CN112341607B - 一种可降解共聚物及其制备方法与应用 - Google Patents

一种可降解共聚物及其制备方法与应用 Download PDF

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CN112341607B
CN112341607B CN202011092834.1A CN202011092834A CN112341607B CN 112341607 B CN112341607 B CN 112341607B CN 202011092834 A CN202011092834 A CN 202011092834A CN 112341607 B CN112341607 B CN 112341607B
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肖海华
唐东升
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Abstract

本发明涉及一种可降解共聚物及其制备方法与应用，该可降解共聚物为一种嵌段共聚物，由一种或两种响应型双溴单体、共轭双溴单体和双锡单体聚合得到；所述响应型双溴单体具有可响应氧化条件、还原条件、乏氧条件或酸碱条件发生断裂的化学键；所述双锡单体含有两个三甲基锡基。该可降解共聚物具有光热效应，经光照快速升高温度，可用于光热治疗等。使用两亲性高分子包覆该可降解共聚物制备成纳米粒，可敏感响应氧化还原、乏氧及酸碱环境发生降解，实现更好的生物相容性。

Description

一种可降解共聚物及其制备方法与应用
技术领域
本发明涉及生化技术领域，具体涉及一种可降解共聚物及其制备方法与应用。
背景技术
纳米科技(nanotechnology)是以1-100nm尺度的物质或结构为研究对象的学科，即指通过一定的微细加工方式直接操纵原子，分子或原子团、分子团，使其重新排列组合，形成新的具有纳米尺度的物质或结构，进而研究其特性及其实际应用的一门新兴科学与技术。纳米科技自上世纪被提出之后，在材料、冶金、化学化工、医学、环境、食品等各领域均表现出巨大的应用前景。
在药物研究领域，由于纳米技术的不断渗透和影响，引发了药物领域一场深远的革命，从而出现了纳米药物这一新名词。纳米药物是指以纳米级高分子纳米粒(nano-particles，NP)、纳米球(nano.spheres NS)、纳米囊(nano-capsules，NC)等为载体，与药物以一定方式结合在一起后制成的药物，其粒径可能超过100nm，但通常应小于500nm。纳米药物也可以是直接将原料药物加工制成的纳米粒。
除了传统的药物可以制备成纳米药物外，将有机共轭聚合物通过两亲性载体包覆制备的纳米粒也广泛应用于药物研究领域。由于药物直接作用于人体，所以药物需满足无毒、生物相容性好、可生物降解等条件。尽管已公开了多种包覆有机共轭聚合物的纳米药物，然而，随着研究的深入，亦发现这些负载有机共轭聚合物的纳米药物存在着诸多不足之处。例如，目前大多有机共轭聚合物是采用单双键交替结构的共轭聚合物，这些共轭聚合物具有稳定的化学结构，在生物体内难以降解代谢，从而阻碍了有机共轭聚合物纳米药物在临床上的进一步发展和应用。
由于有机共轭聚合物存在上述不足，本领域一直致力于寻找可以在生物体内可降解代谢的有机聚合物，以进一步提高有机聚合物纳米药物的治疗效果，减少对正常组织细胞的侵害。
发明内容
本发明的目的在于提供一种可降解共聚物的制备方法和应用，该可降解共聚物为一种嵌段共聚物，可对氧化还原、乏氧及酸碱环境敏感响应，实现生物体内靶向降解代谢。
为此，第一方面，本发明提供了一种可降解共聚物，所述可降解共聚物由共轭双溴单体、双锡单体以及一种或两种响应型双溴单体聚合得到；
所述响应型双溴单体具有可响应氧化条件、还原条件、乏氧条件或酸碱条件发生断裂的化学键；
所述双锡单体含有两个三甲基锡基。
具体地，所述双溴单体为含有两个-Br的化合物，即，所述响应型双溴单体为含有两个-Br，且含有可响应氧化条件、还原条件、乏氧条件或酸碱条件发生断裂的化学键的化合物。所述共轭双溴单体为含有两个-Br，且具有共轭结构的化合物。
在具体实施方式中，所述可降解共聚物由一种响应型双溴单体、一种共轭双溴单体和一种双锡单体聚合得到。在另一具体实施方式中，所述可降解共聚物由两种响应型双溴单体、一种共轭双溴单体和一种双锡单体聚合得到。
进一步，所述可降解共聚物为嵌段共聚物。
进一步，所述响应型双溴单体和所述共轭双溴单体的摩尔数之和，与所述双锡单体的摩尔数之比为1-1.2:1-1.2，优选为1:1；所述响应型双溴单体与所述共轭双溴单体的摩尔数之比为1:4-6，优选为1:5-6，更优选为1:5.5-6。
