CN112194787A - 具有近红外二区光响应性可降解共聚物制备方法与应用 - Google Patents
具有近红外二区光响应性可降解共聚物制备方法与应用 Download PDFInfo
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- CN112194787A CN112194787A CN202010956286.6A CN202010956286A CN112194787A CN 112194787 A CN112194787 A CN 112194787A CN 202010956286 A CN202010956286 A CN 202010956286A CN 112194787 A CN112194787 A CN 112194787A
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Abstract
本发明涉及一种可近红外二区光响应的荧光、光动力和光热可降解共聚物及其制备方法与应用，该共聚物为一种嵌段共聚物，由具有红外二区荧光、光动力和光热的二羟基单体、可特异性响应肿瘤微环境(氧化条件、还原条件、乏氧条件、酸环境)和外界环境(热环境)等条件的二羟基单体、两端具有酸酐或异氰酸酯的单体聚合而成，且用一端具有氨基或羧基的聚乙二醇封端。该共聚物不仅具有穿透力强的近红外二区荧光成像、光动力、光热功能，将其用于药物载体时还可以响应肿瘤微环境，实现药物的靶向释放。
Description
技术领域
本发明涉及生化技术领域，具体涉及一种可近红外二区响应的荧光、光动力、光热的可降解共聚物及其制备方法与应用。
背景技术
对疾病的早期诊断是目前全世界生物学家和医疗工作者关注的热点，特别是利用灵敏度高、特异性强的检测手段实时、原位监测生物标志物具有重大挑战。相比于传统的光学成像技术如超声、CT或MRI等，荧光成像技术由于其非侵入式、高时空分辨率、实时性的显著优势，已经受到医学诊断、治疗等领域的广泛关注。
荧光成像技术在生物医学基础研究和疾病的诊断治疗等方面有着广泛的应用，例如，生物体内蛋白质、金属离子、还原型谷胱甘肽等物质的检测，临床上肿瘤早期诊断，以及为精准区分正常组织与病变组织而采用的荧光成像指导的肿瘤切除术。目前研究和临床常用的为可见光区(400-700nm)和近红外一区(700-900nm)的荧光染料。相较于可见光区和近红外一区荧光，近红外二区(1000nm-1700nm)荧光在机体的散射和组织吸收变少，此波段的生物自荧光效应极低，在体内成像中展现出更深的组织穿透深度和更高的空间分辨率等优势，近红外二区荧光成像技术已成为相关领域研究的热点方向。
在近红外区域中，相比于近红外一区，近红外二区具有两方面明显的优势：一方面是更强的组织穿透深度；另一方面，允许更高的照射剂量(根据美国激光安全使用的国家标准，皮肤可安全暴露于1064nm波长激光的功率密度为1W/cm2。
发明内容
本发明的目的在于提供一种可近红外二区响应的荧光、光动力、光热的可降解共聚物及其制备方法与应用，该共聚物为一种嵌段共聚物，不仅可用于近红外二区荧光成像、近红外二区光动力治疗、近红外二区光热治疗，并且可对氧化还原环境敏感响应，实现靶点定位释药。
为此，本发明的第一方面提供一种具有近红外二区荧光的共聚物，所述共聚物由第一二羟基单体、第二二羟基单体、两端具有酸酐或异氰酸酯的单体、一端具有氨基或羧基的聚乙二醇聚合而成；
所述第一二羟基单体具有近红外二区荧光、近红外二区光动力和/或近红外二区光热功能；
所述第二二羟基单体具有可响应氧化条件、还原条件、乏氧条件、酸环境和/或热环境条件发生断裂的化学键。
进一步，所述共聚物的制备方法包括，先将所述第一二羟基单体、第二二羟基单体、两端具有酸酐或异氰酸酯的单体进行聚合，再加入所述一端具有氨基或羧基的聚乙二醇封端。
进一步，所述共聚物为嵌段共聚物。
进一步，所述第一二羟基单体、第二二羟基单体和两端具有酸酐或异氰酸酯的单体的摩尔比为0.05-0.1:0.9-0.95:1。
进一步，所述第二二羟基单体具有以下化学键中的一种或两种以上：二硫键、二硒键、缩硫醛、缩醛、席夫碱、偶氮、缩酮。
进一步，所述第一二羟基单体具有近红外二区荧光，所述第一二羟基单体选自下组中的一种或两种以上：
进一步，所述第一二羟基单体具有近红外二区光动力，所述第一二羟基单体选自下组中的一种或两种：
进一步，所述第一二羟基单体具有近红外二区光热，所述第一二羟基单体为：
