CN114106297B - 含有两性离子基团的荧光聚合物及其制备方法和应用 - Google Patents
含有两性离子基团的荧光聚合物及其制备方法和应用 Download PDFInfo
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Abstract
本申请提供一种含有两性离子基团的荧光聚合物及其制备方法和应用。含有两性离子基团的荧光聚合物,其主链为具有π‑共轭结构的电子给/受体交替共聚物,侧链包括两性离子基团。含有两性离子基团的荧光聚合物的制备方法:将所述侧链对应的原料通过可逆加成‑断裂链转移聚合引入所述主链对应的聚合物。含有两性离子基团的荧光聚合物的应用,用于制备生物相容性材料和诊疗癌症的药物。本申请提供的含有两性离子基团的荧光聚合物,在水溶液中可以有效克服聚集诱导的荧光淬灭效应。
Description
技术领域
本发明涉及新材料领域,尤其涉及一种含有两性离子基团的荧光聚合物及其制备方法和应用。
背景技术
聚合物胶束作为一种重要的药物递送载体而被广泛地应用于疾病的诊疗。胶束中的聚合物一般充当支架的作用,为各种功能化基团(光敏剂,pH敏感基团,温度敏感基团等)提供锚点,并携带多种药物,包括亲水的核酸,肽或疏水的有机小分子药物等;此外,聚合物主链也可以充当各种功能分子,如有机聚合物染料,作为纳米颗粒的示踪剂,用于研究载体与生物体的相互作用,部分有机聚合物分子有较高的光热转换效率,用作光热治疗和光声成像等。
作为纳米药物载体应具有良好的生物相容性和生物可降解性,在生物体内不会引起严重的免疫反应,并可在相应的时间内代谢掉,从而减小其生物毒性;此外,还应具有延长体内循环时间的亲水基团,能够减少载体与体内免疫蛋白或细胞的相互作用。
常见的延长纳米颗粒的体内循环时间方法是在颗粒表面聚乙二醇基团(PEG),其原理是PEG可以阻止纳米颗粒的聚集,并降低调理作用和免疫细胞的吞噬。但PEG也存在相应的缺点,颗粒表面过多的修饰PEG,虽然会延长颗粒的循环时间,但会增加颗粒进入细胞的难度,导致药物难以到达靶标位置发挥作用;此外PEG存在加速清除现象(acceleratedblood clearance(ABC)phenomenon),第二剂药物的体内循环时间远远小于第一剂。
研发一种可以有效克服聚集诱导的荧光淬灭效应的聚合物,成为亟待解决的问题。
发明内容
本发明的目的在于提供一种含有两性离子基团的荧光聚合物及其制备方法和应用。
本申请提供一种含有两性离子基团的荧光聚合物,其主链为具有π-共轭结构的电子给受体交替共聚物,侧链包括两性离子基团。
优选地,所述电子给受体交替共聚物的结构通式为:
其中,R1为n为正整数。
优选地,n为7、11或20。
优选地,所述电子给受体交替共聚物由电子给体和受体单体缩聚得到。
优选地,所述两性离子基团包括2-甲基丙烯酰氧乙基磷酸胆碱或3-[[2-(甲基丙烯酰氧)乙基]二甲基铵]丙酸。
优选地,所述含有两性离子基团的荧光聚合物的结构通式为:
其中,R2为:
n为7、11或20。
本申请还提供一种所述的含有两性离子基团的荧光聚合物的制备方法,包括:
将所述侧链对应的原料通过可逆加成-断裂链转移聚合引入所述主链对应的聚合物。
优选地,所述制备方法具体包括:
将第一化合物与第二化合物反应得到第三化合物,然后与第四化合物反应得到所述主链对应的聚合物;
将所述主链对应的聚合物与所述侧链对应的原料反应得到所述含有两性离子基团的荧光聚合物;
所述第一化合物为:
所述第二化合物为:
所述第三化合物为:
所述第四化合物为:
所述主链对应的聚合物的结构通式为:
本申请还提供一种所述的含有两性离子基团的荧光聚合物的应用,用于制备生物相容性材料和诊疗癌症的药物。
与现有技术相比,本发明的有益效果至少包括:
本申请提供的含有两性离子基团的荧光聚合物,以上述电子给受体交替共聚物作为主链,并在其侧链引入两性离子基团,获得含有两性离子基团的荧光聚合物,该含有两性离子基团的荧光聚合物在水溶液中可以有效克服聚集诱导的荧光淬灭效应。所用电子给受体交替共聚物,含有窄带隙的π-共轭骨架,不仅可以充当支架的作用,也具有在近红外波长的光吸收和发射的功能,为获得含有两性离子基团的荧光聚合物提供基础。此类电子给受体交替共聚物的带隙和光学性质可以通过改变电子给受体的强弱程度进行调控。