进一步，所述化学键为二硫键，二硒键，缩硫醛，缩醛中的一种或几种。
进一步，所述响应型双溴单体选自以下化合物中的一种或几种，
Figure BDA0002722731790000021
Figure BDA0002722731790000031
进一步，所述共轭双溴单体选自以下化合物中的一种或几种，
Figure BDA0002722731790000032
进一步，所述双锡单体选自以下化合物中的一种或几种，
Figure BDA0002722731790000041
本发明的第二方面，提供了所述可降解共聚物的制备方法，包括使所述响应型双溴单体、共轭双溴单体和双锡单体于无水甲苯中进行聚合反应。
本发明的第三方面，提供了所述可降解共聚物在制备纳米药物中的应用。
本发明的第四方面，提供了一种纳米药物，其包括；a)两亲性聚合物；b)本发明所述的可降解共聚物。
本纳米药物使用两亲性高分子包覆本发明所述可降解共聚物制备成纳米粒，经静脉注射血液循环蓄积在肿瘤部位，用红外二区光照射产生光热，杀伤肿瘤细胞。在肿瘤微环境下，两亲性高分子包覆的聚合物在还原物质、氧化物质、乏氧条件下可降解，实现更好的生物兼容性。
在具体的实施方式中，所述两亲性聚合物为PLGA-PEG、DSPE-PEG或PEG-b-PPG-b-PEG。
本发明在研究过程中，首次合成了多种响应型双溴单体，这种含双溴的单体可以与含双锡的单体在催化剂存在下发生stille欧联反应。双溴单体含有可响应氧化条件、还原条件、乏氧条件或酸碱条件发生断裂的化学键之一，包含该响应型双溴单体的共聚物可响应细胞微环境发生降解。本发明提供的共聚物可作为药物载体，实现靶向释放药物的功能。例如恶性肿瘤中存在乏氧细胞，当本发明的共聚物载体载药到达该细胞时，可响应乏氧条件发生裂解，从而释放药物。
与现有技术相比，本发明的技术方案具有以下优点：
(1)本发明提供的可降解共聚物具有对氧化还原、乏氧及酸微环境敏感响应的特殊化学键，在氧化或还原、乏氧及酸碱环境中易断裂(响应断裂原理如下)，由此可以实现在肿瘤部位降解，实现药物体内代谢、增加生物相容性，减少不良反应。
Figure BDA0002722731790000061
(2)本发明提供的可降解共聚物具有光热效应，该可降解共聚物在600-1200nm范围内均有较强的吸收，其在1064激光照射下，可吸收光能量，再以非辐射热能的方式产热，从而实现用于光热治疗。
(3)本发明提供的可降解共聚物可被两亲性载体包覆自组装为纳米粒，提高药物的稳定性。
(4)本发明提供了相应的制备方法，工艺流程简单，产物稳定性高。
附图说明
通过阅读下文优选实施方式的详细描述，各种其他的优点和益处对于本领域普通技术人员将变得清楚明了。附图仅用于示出优选实施方式的目的，而并不认为是对本发明的限制。在附图中：
图1为可降解聚合物的紫外吸收光谱图；
图2为可降解聚合物的光热变化图；
图3为可降解聚合物的降解变化图；
图4为纳米粒的粒A径图；
图5为包载可降解共聚物的纳米粒的紫外吸收光谱图；
图6为包载可降解共聚物的纳米粒的光热变化图。
具体实施方式
下面将参照附图更详细地描述本公开的示例性实施方式。虽然附图中显示了本公开的示例性实施方式，然而应当理解，可以以各种形式实现本公开而不应被这里阐述的实施方式所限制。相反，提供这些实施方式是为了能够更透彻地理解本公开，并且能够将本公开的范围完整的传达给本领域的技术人员。
实施例1单体1
Figure BDA0002722731790000071
将2,2'-diselanediylbis(ethan-1-ol)(1.45g，5.80mmol)，5-溴噻吩-2-羧酸(3.00g，14.50mmol),EDC(2.78g，14.50mmol)和DMAP(1.77g，14.50mmol)，溶于100mL DMF，室温反应24h，反应体系倒入500mL水中，100mL乙酸乙酯萃取三次，柱层析分离，得白色固体，即式1所示单体，产率65％。
实施例2单体2
Figure BDA0002722731790000081
将2,2'-(丙烷-2,2-二基双(磺胺二基))二乙基-1-醇(1.98g，10.10mmol),5-溴噻吩-2-羧酸(5.22g，25.25mmol),EDC(4.84g，25.25mmol)和DMAP(3.08g，25.25mmol)，溶于100mL DMF，室温反应24h，反应体系倒入500mL水中，100mL乙酸乙酯萃取三次，柱层析分离，得白色固体，即式2所示单体，产率68％。1H NMR(400MHz,CDCl3)δ7.55(d,2H),7.06(d,4H),4.43(t,4H),2.97(t,4H),1.65(s,6H).