进一步，所述第二二羟基单体选自下组中的一种或两种以上：
进一步，所述两端具有酸酐或异氰酸酯的单体选自下组中的一种或两种：
进一步，所述一端具有氨基或羧基的聚乙二醇为一端具有氨基的聚乙二醇；优选为具有氨基的聚乙二醇；在具体的实施方式中，为PEG5000-NH2。
本发明的第二方面，提供了所述共聚物的制备方法，包括使所述第一二羟基单体、第二二羟基单体、两端具有酸酐或异氰酸酯的单体于二甲基甲酰胺(DMF)或二甲基亚砜(DMSO)中进行聚合反应；优选溶剂为DMF。
本发明的第三方面，提供所述共聚物在以下方面的应用：
(1)制备荧光成像试剂；
(2)用于荧光成像。
(3)制备用于光动力治疗的药物；
(4)制备用于光热治疗的药物；
进一步，所述荧光成像为近红外二区荧光成像；所述光动力治疗为近红外二区光动力治疗；所述光热治疗为近红外光热治疗。
本发明在研究过程中，首次合成了多种具有近红外二区荧光、光动力、光热的二羟基结构的单体，进而合成得到了具有近红外二区成像的多嵌段聚合物。此外，本发明提供的共聚物可敏感相应肿瘤微环境，含有如二硫键、二硒键、缩硫醛、缩醛、席夫碱、偶氮、缩酮等化学键。该共聚物不仅可用于荧光成像、光动力治疗、光热治疗，同时还可作为药物载体，用于敏感环境的药物释放，尤其是肿瘤的敏感环境中的药物释放。
与现有技术相比，本发明的技术方案具有以下优点：
(1)本发明提供的共聚物具有近红外二区荧光成像、光动力治疗、光热治疗的功能，相比于近红外一区，近红外二区具有两方面明显的优势：一方面是更强的组织穿透深度；另一方面，允许更高的照射剂量(根据美国激光安全使用的国家标准，皮肤可安全暴露于1064nm波长激光的功率密度为1W/cm2。
(2)本发明提供的共聚物具有肿瘤微环境敏感响应，由此将其用于药物载体时可以实现靶向释放药物，增加靶区药物浓度，降低其在非靶向部分的分布，减少不良反应。
(3)本发明提供的共聚物可在溶液中自组装为纳米粒，对药物进行包载，通过将药物包载入纳米载体中，可显著改善药物的溶解度，提高药物的稳定性。
(4)本发明还提供了相应的制备方法，具有工艺流程简单、产物稳定性高等优点。
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为单体1在二氯甲烷中的紫外吸收光谱图；
图2为单体1在二氯甲烷中的荧光发射光谱图；
图3为式Ⅳ共聚物制备的纳米粒的粒径图；
图4为式XI共聚物制备的纳米粒的粒径图；
图5为式XI共聚物制备的纳米粒的透射电镜图。
图6为式Ⅳ共聚物制备的纳米粒的紫外吸收光谱图；
图7为式Ⅳ共聚物制备的纳米粒的荧光发射光谱图；
图8为式XI共聚物制备的纳米粒的紫外吸收光谱图；
图9为式XI共聚物制备的纳米粒的荧光发射光谱图；
图10为注射式XI共聚物制备的纳米粒后的小动物成像图。
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
将式a反应物(10g，36.6mmol)完全溶解于150ml甲苯中，加入反应物Ethyl(triphenylphosphoranylidene)acetate(14.03g，40.3mmol)，氮气保护，室温反应48h，萃取得式b产物，无需分离直接进行下一步反应。
将式b产物(10g，29.1mmol)完全溶解于250ml甲醇中，加入适量的雷尼镍，通入1.5L氢气，室温反应12h；反应混合物过滤，旋干滤液，得到式c产物，无需分离进行下一步。
将式c产物(11.3g，32.7mmol)完全溶解于150ml四氢呋喃中，置于冰水浴，分三次加入H4AlLi(2g，52.7mmol)，反应4h后，撤掉冰水，恢复室温反应12h。反应结束后加入水和乙酸乙酯萃取，加入无水硫酸镁干燥，过滤，将滤液旋干，得到式d产物，无需分离直接进行下一步反应。
将式d产物(10g，33mmol)完全溶解于250ml DMF中，置于冰水浴，加入咪唑(3.37g，49.5mmol)和叔丁基二甲基硅烷(7.43g，49.3mmol)，反应10h；得到混合物用乙酸乙酯萃取，无水硫酸镁干燥，过滤，将滤液加入硅胶粉旋干，层析柱分离(PE:EA＝10：1)，得到式e产物：
1H NMR(300MHz,CDCl3)δ7.30–7.15(m,5H),7.14–6.86(m,9H),3.65(t,J＝6.3Hz,2H),2.63(t,J＝7.7Hz,2H),1.91–1.72(m,2H),0.91(s,9H),0.05(s,6H).
