CN102112158B - 生物相容性高分子与具有生物相容性的磁性纳米微粒 - Google Patents

生物相容性高分子与具有生物相容性的磁性纳米微粒 Download PDF

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CN102112158B
CN102112158B CN2008801299634A CN200880129963A CN102112158B CN 102112158 B CN102112158 B CN 102112158B CN 2008801299634 A CN2008801299634 A CN 2008801299634A CN 200880129963 A CN200880129963 A CN 200880129963A CN 102112158 B CN102112158 B CN 102112158B
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张文祥
谢文元
黄秀华
林进益
王先知
邓克立
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Abstract

本发明公开了一种生物相容性高分子，可用以化学键结修饰磁性纳米微粒。该生物相容性高分子可以偶联特异性靶向分子或/及荧光染剂。本发明还公开了一种具有生物相容性的磁性纳米微粒，其含有上述生物相容性高分子。

Description

生物相容性高分子与具有生物相容性的磁性纳米微粒
技术领域
本发明涉及一种生物相容性高分子，且特别涉及一种以共价键结修饰磁性纳米微粒的生物相容性高分子。
背景技术
磁振造影(MRI)是早期癌症诊断和治疗的有吸引力的非破坏性方法。MRI成像的主要信号来源是由观察强磁场下质子磁旋(magnetic spin)与无线电波频率电磁辐射的干涉而得。诊断时，将欲分析的器官或组织放置于强磁场下，利用无线电波能量的撞击，接着质子的核磁化产生弛豫现象(relaxation)而形成影像。
MRI侦测体内影像的侦测极限约在1mm，这项限制显示了显影剂对比度的重要。磁性纳米微粒应用在MRI显影剂上有提升对比度的特性，再使用生物相容性高分子作修饰，可达到生物相容性效果。若在生物相容性高分子偶联特异性靶向分子(specific targeting agent)及荧光染剂，则此含有特异性靶向分子及荧光染剂的磁性纳米微粒可增加侦测特异性、提高灵敏度、及同时观察荧光信号。
美国专利公开US2007/0148095(台湾专利公开200724904)中公开一种多功能磁性纳米微粒，并以生物相容性高分子修饰此磁性纳米微粒，且在生物相容性高分子上偶联特异性靶向分子及荧光染剂。此生物相容性高分子包括：聚乙二醇(PEG)、聚乳酸-聚乙二醇(PLA-PEG)、聚丙交酯(PLA)、聚乙交酯(PGA)、聚己内酯(PCL)、或聚甲基丙烯酸甲酯(PMMA)。
美国专利公开US2007/0148095中公开一种硅烷化合物用于修饰磁性纳米微粒，和用于使用该纳米微粒探测和治疗所关注的组织。
市售的MRI对比度增强剂包括
Figure BDA0000039982550000011
(葡聚糖涂覆的氧化铁)或
Figure BDA0000039982550000012
(羧基葡聚糖涂覆的氧化铁)。
发明内容
本发明提供一种生物相容性高分子，其结构如式(I)所示：
Figure BDA0000039982550000021
其中，R1为烷基、芳基、羧基、或氨基；
R2为烷基、或芳基；
n为5到1000的整数；
m为1到10的整数。
另一方面，本发明提供一种具有生物相容性的磁性纳米微粒，包含：
磁性纳米微粒；
共价偶联至该磁性纳米微粒的式(II)的生物相容性高分子：
Figure BDA0000039982550000022
其中，R1为烷基、芳基、羧基、或氨基；
n为5到1000的整数；
m为1到10的整数。
附图说明
本发明可通过阅读以下的实施方式和实施例，同时参照以下附图而更加全面地理解：
图1为合成流程图，用以说明本发明的生物相容性高分子的合成流程。
图2绘示用本发明的生物相容性高分子修饰的磁性纳米微粒。
具体实施方式
以下描述是进行本发明的最佳模式。本说明书是出于说明本发明的一般原理的目的，不应该认为是限制。本发明的范围通过参考所附权利要求而确定。
本发明的生物相容性高分子由通式(I)所示：
Figure BDA0000039982550000031
其中，R1为烷基、芳基、羧基、或氨基至少之一的官能团；
R2为烷基、或芳基；
n为5到1000的整数；
m为1到10的整数。