实施例3单体3
Figure BDA0002722731790000082
将双(2-羟基乙基)二硫醚(4.01g，26.00mmol),5-溴噻吩-2-羧酸(13.45g，65.00mmol),EDC(12.46g，65.00mmol)和DMAP(7.94g，65.00mmol)，溶于100mL DMF，室温反应24h，反应体系倒入500mL水中，100mL乙酸乙酯萃取三次，柱层析分离，得白色固体，即式3所示单体，产率66％。1H NMR(400MHz,CDCl3)δ7.55(d,2H),7.08(d,4H),4.54(t,4H),3.04(t,4H).
实施例4单体4
Figure BDA0002722731790000083
四价羟基顺铂(0.59g，1.77mmol),5-溴噻吩-2-羧酸(0.92g，4.43mmol),EDC(0.85g，4.43mmol)和DMAP(0.54g，4.43mmol)，溶于20mL DMF，室温反应24h，反应体系直接旋干溶剂，柱层析分离，得白色固体，即式4所示单体，产率66％。
实施例5单体5
Figure BDA0002722731790000091
5-溴噻吩-2-羧酸(1.50g，7.24mmol),DCC(0.74g，3.59mmol)溶于30mL无水乙醚中，室温反应24h，反应体系过滤得到上清滤液，将滤液旋干，加入20mL无水DMF中以及四价羟基奥沙利铂(0.20g，0.46mmol),反应液直接旋干，柱层析分离，得白色固体，即式5所示单体，产率41％。1H NMR(400MHz,CDCl3)δ8.47(d,2H),8.00(s,2H),7.42(d,2H),7.29(d,2H),2.74(s,2H),2.16(d,2H),1.56(d,4H),1.23(d,2H).
实施例6式I共聚物
Figure BDA0002722731790000092
称取式22所示双锡单体(136.5mg,0.12mmol)，式9所示双溴单体(36.5mg,0.10mmol)，式1所示双溴单体(11.26mg,0.02mmol)，P(o-tol)3(2.9mg,0.0096mmol)，dba3pd2(2.19mg,0.0024mmol)溶于5mL脱气甲苯中，氮气保护，120℃反应3h，反应完成后，趁热将反应滴入500mL无水甲醇中，静止30min，过滤得到墨绿色沉淀，烘干即可得到产物，即式I所示共聚物(其中m,n均为摩尔比值；m＝0.8,n＝0.2)。1H NMR(400MHz,CDCl3)δ8.47,8.00,7.42,4.53,3.20,2.74,2.22,2.19,2.17,2.16,1.56,1.23.
实施例7式II共聚物
Figure BDA0002722731790000101
称取式22所示双锡单体(139.0mg,0.13mmol)，式9所示双溴单体(38.5mg,0.11mmol)，式2所示双溴单体(11.4mg,0.02mmol)，P(o-tol)3(3.0mg,0.010mmol)，dba3pd2(2.4mg,0.0026mmol)溶于5mL脱气甲苯中，氮气保护，120℃反应3h，反应完成后，趁热将反应滴入500mL无水甲醇中，静止30min，过滤得到墨绿色沉淀，烘干即可得到产物，即式II所示共聚物(其中m,n均为摩尔比值；m＝0.8,n＝0.2)。1H NMR(400MHz,CDCl3)δ8.52,8.09,7.52,4.33,3.10,2.76,2.32,2.29,2.27,2.19,1.56,1.50,1.23.
