CN1318481C - 一种可生物降解荧光聚膦腈及其合成方法 - Google Patents
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Abstract
本发明提供一种可生物降解荧光聚膦腈及其合成方法。合成方法为:首先将一定量的色氨酸酯加入到含有聚膦腈的有机溶液中反应48小时,然后再将过量的另一种氨基酸酯、端胺基甲氧基聚氧乙烯或端胺基聚(N-异丙基丙烯酰胺)加入到反应体系中继续反应48小时,通过胺基对P-Cl键的取代得到荧光聚膦腈。该合成方法实施过程简单,且得到的聚膦腈在有机溶液和固体状态均具有很强的荧光特性,可作为药物控释载体或荧光探针。
Description
技术领域
本发明涉及化学合成,尤其涉及一种可生物降解荧光聚膦腈及其合成方法。
背景技术
近年来,生物降解材料在医药领域受到广泛关注。一些材料已在临床中得到应用,例如聚(丙交酯-共-乙交酯)(PLGA)已被美国FDA批准作为可吸收缝合线和药物控释载体。到目前为止,研究较多的生物降解聚合物有聚酯、聚氨基酸、聚酸酐、聚原酸酯、聚碳酸酯等。这些聚合物多是通过选择不同的单体进行均聚,或以两种或两种以上的单体进行共聚来调控最终聚合物的降解性能(水解、酶解)及加工性能(溶解性、熔融性、机械强度等)。因此,就这几类聚合物来说,它们的性能可控或可调范围较窄,较难满足各种药物控制释放的需要,达到药物的最佳治疗效果。生物可降解聚膦腈是一类新型的药物控释载体材料,其化学结构是由交替的氮、磷原子以交替的单键、双键构成的无机主链,以及通过侧链衍生化后引入的性能各异的有机基团构成。其反应的灵活性使聚膦腈成为理化性质变化范围很广的高分子材料,适用于制备多种药物控释系统[1]。聚膦腈的这一特点无疑是前述几类生物降解型高分子所无法比拟的,并且大量的体内外研究表明侧基含氨基酸酯基团的聚膦腈具有良好的生物降解性[2]。
另一方面,药物控释制剂的深入发展要求考察载体(一般为微球或纳米粒)在体内的分布、降解吸收、载体材料与组织、细胞的相互作用等。基于荧光探针标记的荧光显微技术是这些研究中经常用到的方法。常用的荧光标记物有异硫氰酸荧光素(FITC)、罗丹明(Rhodamine)等[3-9]。小分子荧光标记物的引入一方面会导致载体(比如微球)表面性能的改变;另一方面,在长期的研究过程中,标记物会从载体中释放出来,给研究造成干扰。通过共价键将探针分子引入聚合物载体也是经常用到的方法,但该法增加了载体合成的难度,因此也限制了这一研究领域更加深入的发展。蒋宏亮等人较为系统的研究了具有荧光性能的可降解聚酸酐,该类材料为研究诸如微球等口服制剂在胃肠道的分布吸收情况提供了极大的便利,并已经有较好的结果报道[10-15]。但聚酸酐合成方法的局限性使得材料的结构调控及功能化受到一定的限制,同时该类材料较快的降解性能也不利于载体更长期的研究。另一方面,使用该类材料为载体时,制备分散性良好的纳米粒受到一定限制。而通过两亲聚膦腈的自组装性能,可以制备粒径大小及分散性均可调控的纳米粒。
发明内容
本发明的目的是提供一种可生物降解荧光聚膦腈,其化学结构为:
其中:
R1=CH3,CH2CH3,CH2CH2CH3,CH(CH3)2
R2=CH3,CH2CH3,CH2CH2CH3,CH(CH3)2
n=5-500
m=5-300
x=1.9-0,y=0.1-2(x+y≤2.0)
本发明的另一个目的是提供这种可生物降解荧光聚膦腈的合成方法,通过以下步骤实现:(1)氮气保护下,将含有0.005-0.2mol色氨酸酯和40ml有机溶剂的溶液加入到含有0.1mol P-Cl的聚膦腈和50ml有机溶剂的溶液中,同时加入0.005-0.2mol三乙胺后于10-65℃磁力搅拌下反应;(2)48小时后向该反应体系中加入含有0.2-0.0mol氨基酸酯、端胺基甲氧基聚氧乙烯或端胺基聚(N-异丙基丙烯酰胺)和50ml有机溶剂的溶液,同时加入0.2-0.0mol三乙胺,接着10-65℃继续反应;(3)48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物即可生物降解荧光聚膦腈。步骤(1)中所说的有机溶剂为四氢呋喃。步骤(2)中所说的氨基酸酯选用甘氨酸、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、蛋氨酸、苯丙氨酸,色氨酸的甲酯、乙酯,丙酯或异丙酯中任一种。
本发明的技术特点是:
(1)材料合成过程简单,产率高,聚合物的理化性能可以简单地通过在合成过程中加入不同性能的取代物而在很大的范围内调控;
(2)得到聚合物在有机溶液和固体状态均具有很强的荧光特性,聚合物微球可以在蓝光和绿光激发下分别发射强烈的绿色和红色荧光,因此双通道激发可以避免体内荧光物的干扰;
(3)色氨酸酯与其他氨基酸酯、端胺基甲氧基聚氧乙烯或端胺基聚(N-异丙基丙烯酰胺)共取代得到的聚膦腈仍具有良好的荧光特性;
(4)通过两亲聚膦腈,即色氨酸酯与端胺基甲氧基聚氧乙烯或端胺基聚(N-异丙基丙烯酰胺)共取代的聚合物的自组装性能,可以制备粒径大小及分布均可调控的纳米粒;
(5)所得到的聚合物具有良好的可生物降解性。
(6)该合成方法实施过程简单,且得到的聚膦腈在有机溶液和固体状态均具有很强的荧光特性,可作为药物控释载体或荧光探针。
附图说明
图1是聚[二(色氨酸乙酯)膦腈]在DMF溶液中的三维荧光谱图;
图2是由聚[二(色氨酸乙酯)膦腈]制备的微球的明视野及荧光激发的图片;
图3是聚[(色氨酸乙酯)1.50(端胺基聚(N-异丙基丙烯酰胺))0.38膦腈]的三维荧光谱图;
图4是由透析法制备的两亲性聚[(色氨酸乙酯)1.50(端胺基聚(N-异丙基丙烯酰胺))0.38膦腈]的纳米粒的透射电镜图片;
图5是聚[(色氨酸乙酯)1.16(端胺基甲氧基聚氧乙烯)0.70膦腈]的三维荧光谱图;
图6是由透析法制备的两亲性聚[(色氨酸乙酯)1.16(端胺基甲氧基聚氧乙烯)0.70膦腈]的纳米粒的透射电镜图片。
具体实施方式
下面结合附图和实施例对本发明做详细说明。