将式e化合物(3.21g，7.7mmol)完全溶解于50ml二氯甲烷中，置于冰水浴中，分三次加入NBS(1.37g，7.7mmol)，完全溶解后，撤掉冰水浴，室温反应过夜。得到式f产物，无需分离进行下一步。
将式f产物(2.2g，4.44mmol)、醋酸钾(1.05g，10.4mmol)、双(三苯基膦)二氯化钯(312mg，0.444mmol)、硼酸酯(bis(pinacolate)diboron)(1.36g，5.35mmol)完全溶解于30ml二氧六环中，氮气保护，温度80℃，反应过夜；反应结束后加水，乙酸乙酯萃取，加入无水硫酸镁干燥，加入硅胶粉旋干，层析柱分离(PE:EA＝10:1)，得到式g产物：
1H NMR(300MHz,CDCl3)δ7.59(d,2H),7.18(m,3H),7.03(d,4H),6.95(m,3H),3.59(t,J＝6.3Hz,2H),2.59(t,J＝7.7Hz,2H),1.91–1.72(m,2H),0.91(s,9H),0.05(s,6H).
将式g化合物(427.98mg，0.787mmol)、式h化合物(150mg，0.225mmol)、饱和碳酸钾溶液3ml、三苯基膦钯100mg、乙醇2ml完全溶解在15ml甲苯中，氮气保护，温度90℃，反应过夜；得到的混合物加入硅胶粉旋干，层析柱分离(PE:EA＝10：1)，得到式i产物：
1H NMR(400MHz,CDCl3)δ7.95-7.93(d,4H),7.58-7.55(d,4H),7.31-7.26(d,8H),7.26-7.02(m,18H),3.68-3.64(t,4H),2.69-2.58(m,8H),1.88-1.81(m,4H),1.60-1.58(m,4H),1.29(s,12H),0.07-0.05(d,12H).
将式i化合物(15mg，0.0112mmol)完全溶解于20vml二氯甲烷中，加入离子交换树脂200mg，室温反应1h；反应结束后加入硅胶粉旋干，层析柱分离(DCM:MeOH＝20：1)，得到单体1。
1H NMR(300MHz,CDCl3)δ7.98-7.96(d,4H),7.60-7.57(d,4H),7.30(s,8H),7.18-7.12(t,16H),3.76-3.72(t,4H),2.66-2.61(t,4H),1.99-1.90(m,4H),1.63-1.61(d,4H),1.31-1.26(d,16H),0.89-0.87(t,6H)
用紫外可见分光光度计(UV-2450PC，Shimazu)进行紫外吸收的测定，单体1在二氯甲烷中的检测结果如图1所示；
用稳态瞬态荧光光谱仪(FLS980)测定荧光光谱，用808nm的激光激发，单体1在二氯甲烷中的检测结构如图2所示；
实施例2单体2
称取式g化合物(0.543g，1mM)，4,7-二溴-5,6-二硝基苯并[c][1,2,5]噻二唑(0.190g，0.5mM)和四三苯基膦钯(115mg，0.01mM)，溶解在10mL甲苯溶液中，再向反应液中加入2.5mL碳酸钾溶液(2M)，在氩气保护下110℃反应48h，柱层析分离得红色半固体产物，即为式j化合物4,4'-(5,6-二硝基苯并[c][1,2,5]噻二唑-4,7-二基)双(N-(4-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)苯基)-N-苯基苯胺)：
1H NMR(400MHz,CDCl3)δ7.39(d,J＝8.6Hz,4H),7.32(t,J＝7.7Hz,4H),7.15(ddd,J＝22.0,14.8,8.3Hz,18H),3.66(t,J＝6.3Hz,4H),2.74–2.61(m,4H),1.91–1.79(m,4H),0.91(s,18H),0.06(s,12H).
