)/n(Cys)分别为10/1、20/1、30/1、40/1和50/1)的分子量及其分布进行测试,测试过程:称取0.01g的待测样品,由Waters 1515HPLC在以四氢呋喃(THF)为溶剂、聚苯乙烯为标样、流速为1mL/min、温度为35℃的条件下测定聚合物的分子量及其分布,得到的测试结果如图3所示。
由图3可知:PLAC10、PLAC20、PLAC30、PLAC40和PLAC50均只有一处明显的尖峰,在高分子量区和低分子量区均无拖尾,说明为聚合良好的均聚物,重均分子量(Mw)依次为2100Da、2200Da、2800Da、2500Da和2400Da(分子量数据按100Da取整),可见,随着n(LA)/n(Cys)增大,重均分子量的变化趋势为先增大后减小。
3)对实施例1~5中的PLAC10、PLAC20、PLAC30、PLAC40和PLAC50的热性能进行测试,测试过程:称取0.05g的待测样品,采用美国Perkn-Elemer DSC7热分析仪测定热性能,设置载气氮气的流速为20mL/min,升温速率为10℃/min,测定聚合物的玻璃化转变温度Tg和Tm,得到的测试结果如图4所示。
由图4可知:Cys对PLA链段的规整性影响较大,在n(LA)/n(Cys)的投料比例较小时,LA与Cys的聚合相对更容易,此时分子量也相对较低,由此链段规整性受较大影响,Tg相应较小,而当增大LA的投料量时,分子量相应增加,增长的PLA链段使得Tg有所上升,因此当n(LA)/n(Cys)为50/1时,开始出现熔融峰,并且数值接近聚乳酸均聚物(PDLLA)的54.6℃。
4)对实施例1~5中的PLAC10、PLAC20、PLAC30、PLAC40和PLAC50的结晶性能进行测试,测试过程:称取0.05g的待测样品,采用德国Bruker公司D8 Advance型X衍射仪测定,选择Cu靶,Kα射线,单色器滤波,λ为1.5406×10-10m,扫描范围为2θ=5°~50°,步进扫描为△2θ=0.030°,每步为5s,测定聚合物的结晶峰及结晶度,得到的测试结果如图5所示。
由图5可知:随着LA投料的增加,聚合物的特征结晶峰强度整体呈增强趋势,但仍然低于聚乳酸均聚物(PDLLA),受Cys单体接入的影响,变化的趋势与热性能变化趋势一致。
5)对实施例3中的PLAC30的可还原性进行测试,测试过程:取一个装有磁子的10mL的圆底烧瓶,加入100mg的PLAC30和3mL的N,N-二甲基甲酰胺(DMF),并在室温搅拌下加入61.2mg(400mmol)的二硫苏糖醇(DTT),进行还原降解,24h后加入去离子水沉析,离心、干燥后得到还原降解产物,再参考1)中的操作测试经还原降解后的PLAC30的分子量及其分布,得到的测试结果如图6所示。
由图6可知:经DTT作用后的产物在流出时间上明显推后(在还原性DTT的作用下,含有二硫键的聚乳酸会发生还原性降解,导致二硫键断裂,降解产物的分子量显著降低,反映在GPC测试结果上则表现为流出时间的延后),Mw具体数值由2800Da变为了1300Da,相比于PLAC30的Mw减小了约一半,说明Cys被成功地引入了PLA链段中,合成得到了预期结构的产物。
此外,经测试(测试方法同上),PLAC10、PLAC20、PLAC40和PLAC50同样具有较好的可还原性。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述的含二硫键的聚乳酸,其特征在于:所述含二硫键的聚乳酸的重均分子量为2100Da~2800Da。
3.一种如权利要求1或2所述的含二硫键的聚乳酸的制备方法,其特征在于,包括以下步骤:
1)将乳酸单体预聚,得到预聚物;
2)将预聚物、胱胺单体和催化剂混合进行熔融聚合,即得含二硫键的聚乳酸。
4.根据权利要求3所述的制备方法,其特征在于:所述乳酸单体、胱胺单体的摩尔比为1~120:1。
5.根据权利要求3或4所述的制备方法,其特征在于:步骤1)所述预聚在真空度为1kPa~10kPa、温度为100℃~180℃的条件下进行,聚合时间为3h~10h。
6.根据权利要求3或4所述的制备方法,其特征在于:步骤1)所述乳酸单体进行过常压脱水处理。
7.根据权利要求3或4所述的制备方法,其特征在于:步骤2)所述催化剂为ZnCl2、SnCl2、对甲苯磺酸、ZnO、SnO中的至少一种。
8.根据权利要求3或4所述的制备方法,其特征在于:步骤2)所述催化剂的添加量为预聚物质量的0.02%~4%。
9.根据权利要求3或4所述的制备方法,其特征在于:步骤2)所述熔融聚合在真空度为1kPa~10kPa、温度为100℃~180℃的条件下进行,聚合时间为3h~10h。
10.一种如权利要求1或2所述的含二硫键的聚乳酸在制备药物载体、药物或伤口敷料中的应用。
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