实施例1
氮气保护下,将含有0.2mol色氨酸乙酯的THF溶液40ml加入到含有0.1mol P-Cl的聚膦腈的50ml THF溶液中,同时加入0.2mol三乙胺后于40℃磁力搅拌下反应。48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[二(色氨酸乙酯)膦腈] (R1=CH2CH3,R2=CH2CH3,
所得聚合物在DMF及固态状态下的荧光特性参见见图1和图2。
实施例2
氮气保护下,将含有0.008mol色氨酸乙酯的40ml THF溶液加入到含有0.1mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.008mol三乙胺后于50℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.2mol苯丙氨酸乙酯的50ml THF溶液,同时加入0.2mol三乙胺,接着50℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸乙酯)0.11(苯丙氨酸乙酯)1.75膦腈](R1=CH2CH3,R2=CH2CH3,R3=CH2C6H5)。聚合物在DMF中的3-D荧光光谱与图1相似。
实施例3
氮气保护下,将含有0.015mol色氨酸乙酯的40ml THF溶液加入到含有0.1mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.015mol三乙胺后于45℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.15mol亮氨酸乙酯的50ml THF溶液,同时加入0.15mol三乙胺,接着45℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸乙酯)0.20(亮氨酸乙酯)1.80膦腈](R1=CH2CH3,R2=CH2CH3,R3=CH2CH(CH3)2)。聚合物在DMF中的3-D荧光光谱与图1相似。
实施例4
氮气保护下,将含有0.02mol色氨酸乙酯的40ml THF溶液加入到含有0.1mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.02mol三乙胺后于55℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.15mol缬氨酸乙酯的50ml THF溶液,同时加入0.15mol三乙胺,接着55℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸乙酯)0.31(缬氨酸乙酯)1.69膦腈](R1=CH2CH3,R2=CH2CH3,R3=CH(CH3)2)。聚合物在DMF中的3-D荧光光谱与图1相似。
实施例5
氮气保护下,将含有0.025mol色氨酸乙酯的40ml THF溶液加入到含有0.1mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.025mol三乙胺后于60℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.15mol异亮氨酸乙酯的50ml THF溶液,同时加入0.15mol三乙胺,接着60℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸乙酯)0.40(异亮氨酸乙酯)1.60膦腈](R1=CH2CH3,R2=CH2CH3,R3=CH(CH3)CH2CH3)。聚合物在DMF中的3-D荧光光谱与图1相似。
实施例6
氮气保护下,将含有0.05mol色氨酸乙酯的40ml THF溶液加入到含有0.1mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.05mol三乙胺后于45℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.1mol蛋氨酸乙酯的50ml THF溶液, 同时加入0.1mol三乙胺,接着45℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸乙酯)0.80(蛋氨酸乙酯)1.20膦腈](R1=CH2CH3,R2=CH2CH3,R3=CH2CH2SCH3)。聚合物在DMF中的3-D荧光光谱与图1相似。
实施例7
氮气保护下,将含有0.08mol色氨酸乙酯的40ml THF溶液加入到含有0.1mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.08mol三乙胺后于50℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.1mol甘氨酸乙酯的50ml THF溶液,同时加入0.1mol三乙胺,接着50℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸乙酯)1.50(甘氨酸乙酯)050膦腈](R1=CH2CH3,R2=CH2CH3,R3=H)。聚合物在DMF中的3-D荧光光谱与图1相似。
实施例8
氮气保护下,将含有0.075mol色氨酸乙酯的40ml THF溶液加入到含有0.1 mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.075mol三乙胺后于55℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.08mol丙氨酸乙酯的50ml THF溶液,同时加入0.08mol三乙胺,接着55℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸乙酯)1.16(丙氨酸乙酯)0.84膦腈](R1=CH2CH3,R2=CH2CH3,R3=CH3)。聚合物在DMF中的3-D荧光光谱与图1相似。