称取式j化合物(105mg，0.1mM)和四甲基氯硅烷(50mg，1mM)溶解在5mL吡啶中100℃反应24h，二氯甲烷萃取产物后，无需分离，浓缩得到20mL二氯甲烷溶液，向该溶液中加入200mg Amberlyst 15，室温搅拌反应过夜，柱层析分离得产物，即为单体2：
1H NMR(300MHz,DMSO)δ8.14(d,J＝8.4Hz,4H),7.38(t,J＝7.4Hz,4H),7.23(d,J＝8.2Hz,5H),7.13(dd,J＝14.1,8.1Hz,11H),4.50(t,J＝4.8Hz,2H),2.68–2.57(m,4H),1.99(d,J＝7.0Hz,7H),1.81–1.65(m,5H).
实施例3单体3
称取对硝基苯酚(13.9g，0.1M)，溴丁醇(13.7g，0.1M)，溶解在100mLDMF中，再把碳酸钾(20g，0.2M)加入到上述体系，在80℃下反应8h，冷却至室温后加入三倍体积的去离子水，乙酸乙酯萃取得3-(4-硝基苯氧基)丙-1-醇的粗产物，无需分离进行下一步反应。
上一步所得所有产物溶解在100mL DMF中，并加入咪唑(10g,0.15M)和叔丁基氯二甲基硅烷(15g，0.1M)室温下搅拌4h后，上述体系加入三倍体积水，乙酸乙酯萃取得产物。将上述产物溶解在150mL乙醇中，在加入1g钯碳，氢气氛围下过夜反应，过滤除去钯碳，浓缩后柱层析分离得产物4-(3-((叔丁基二甲基甲硅烷基)氧基)丙氧基)苯胺：
1H NMR(300MHz,DMSO)δ6.81(d,J＝7.7Hz,2H),6.47(d,J＝7.7Hz,2H),4.78(s,2H),3.87(t,J＝5.9Hz,2H),3.72(t,J＝7.1Hz,2H),1.48(tt,J＝13.4,6.8Hz,2H),0.85(s,9H),0.01(s,6H).
称取4-(3-((叔丁基二甲基甲硅烷基)氧基)丙氧基)苯胺(2.81g，0.01M)，(2-(4-溴苯基)乙烯-1,1,2-三基)三苯(4g，0.01M)，碳酸铯(8g，0.02M)和四三苯基膦钯(200mg)溶解在30mL DMF中，氩气保护，100摄氏度反应12h，柱层析分离得产物4-(3-((叔丁基二甲基甲硅烷基)氧基)丙氧基)-N-(4-(1,2,2-三苯基乙烯基)苯基)苯胺：
1H NMR(300MHz,DMSO)δ7.86(s,1H)，6.64-7.71(m,23H),6.47(d,J＝7.7Hz,2H),3.93(t,J＝5.9Hz,2H),3.72(t,J＝7.1Hz,2H),1.48(tt,J＝13.4,6.8Hz,2H),0.85(s,9H),0.01(s,6H).
称取4-(3-((叔丁基二甲基甲硅烷基)氧基)丙氧基)-N-(4-(1,2,2-三苯基乙烯基)苯基)苯胺(1.22g，2mM)，4,7-双(5-溴噻吩-2-基)-5,6-二硝基苯并[c][1,2,5]噻二唑(0.55g，1mM)和四三苯基膦钯(100mg)溶解在10mL DMF中再加入碳酸铯(2g)，氩气保护反应12h，萃取后的产物溶解在50mL二氯甲烷中加入Amberlyst 15(1g)，室温搅拌反应过夜，柱层析分离得产物，即为单体3：
1H NMR(400MHz,CDCl3)δ 8.21(d,4H,J＝8.5Hz),7.35-7.31(m,4H),7.26-7.19(m,36H),7.08-7.06(m,4H),6.98(s,8H),4.40(t,J＝4.8Hz,2H),2.59–2.47(m,4H),1.91–1.75(m,4H).