实施例8式III共聚物
Figure BDA0002722731790000111
称取式22所示双锡单体(144.2mg,0.13mmol)，式9所示双溴单体(38.5mg,0.11mmol)，式3所示双溴单体(10.6mg,0.02mmol)，P(o-tol)3(3.0mg,0.010mmol)，dba3pd2(2.4mg,0.0026mmol)溶于5mL脱气甲苯中溶于5mL脱气甲苯中，氮气保护，120℃反应3h，反应完成后，趁热将反应滴入500mL无水甲醇中，静止30min，过滤得到墨绿色沉淀，烘干即可得到产物即式III所示共聚物(其中m,n均为摩尔比值；m＝0.8,n＝0.2)。1H NMR(400MHz,CDCl3)δ8.40,8.03,7.41,4.43,3.22,2.69,2.12,2.10,2.07,1.56,1.23.
实施例9式IV共聚物
Figure BDA0002722731790000121
称取式22所示双锡单体(150.2mg,0.14mmol)，式9所示双溴单体(42.0mg,0.12mmol)，式4所示双溴单体(14.2mg,0.02mmol)，P(o-tol)3(3.3mg,0.011mmol)，dba3pd2(2.6mg,0.0028mmol)溶于5mL脱气甲苯中溶于5mL脱气甲苯中，氮气保护，120℃反应3h，反应完成后，趁热将反应滴入500mL无水甲醇中，静止30min，过滤得到墨绿色沉淀，烘干即可得到产物即式IV所示共聚物(其中m,n均为摩尔比值；m＝0.8,n＝0.2)。1H NMR(400MHz,CDCl3)δ8.47,8.00,7.42,6.99,2.74,2.32,2.19,2.17,2.16,1.56,1.23.
实施例10式V共聚物
Figure BDA0002722731790000122
称取式22所示双锡单体(149.7mg,0.13mmol)，式9所示双溴单体(38.5mg,0.11mmol)，式5所示双溴单体(16.1mg,0.02mmol)，P(o-tol)3(3.0mg,0.010mmol)，dba3pd2(2.4mg,0.0026mmol)溶于5mL脱气甲苯中溶于5mL脱气甲苯中，氮气保护，120℃反应3h，反应完成后，趁热将反应滴入500mL无水甲醇中，静止30min，过滤得到墨绿色沉淀，烘干即可得到产物即式V所示共聚物(其中m,n均为摩尔比值；m＝0.8,n＝0.2)。1H NMR(400MHz,CDCl3)δ8.47,8.32,8.11 8.00,7.42,2.74,2.22,2.12,2.10,1.56,1.23.
实施例11式VI共聚物
Figure BDA0002722731790000131
称取式22所示双锡单体(148.2mg,0.13mmol)，式9所示双溴单体(38.5mg,0.11mmol)，式6所示双溴单体(6.8mg,0.02mmol)，P(o-tol)3(3.0mg,0.010mmol)，dba3pd2(2.4mg,0.0026mmol)溶于5mL脱气甲苯中，氮气保护，120℃反应3h，反应完成后，趁热将反应滴入500mL无水甲醇中，静止30min，过滤得到墨绿色沉淀，烘干即可得到产物，即式Ⅵ所示共聚物(其中m,n均为摩尔比值；m＝0.8,n＝0.2)。1H NMR(400MHz,CDCl3)δ8.47,8.00,7.51,7.45,7.42,2.22,2.19,2.17,2.16,1.56,1.23.