实施例9
氮气保护下,将含有0.08mol色氨酸乙酯的40ml THF溶液加入到含有0.1mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.08mol三乙胺后于55℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.05mol数均分子量为1600的端胺基聚(N-异丙基丙烯酰胺)(m=14)的50ml THF溶液,同时加入0.05mol三乙胺,接着55℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸乙酯)1.50(端胺基聚(N-异丙基丙烯酰胺))0.38膦腈](R1=CH2CH3)。图3为所得聚合物在DMF溶液中的3-D荧光谱图,图4为透析法制备的聚合物纳米粒的TEM图片。
实施例10
氮气保护下,将含有0.075mol色氨酸乙酯的40ml THF溶液加入到含有0.1mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.075mol三乙胺后于55℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.06mol数均分子量为1000的端胺基甲氧基聚氧乙烯(m=23)的50ml THF溶液,同时加入0.06mol三乙胺,接着60℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸乙酯)1.16(端胺基甲氧基聚氧乙烯)0.70膦腈](R1=CH2CH3)。图5为所得聚合物在DMF溶液中的3-D荧光谱图,图6为透析法制备的聚合物纳米粒的TEM图片。
实施例11
氮气保护下,将含有0.2mol色氨酸甲酯的THF溶液40ml加入到含有0.1mol P-Cl的聚膦腈的50ml THF溶液中,同时加入0.2mol三乙胺后于40℃磁力搅拌下反应。48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[二(色氨酸甲酯)膦腈](R1=CH3,R2=CH3,
所得聚合物在DMF及固态状态下的荧光特性与实施例1所得聚合物类似。
实施例12
氮气保护下,将含有0.0075mol色氨酸丙酯的40ml THF溶液加入到含有0.1mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.0075mol三乙胺后于50℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.2mol甘氨酸甲酯的50ml THF溶液,同时加入0.2mol三乙胺,接着50℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸丙酯)0.11(甘氨酸甲酯)1.76膦腈](R1=CH2CH2CH3,R2=CH3,R3=H)。聚合物在DMF中的3-D荧光光谱与图1相似。
实施例13
氮气保护下,将含有0.009mol色氨酸甲酯的40ml THF溶液加入到含有0.1 mol P-Cl的聚膦腈和50ml THF的溶液中,同时加入0.009mol三乙胺后于50℃磁力搅拌下反应;48小时后向该反应体系中加入含有0.2mol丙氨酸异丙酯的50ml THF溶液,同时加入0.2mol三乙胺,接着50℃继续反应;48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物,即聚[(色氨酸甲酯)0.16(丙氨酸异丙酯)1.78膦腈](R1=CH3,R2=CH(CH3)2,R3=CH3)。聚合物在DMF中的3-D荧光光谱与图1相似。
无需进一步详细阐述,相信采用前面所公开的内容,本领域技术人员可最大限度地应用。因此,前面的优选具体实施方案应被理解为仅是举例说明,而非以任何方式限制本发明的范围。
本发明涉及的部分参考文献
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Claims (5)
2.根据权利要求1所述的一种可生物降解荧光聚膦腈的合成方法,其特征是通过以下步骤完成:
(1)氮气保护下,将含有0.005-0.2mol色氨酸酯和40ml有机溶剂的溶液加入到含有0.1mol P-Cl的聚膦腈和50ml有机溶剂的溶液中,同时加入0.005-0.2mol三乙胺后于10-65℃磁力搅拌下反应;
(2)48小时后向该反应体系中加入含有0.2-0.0mol氨基酸酯或端胺基甲氧基聚氧乙烯和50ml有机溶剂的溶液,同时加入0.2-0.0mol三乙胺,接着10-65℃继续反应;
(3)48小时后停止反应,过滤,滤液浓缩后用乙醚沉淀并真空干燥得到目的聚合物即可生物降解荧光聚膦腈。
3.根据权利要求2所述的一种可生物降解荧光聚膦腈的合成方法,其特征是:步骤(1)所说的有机溶剂为四氢呋喃。
4.根据权利要求2所述的一种可生物降解荧光聚膦腈的合成方法,其特征是:步骤(2)所说的氨基酸酯选用甘氨酸、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、蛋氨酸、苯丙氨酸,色氨酸的甲酯、乙酯,丙酯或异丙酯中任一种。
5.根据权利要求1所述的一种可生物降解荧光聚膦腈在制备药物控释载体或荧光探针中的应用。
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US6288210B1 (en) * | 1999-11-12 | 2001-09-11 | Virginia Tech. Intellectual Properties, Inc. | High refractive index thermoplastic polyphosphonates |
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