实施例4单体5：(2-(2,4,5-三甲氧基苯基)-1,3-二恶烷-5,5-二基)二甲醇
将季戊四醇(13.6g，100mmol)，2,4,5-三甲氧基苯甲醛(3.14g，10mmol)和对甲苯磺酸(0.1eq)，溶于100mL DMF，50℃反应三天，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，即单体4，产率67％。
1H NMR(400MHz,DMSO)δ6.96(s,1H),6.65(s,1H),5.58(s,1H),4.61(s,1H),4.49(s,1H),3.85(d,J＝11.3Hz,2H),3.78(d,J＝9.3Hz,6H),3.73(s,1H),3.69(d,J＝4.7Hz,5H),3.22(s,2H),2.50(s,10H).
实施例5单体6：(2-(2,4,6-三甲氧基苯基)-1,3-二恶烷-5,5-二基)二甲醇
将季戊四醇(13.6g，100mmol)，2,4,6-三甲氧基苯甲醛(3.14g，10mmol)和对甲苯磺酸(0.1eq)，溶于100mL DMF，50℃反应三天，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，即单体5，产率69％。
1H NMR(400MHz,DMSO)δ6.96(s,1H),6.65(s,1H),5.58(s,1H),4.61(s,1H),4.49(s,1H),3.85(d,J＝11.3Hz,2H),3.78(d,J＝9.3Hz,6H),3.73(s,1H),3.69(d,J＝4.7Hz,5H),3.22(s,2H),2.50(s,10H).
实施例6单体7：(2-(1,2,3,4,5,6-五氟基苯基)-1,3-二恶烷-5,5-二基)二甲醇
将季戊四醇(13.6g，100mmol)，五氟苯甲醛(3.14g，10mmol)和对甲苯磺酸(0.1eq)，溶于100mL DMF，50℃反应3天，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，即单体6，产率69％。
1H NMR(300MHz,DMSO)δ5.83(s,1H),4.65(t,J＝5.1Hz,1H),4.57(t,J＝5.1Hz,1H),3.92(d,J＝11.2Hz,2H),3.82(d,J＝11.3Hz,2H),3.72(d,J＝5.0Hz,2H),3.23(d,J＝4.9Hz,2H).
实施例7单体8：(1,2-diselenolane-4,4-二基)二甲醇
称取硼氢化钠(1g，12.66mM)，硒单质(0.5g，13.51mM)溶于25mL去离子水中，反应十分钟，再向溶液中加入硒单质(0.5g，13.51mM)，室温搅拌15分钟，2,2-双(溴甲基)丙烷-1,3-二醇(1.6g，12.66mM)，70℃加热6h，乙酸乙酯萃取，柱层析分离得白色产物，即单体7。
1H NMR(300MHz,DMSO-d6)δ4.78(s,2H),3.40(s,4H),2.74(s,4H).
实施例8单体9：2,2-双(碘甲基)丙烷-1,3-二醇
称取2,2-双(溴甲基)丙烷-1,3-二醇(1.6g，12.66mM)，碘化钠(3.79g，25.32mM)在10mL DMF中室温搅拌过夜，加入三倍体积水沉淀得产物，即单体8。
实施例9单体10
称取硼氢化钠(1g，12.66mM)，硒单质(0.5g，13.51mM)溶于25mL去离子水中，反应十分钟，再向溶液中加入硒单质(0.5g，13.51mM)，室温搅拌15分钟，溴乙醇(1.6g，12.66mM)，70℃加热6h，乙酸乙酯萃取，柱层析分离得黄色油状产物，即单体9。
1H NMR(400MHz,DMSO-d6)δ4.99(t,2H),3.65(m,4H),3.01(m,4H).
实施例10单体11
称取2,2'–(丙烷-2,2-二基双(磺胺二基))二乙酸(1g，4.46mM)和四氢铝锂(0.34g，8.9mM)溶于25mL四氢呋喃中，70℃反应过夜，反应体系冷却至室温，缓慢加入水，淬灭未反应的四氢铝锂，乙酸乙酯萃取，柱层析分离得黄色油状产物，即单体10。
1H NMR(400MHz,DMSO-d6)δ4.83(t,2H),3.53(d,4H),2.65(t,4H),1.59(s,6H).