图1是合成流程图，说明本发明的生物相容性高分子的合成流程，其中R1、R2、n和m具有如上所述的含义。如图1中所示，该合成方案包括利用丁二酸酐(succinic anhydride)化合物将聚乙二醇(PEG)的羟基端基转换成为羧基，然后将硅烷基偶联到该PEG上。适合R1和R2的烷基包括C1-C20直链或具有分枝结构的烷基。在一实施例中R1和R2独立地为C1-C6直链或具有分枝结构的烷基，例如甲基，乙基，丙基，异丙基，正丁基，仲丁基，叔丁基，正戊基，异戊基，叔戊基，正己基，异己基。适合R1和R2的芳基包括C6-C12有取代基或未取代基的芳基，例如苯基，联苯基，萘基等，且其取代基的实例包括：羟基，卤烷基，烷氧基，氰基，硝基，氨基，或烷氨基等。亚甲基单元的数目(m)优选为1到10的整数，氧基亚乙基的数目(n)优选为5到1000的整数(相当于PEG的分子量大约为200至50000g/mole的聚乙二醇)。在一实施例中m大约是3，n大约是15。
在图1中合成的生物相容性聚合物是有用的，这是因为它能够化学地修饰氧化铁纳米微粒的表面，从而增加生物相容性。此外，本发明的生物相容性聚合物是有用的，还因为它能够标记微粒(例如：纳米粒子、磁性粒子、磁性纳米粒子、超顺磁性粒子)，从而使该微粒与靶向分子(targeting agent)、荧光剂、医疗试剂、或诊断用试剂中的一种或者多种还具有反应性。
本发明还提供一种具有生物相容性的磁性纳米微粒，包含：
磁性纳米微粒；
共价偶联至该磁性纳米微粒的式(II)的生物相容性高分子：
Figure BDA0000039982550000041
其中，R1为烷基、芳基、羧基、或氨基；
n为5到1000的整数；
m为1到10的整数；
图2为用本发明的生物相容性高分子修饰的磁性纳米微粒的示意图。磁性纳米微粒优选由铁、钴、镍、和其氧化物中的至少一种制成。应该理解，该纳米微粒可由单种或者复合磁性材料制成，但是超顺磁性材料是特别优选的。在该生物相容性高分子化学键合至该磁性纳米微粒之后，可将该端基R1转化成反应性官能团，例如羧基或氨基，以容许与特异性靶向分子或/和荧光染剂进行偶联。但是R1不为烷基、芳基，因为烷基、芳基不能与靶向分子或荧光染剂偶联。在一实施例中R1是羧基。亚甲基单元的数目(m)优选为1到10的整数，氧基亚乙基的数目(n)优选为5到1000的整数。在一实施例中m大约是3，n大约是15。优选将该生物相容性高分子涂覆在磁性纳米微粒上形成核壳结构。更优选该生物相容性高分子形成涂覆在该磁性纳米微粒上的单层。
实验结果表明，本发明的生物相容性高分子可提高磁性纳米微粒的r2值，达到目前市面上的显影剂，
Figure BDA0000039982550000042
和
Figure BDA0000039982550000043
的r2值的约2倍，因此当该磁性纳米微粒作为MRI显影剂时，可提供的影像对比度更大提高。
该靶向分子优选以共价键与生物相容性高分子键结。常用的靶向分子包括：抗体、蛋白质、肽、酶、糖类、糖蛋白、核酸、和脂质。在与上述靶向分子偶联后的磁性纳米微粒的粒径大约为3-500nm。本领域技术人员可在该纳米微粒上附接任何合适的靶向分子，从而得到其特异性。例如可使用叶酸分子特异性靶向(specify)具有叶酸受体的乳癌细胞上。叶酸的结构容许与胺封端的或者羧基封端的生物相容性高分子偶联。例如，叶酸容许通过形成-CONH-连接基团而与胺封端的生物相容性聚合物偶联。
可将荧光染剂进一步偶连至该磁性纳米微粒，从而提供用于光学成像技术例如NIR成像的光学信号，由此容许通过不同的成像技术实时监视焦点。优选将该荧光染剂以共价键与生物相容性高分子偶联。适当的荧光染剂包括：有机染剂或无机染剂、和有机金属络合物等。荧光染剂的激发与发射波长可为可见光(VIS)、近红外光(NIR)、或紫外光(UV)。经过上述荧光染剂与靶向分子偶联后的纳米微粒，其粒径优选为15-200nm。
不意图以任何方式限制本发明，通过以下实施例进一步说明本发明：
实施例1：纳米微粒的制备
将FeCl2.4H2O 11.6g(0.058mole)、FeCl3.6H2O 11.6g(0.096mole)与400ml去离子水放入三颈瓶中，用搅拌器以300rpm在25℃环境下搅拌。将2.5N NaOH(170ml)以固定流速47μl/秒滴入三颈瓶中。在添加2.5N NaOH后测得的pH值为11～12，加入20ml油酸，并搅拌30分钟。接下来缓慢添加6N HCl溶液，将pH值调整为约1，由此使包覆油酸的氧化铁微粒沉淀。收集沉淀，用去离子水洗涤4～5次，将多余的油酸洗掉，并干燥。
实施例2：生物相容性高分子mPEG-硅烷的合成
将分子量750的甲氧基聚乙二醇(mPEG)300g(0.4mol)与N-甲基2-吡咯烷酮600ml置于抽真空的1000ml圆底烧瓶中(真空度20托)2小时以上。
加入丁二酸酐48g(0.48mol)与4-二甲基氨基吡啶(4-Dimethylamino-pyridine，DMAP)19.5g(0.159mol)，在30℃下反应两天。
以1ml/min的速度加入亚硫酰氯(thionyl chloride)36ml(0.48mol)，并将混合物搅拌2～3小时。接着再以1ml/min的速度加入三乙胺(triethylamine)133.8ml(0.96mol)。待温度冷却至室温后，过滤混合物从而移除沉淀物，加入3-氨基丙基三乙氧基硅烷94.5ml(0.4mol)反应至少8小时。