实施例12式VII共聚物
Figure BDA0002722731790000141
称取式24所示双锡单体(133.5mg,0.16mmol)，式12所示双溴单体(31.3mg,0.056mmol)，式7所示双溴单体(53.8mg,0.08mmol)，式3所示双溴单体(12.7mg,0.024mmol)，P(o-tol)3(4.0mg,0.013mmol)，dba3pd2(2.93mg,0.0032mmol)溶于5mL脱气甲苯中，氮气保护，120℃反应3h，反应完成后，趁热将反应滴入500mL无水甲醇中，静止30min，过滤得到墨绿色沉淀，烘干即可得到产物，即式Ⅶ所示共聚物(其中x,y,n均为摩尔比值；x＝0.4,y＝0.4,n＝0.2)。1H NMR(400MHz,CDCl3)δ9.70,9.41,8.95,8.01,7.82,7.53,7.19,6.81,4.14,2.88,1.90,1.46,1.01,0.67.
用紫外可见分光光度计(UV-2450PC，Shimazu)对式Ⅶ所示共聚物进行紫外吸收的测定，检测结果如图1所示，由图1可知，包式Ⅶ所示共聚物在600-1300均有很强的吸收。
用1.0W的红外LED灯对Ⅶ所示共聚物体系进行光照，测得Ⅶ所示共聚物体系温度随时间变化曲线，如图2所示，随着时间的增加体系温度升高，8min时体系温度到达77℃。
分别在Ⅶ所示共聚物的THF溶液中加入10mmol GSH，至于37℃下孵育0、4、8、16、24小时，通过凝胶渗透色谱(GPC)测定其分子量变化，检测结果如图3所示，由图3可知，包式Ⅶ所示共聚物在24小时后，分子量由21.4KDa降到8.4KDa。
实施例13纳米粒的制备
称取实施例12制备的式Ⅶ可降解共聚物1mg，两亲性聚合物PLGA-PEG 50mg置于含有10mL THF的25mL小瓶中，超声至两组分完全溶解，快速旋干，在超声下滴加5mL水，用截留分子量为3500的透析袋透析12h，透析液在转速3000转/min离心3min，弃去沉淀，制备得到纳米胶束体系。使用动态光散射仪(DLS)测定其粒径，检测结果如图4所示，其平均粒径(z-average)为133nm，聚合物分散指数(Polymer dispersity index，PDI)为0.082。
用紫外可见分光光度计(UV-2450PC，Shimazu)进行紫外吸收的测定，检测结果如图5所示，由图5可知，包载染料的纳米胶束在600-1300均有很强的吸收。
用1.0W的红外LED灯对包载染料的纳米胶束体系进行光照，测得覆在染料纳米胶束体系温度随时间变化曲线，如图6所示，随着时间的增加体系温度升高，8min时体系温度到达77℃。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求的保护范围为准。

Claims (8)

1.一种可降解共聚物，其特征在于，所述可降解共聚物由共轭双溴单体、双锡单体以及一种或两种响应型双溴单体聚合得到；
所述响应型双溴单体选自以下化合物中的一种或几种，
Figure FDA0003254156700000011
所述共轭双溴单体选自以下化合物中的一种或几种，
Figure FDA0003254156700000012
Figure FDA0003254156700000021
所述双锡单体选自以下化合物中的一种或几种，
Figure FDA0003254156700000022
2.如权利要求1所述的可降解共聚物，其特征在于，所述响应型双溴单体和所述共轭双溴单体的摩尔数之和，与所述双锡单体的摩尔数之比为1-1.2:1-1.2；所述响应型双溴单体与所述共轭双溴单体的摩尔数之比为1:4-6。
3.如权利要求1所述的可降解共聚物，其特征在于，所述可降解共聚物包括：
Figure FDA0003254156700000031
Figure FDA0003254156700000041
其中，m与n的摩尔比值为0.7-0.9:0.1-0.3；x、y、n的摩尔比值为0.4-0.5:0.4-0.5:0.2。
4.如权利要求3所述的可降解共聚物，其特征在于，所述m与n的摩尔比值为0.8:0.2。
5.如权利要求3所述的可降解共聚物，其特征在于，所述x、y、n的摩尔比值为0.4:0.4:0.2。
6.权利要求1-5任一项所述可降解共聚物的制备方法，其特征在于，包括使所述响应型双溴单体、共轭双溴单体和双锡单体于无水甲苯中进行聚合反应。
7.权利要求1-5任一项所述可降解共聚物在制备纳米药物中的应用。
8.一种纳米药物，其特征在于，所述纳米药物包括；a)两亲性聚合物；b)权利要求1-5任一项所述的可降解共聚物。
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