实施例11单体13
称取顺铂(1g,3.33mmol)至于25mL过氧化氢中，室温反应过夜，过滤并干燥得微黄色产物，即单体12。
实施例12单体14
称取奥沙利铂(1g,2.33mmol)至于10mL过氧化氢中，室温反应过夜，过滤并干燥得微白色产物，即单体13。
实施例13式I共聚物
称取单体1(10mg,0.009mmol)，单体12(26.3mg,0.171mmol)，单体18(40.5mg,0.18mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式I所示共聚物，其中x和y的比值为0.05:0.95。
实施例14式II共聚物
称取单体1(10mg,0.009mmol)，单体12(26.3mg,0.171mmol),单体20(40.7mg,0.18mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式II所示共聚物，其中x和y的比值为0.05:0.95。
实施例15式III共聚物
称取单体1(10mg,0.009mmol)，单体11(33.52mg,0.171mmol)，单体18(40.5mg,0.18mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式III所示共聚物，其中x和y的比值为0.05:0.95。
实施例16式IV共聚物
称取单体1(10mg,0.009mmol)，单体11(33.52mg,0.171mmol)，单体20(40.7mg,0.18mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式IV所示共聚物，其中x和y的比值为0.05:0.95。
实施例17式V共聚物
称取单体1(10mg,0.009mmol)，单体13(56.9mg,0.171mmol)，单体18(40.5mg,0.18mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式V所示共聚物，其中x和y的比值为0.05:0.95。
实施例18式VI共聚物
称取单体1(10mg,0.009mmol)，单体13(56.9mg,0.171mmol)，单体20(40.7mg,0.18mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式VI所示共聚物，其中x和y的比值为0.05:0.95。
实施例19式VII共聚物
称取单体2(10mg,0.01255mmol)，单体11(46.75mg,0.23845mmol),单体18(56.224mg,0.251mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入5-10mL去离子水，透析48h，冻干得产物，即式VII所示共聚物，其中x和y的比值为0.05:0.95。
实施例20式VIII共聚物
称取单体2(10mg,0.01255mmol)，单体11(46.8mg,0.23845mmol),单体20(56.5mg,0.251mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式VIII所示共聚物，其中x和y的比值为0.05:0.95。
实施例21式IX共聚物
称取单体2(10mg,0.01255mmol)，单体12(36.7mg,0.23845mmol),单体18(56.2mg,0.251mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式IX所示共聚物，其中x和y的比值为0.05:0.95。
实施例22式X共聚物
称取单体2(10mg,0.01255mmol)，单体12(36.7mg,0.23845mmol)，单体20(56.5mg,0.251mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式X所示共聚物，其中x和y的比值为0.05:0.95。
实施例23式XI共聚物
称取单体2(10mg,0.01255mmol)，单体13(79.4mg,0.23845mmol)，单体18(56.2mg,0.251mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式XI所示共聚物，其中x和y的比值为0.05:0.95。
实施例24式XII共聚物
称取单体2(10mg,0.01255mmol)，单体13(79.4mg,0.23845mmol),单体20(56.5mg,0.251mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式XII所示共聚物，其中x和y的比值为0.05:0.95。
实施例25式XIII共聚物
称取单体3(10mg,0.00723mmol)，单体11(26.9mg,0.137mmol),单体18(32.39mg,0.1446mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式XIII所示共聚物，其中x和y的比值为0.05:0.95。
实施例26式XIV共聚物
称取单体3(10mg,0.00723mmol)，单体11(26.9mg,0.137mmol)),单体20(32.5mg,0.1446mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式XIV所示共聚物，其中x和y的比值为0.05:0.95。
实施例27式XV共聚物