将反应混合物添加到9L异丙醚中再沉淀，收集沉淀物，将其再溶于500ml甲苯，并以5000rpm离心5分钟，收集上层清夜。再将上层清液添加到9L异丙醚中用于再沉淀。收集棕色油状液体并在真空下干燥，得到生物相容性高分子mPEG-硅烷。
实施例3：生物相容性高分子COOH-PEG-硅烷的合成
将分子量750的聚乙二醇(PEG)300g(0.4mol)与N-甲基2-吡咯烷酮600ml置于抽真空的1000ml圆底烧瓶中(真空度20托)2小时以上。
加入丁二酸酐96g(0.96mol)与4-二甲基氨基吡啶39.0g(0.318mol)，在30℃下反应两天，得到两端具有羧基的聚乙二醇(COOH-PEG)。
以1ml/min的速度加入亚硫酰氯36ml(0.48mol)并搅拌2～3小时。接着再以1ml/min的速度加入三乙胺133.8ml(0.96mol)。待温度冷却至室温之后，过滤该混合物从而移除沉淀物。然后，加入3-氨基丙基三乙氧基硅烷94.5ml(0.4mol)，反应至少8小时。
将反应混合物添加到9L异丙醚中再沉淀，收集沉淀物，将其再溶于500ml甲苯，并以5000rpm离心5分钟，收集上层清夜。再将上层清液添加到9L异丙醚中用于再沉淀。收集棕色油状液体并在真空下干燥，得到生物相容性高分子COOH-PEG-硅烷。
实施例4：氧化铁纳米微粒表面修饰PEG硅烷
向含有实施例1的10g氧化铁的甲苯溶液1-1.2L中，加入250g的mPEG-硅烷或COOH-PEG-硅烷，将混合物超声处理2-3小时。在添加1.5L去离子水之后，将混合物用于超滤装置进行纯化及浓缩至100ml，得到用生物相容性高分子修饰的氧化铁纳米微粒。
实施例5：靶向分子修饰
取226μl叶酸溶液(叶酸/二甲基亚砜：10mg/ml)于50ml棕色圆底瓶中。向该溶液中加入5ml二甲基亚砜及176.5μl二环己基碳二亚胺溶液(二环己基碳二亚胺/二甲基亚砜：5mg/ml)，并反应1小时。然后，加入98.5μl NHS溶液(N-羟基丁二酰亚胺/二甲基亚砜：5mg/ml)，并搅拌1小时。然后加入289μl乙二胺，得到溶液A。
在真空下，将实施例4的经由COOH-PEG-硅烷修饰的氧化铁纳米微粒1ml(4.48mg/ml)和10ml DMSO置于50ml圆底瓶中，保持1小时。将176.5μl二环己基碳二亚胺溶液(二环己基碳二亚胺/二甲基亚砜：5mg/ml)添加到该溶液中并搅拌1小时。然后，加入98.5μl NHS溶液(N-羟基丁二酰亚胺/二甲基亚砜：5mg/ml)，并搅拌1小时，得到溶液B。
将溶液A 2895μl(1/2体积)添加到溶液B中，并搅拌8小时。将得到的溶液加入透析膜(MW：3000)，用水进行透析。然后，将该溶液通过超滤装置浓缩至2ml，得到偶联有靶向分子的氧化铁纳米微粒。
实施例6：与荧光染剂偶联
将10-6mol/ml NIR染剂CypHer5E(Amersham Biosciencese公司)1ml与10-6mol乙二胺混合并搅拌1小时，得到溶液C。
将实施例5的2mg/ml已偶联叶酸的氧化铁微粒溶于10ml去离子水中，接着加入10-6mol 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide；EDC)。在将混合物搅拌1小时后，加入10-6mol N-羟基丁二酰亚胺(NHS；N-hydroxysuccinimide)，并再搅拌1小时，得到溶液D。
将溶液C加入溶液D中并搅拌8小时。将得到的溶液装入透析膜(MW：3000)，用水进行透析。然后，将该溶液通过超滤装置浓缩至2ml，得到与荧光染剂和靶向分子偶联的氧化铁纳米微粒。
实施例7：弛豫性(relaxivity)测试
比较实施例5的经修饰的氧化铁纳米微粒与US 2006/0216239产品及商业显影剂即和
Figure BDA0000039982550000072
的弛豫性r1、r2值。
配制不同浓度的氧化铁溶液(0.1、0.2、0.3、0.4、0.5mM)，以来自BRUKER的Minispec mq 20测量各浓度溶液的T1或T2弛豫时间(relaxation time)。以弛豫时间的倒数为纵轴，溶液浓度为横轴，建立线性关系。此线性关系的斜率即为r1或r2弛豫性。
如表1所示，本发明的修饰后的氧化铁纳米微粒的r2弛豫性约为
Figure BDA0000039982550000073
的2倍，约为US2006/0216239的现有技术产品的1.4倍。因此，由于较高的r2弛豫性而增加了对比度的提高。
表1、本发明、US2006/0216239与目前临床用的MRI造影剂的r2与r1的比较
Figure BDA0000039982550000081
*直径以TEM测量
虽然本发明已以优选实施例披露如上，然其并非用以限定本发明，任何本发明所属技术领域中的技术人员，在不脱离本发明的精神和范围内，应可作任意更改与润饰。因此，本发明的保护范围应以所附权利要求书限定的范围为准。

Claims (21)

1.一种生物相容性高分子，其结构如式(I)所示：
Figure FDA00001618290300011
式(I)
其中，R1为烷基或羧基；
R2为烷基、或芳基；
n为5到1000的整数；
m为1到10的整数。
2.如权利要求1所述的生物相容性高分子，其中R1和R2各自独立地为C1-C20直链或具有分枝结构的烷基。
3.如权利要求1所述的生物相容性高分子，其中R2为C6-C12有取代基或不具取代基的芳基。
4.如权利要求1所述的生物相容性高分子，其中R1为甲基。
5.如权利要求1所述的生物相容性高分子，其中R2为乙基。
6.如权利要求1所述的生物相容性高分子，其中n为15。
7.如权利要求1所述的生物相容性高分子，其中m为3。
8.一种具有生物相容性的磁性纳米微粒，包含：
磁性纳米微粒；
共价偶联至该磁性纳米微粒的式(II)的生物相容性高分子：
Figure FDA00001618290300012
式(II)
其中，R1为烷基或羧基；
n为5到1000的整数；
m为1到10的整数。
9.如权利要求8所述的具有生物相容性的磁性纳米微粒，其中R1为羧基。
10.如权利要求8所述的具有生物相容性的磁性纳米微粒，其中该磁性纳米微粒是超顺磁性纳米微粒。
11.如权利要求8所述的具有生物相容性的磁性纳米微粒，其中该磁性纳米微粒包含下列中的至少一种：铁、钴、镍、及其氧化物。
12.如权利要求9所述的具有生物相容性的磁性纳米微粒，其中R1偶联至特异性靶向分子，该特异性靶向分子包括抗体、蛋白质、肽、酶、糖类、糖蛋白、核酸、或脂质。
13.如权利要求12所述的具有生物相容性的磁性纳米微粒，其中该磁性纳米微粒的粒径为3-500nm。
14.如权利要求12所述的具有生物相容性的磁性纳米微粒，其中该生物相容性高分子偶联至荧光染剂。
15.如权利要求14所述的具有生物相容性的磁性纳米微粒，其中含有该荧光染剂与该特异性靶向分子的磁性纳米微粒的粒径为15-200nm。
16.如权利要求14所述的具有生物相容性的磁性纳米微粒，其中该荧光染剂显示出以下的至少之一：紫外、近红外和可见光的激发或发射波长。
17.如权利要求14所述的具有生物相容性的磁性纳米微粒，其中该荧光染剂包括有机染剂、无机染剂、或有机金属络合物。
18.如权利要求14所述的具有生物相容性的磁性纳米微粒，其中该荧光染剂与该特异性靶向分子系以共价键与该生物相容性高分子键结。
19.如权利要求14所述的具有生物相容性的磁性纳米微粒，其中该特异性靶向分子与该生物相容性高分子通过-CONH-连接基团偶联。
20.如权利要求8所述的具有生物相容性的磁性纳米微粒，其中该生物相容性高分子被涂覆于该磁性纳米微粒上形成核壳结构。
21.如权利要求20所述的具有生物相容性的磁性纳米微粒，其中该生物相容性高分子形成涂覆在该磁性纳米微粒上的单层。
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Correction item: Description

Correct: Zheng Que

False: Cuo Wu

Number: 36

Page: Quan Wen

Volume: 28

CI03 Correction of invention patent