称取单体4(10mg,0.010567mmol)，单体12(36.7mg,0.23845mmol),单体18(32.39mg,0.1446mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式XV所示共聚物，其中x和y的比值为0.05:0.95。
实施例28式XVI共聚物
称取单体4(10mg,0.010567mmol)，单体11(26.9mg,0.137mmol),单体18(32.39mg,0.1446mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式XVI所示共聚物，其中x和y的比值为0.05:0.95。
实施例29式XVII共聚物
称取单体4(10mg,0.010567mmol)，单体12(36.7mg,0.23845mmol),单体20(32.5mg,0.1446mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式XVII所示共聚物，其中x和y的比值为0.05:0.95。
实施例30式XVIII共聚物
称取单体4(10mg,0.010567mmol)，单体11(26.9mg,0.137mmol),单体20(32.5mg,0.1446mmol)溶于5mL DMF，氮气保护，室温反应24h，再向反应体系中加入PEG5000-OH(100mg,0.02mmol)，氮气保护，50℃反应过夜，反应体系加入10mL去离子水，透析48h，冻干得产物，即式XVIII所示共聚物，其中x和y的比值为0.05:0.95。
实施例31制备纳米粒
称取实施例16制备的式Ⅳ共聚物10mg，置于含有0.5mL DMF的5mL小瓶中，反应体系持续搅拌，再向有机相缓慢滴加1.5mL水，搅拌10min，把反应体系用截留分子量为7000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3所示，其平均粒径(z-average)为102.9nm，聚合物分散指数(Polymer dispersity index，PDI)为0.212。
称取实施例23制备的式XI共聚物10mg，置于含有0.5mL DMF的5mL小瓶中，反应体系持续搅拌，再向有机相缓慢滴加1.5mL水，搅拌10min，把反应体系用截留分子量为7000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，聚合物分散指数(Polymerdispersity index，PDI)为0.19。
用场发射透射电子显微镜JEM-2100F拍摄式XI共聚物制备的纳米粒的电镜图如图5所示。
用紫外可见分光光度计(UV-2450PC，Shimazu)进行紫外吸收的测定，式Ⅳ共聚物制备的纳米粒的紫外吸收结果如图6所示；式XI共聚物制备的纳米粒的紫外吸收结果如图8所示。
用稳态瞬态荧光光谱仪(FLS980)测定荧光光谱，用808nm的激光激发，式Ⅳ共聚物制备的纳米粒的荧光光谱如图7所示(发射强度归1化)；式XI共聚物制备的纳米粒的荧光光谱如图9所示(发射强度归1化)。
实施例32小动物成像
用小动物活体功能结构成像系统(Spectrum CT)进行小动物成像，将实施例31制备得到的式XI共聚物的纳米粒经尾静脉注射到荷瘤小鼠中，注射剂量为150μm/只，3h后进行小动物成像，结果如图10所示，可知纳米粒富集在肿瘤位置，呈现出良好的靶向性。
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 (12)
1.一种具有近红外二区光响应的共聚物，其特征在于，所述共聚物由第一二羟基单体、第二二羟基单体、两端具有酸酐或异氰酸酯的单体聚合而成，且用一端具有氨基或羧基的聚乙二醇封端；
所述第一二羟基单体具有近红外二区荧光、光动力和/或光热功能；
所述第二二羟基单体具有可响应氧化条件、还原条件、乏氧条件、酸环境和/或热环境条件发生断裂的化学键。
2.如权利要求1所述的共聚物，其特征在于，所述共聚物为嵌段共聚物。
3.如权利要求1所述的共聚物，其特征在于，所述第一二羟基单体、第二二羟基单体和两端具有酸酐或异氰酸酯的单体的摩尔比为0.05-0.1:0.9-0.95:1。
4.如权利要求1所述的共聚物，其特征在于，所述第二二羟基单体具有以下化学键中的一种或两种以上：二硫键、二硒键、缩硫醛、缩醛、席夫碱、偶氮、缩酮。
5.如权利要求1所述的共聚物，其特征在于，所述第一二羟基单体具有近红外二区荧光，所述第一二羟基单体选自下组中的一种或两种以上：
6.如权利要求1所述的共聚物，其特征在于，所述第一二羟基单体具有近红外二区光动力，所述第一二羟基单体选自下组中的一种或两种：
7.权利要求1所述的共聚物，其特征在于，所述第一二羟基单体具有近红外二区光热，所述第一二羟基单体为：
8.如权利要求1所述的共聚物，其特征在于，所述第二二羟基单体选自下组中的一种或两种以上：
9.如权利要求1所述的共聚物，其特征在于，所述两端具有酸酐或异氰酸酯的单体选自下组中的一种或两种：
10.如权利要求1所述的共聚物，其特征在于，所述共聚物包括：
其中，x和y的比值为0.05-0.1:0.9-0.95；优选为0.05:0.95。
11.如权利要求1-10任一项所述共聚物的制备方法，其特征在于，包括使所述第一二羟基单体、第二二羟基单体、两端具有酸酐或异氰酸酯的单体于二甲基甲酰胺或二甲基亚砜中进行聚合反应。
12.如权利要求1-10任一项所述共聚物在以下方面的应用：
(1)制备荧光成像试剂；
(2)用于荧光成像；
(3)制备用于光动力治疗的药物；
(4)制备用于光热治疗的药物；
优选地，所述荧光成像为近红外二区荧光成像；所述光动力治疗为近红外二区光动力治疗；所述光热治疗为近红外二区光热治疗。
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