本申请提供的含有两性离子基团的荧光聚合物的制备方法,创造性的将具有π-共轭骨架的电子给受体交替共聚物与两性离子基团以及药物分子结合,此类聚合物在疾病的诊疗和生物相容性材料等方面具有广泛用途。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,应当理解,以下附图仅示出了本发明的某些实施例,因此不应被看作是对本发明范围的限定。
图1为本申请提供的含有两性离子基团的荧光聚合物的结构示意图;
图2是聚合物3和聚合物4的四氢呋喃溶液及其纳米颗粒水溶液在自然光和紫外光下的照片;
图3是MPC聚合物纳米颗粒水溶液和CBMA聚合物纳米颗粒水溶液在自然光和紫外光下的照片;
图4为CBMA和MPC系列聚合物纳米颗粒的紫外可见光吸收谱图;
图5为CBMA和MPC系列聚合物纳米颗粒的荧光发射光谱;
图6为CBMA系列聚合物的傅里叶红外吸收光谱;
图7为MPC系列聚合物的傅里叶红外吸收光谱。
具体实施方式
如本文所用之术语:
“由……制备”与“包含”同义。本文中所用的术语“包含”、“包括”、“具有”、“含有”或其任何其它变形,意在覆盖非排它性的包括。例如,包含所列要素的组合物、步骤、方法、制品或装置不必仅限于那些要素,而是可以包括未明确列出的其它要素或此种组合物、步骤、方法、制品或装置所固有的要素。
连接词“由……组成”排除任何未指出的要素、步骤或组分。如果用于权利要求中,此短语将使权利要求为封闭式,使其不包含除那些描述的材料以外的材料,但与其相关的常规杂质除外。当短语“由……组成”出现在权利要求主体的子句中而不是紧接在主题之后时,其仅限定在该子句中描述的要素;其它要素并不被排除在作为整体的所述权利要求之外。
当量、浓度、或者其它值或参数以范围、优选范围、或一系列上限优选值和下限优选值限定的范围表示时,这应当被理解为具体公开了由任何范围上限或优选值与任何范围下限或优选值的任一配对所形成的所有范围,而不论该范围是否单独公开了。例如,当公开了范围“1~5”时,所描述的范围应被解释为包括范围“1~4”、“1~3”、“1~2”、“1~2和4~5”、“1~3和5”等。当数值范围在本文中被描述时,除非另外说明,否则该范围意图包括其端值和在该范围内的所有整数和分数。
在这些实施例中,除非另有指明,所述的份和百分比均按质量计。
“质量份”指表示多个组分的质量比例关系的基本计量单位,1份可表示任意的单位质量,如可以表示为1g,也可表示2.689g等。假如我们说A组分的质量份为a份,B组分的质量份为b份,则表示A组分的质量和B组分的质量之比a:b。或者,表示A组分的质量为aK,B组分的质量为bK(K为任意数,表示倍数因子)。不可误解的是,与质量份数不同的是,所有组分的质量份之和并不受限于100份之限制。
“和/或”用于表示所说明的情况的一者或两者均可能发生,例如,A和/或B包括(A和B)和(A或B)。
如图1中A和B所示,本申请还提供一种含有两性离子基团的荧光聚合物,其主链为具有π-共轭结构的电子给受体交替共聚物(图中的中央横线所示),侧链包括两性离子基团(图中+、-基团)。
在一个可选的实施方式中,所述电子给受体交替共聚物的结构通式为:
其中,R1为n为正整数。
在一个可选的实施方式中,n为7、11或20。
在一个可选的实施方式中,所述电子给受体交替共聚物由电子给体和受体单体缩聚得到。
上述电子给受体交替共聚物的制备反应方程式如下所示:
在一个可选的实施方式中,所述两性离子基团包括2-甲基丙烯酰氧乙基磷酸胆碱或3-[[2-(甲基丙烯酰氧)乙基]二甲基铵]丙酸。
在一个可选的实施方式中,所述含有两性离子基团的荧光聚合物的结构通式为:
其中,R2为:
n为7、11或20。
本申请还提供一种所述的含有两性离子基团的荧光聚合物的制备方法,包括:
将所述侧链对应的原料通过可逆加成-断裂链转移聚合引入所述主链对应的聚合物。
在一个可选的实施方式中,所述制备方法具体包括:
将第一化合物与第二化合物反应得到第三化合物,然后与第四化合物反应得到所述主链对应的聚合物;
将所述主链对应的聚合物与所述侧链对应的原料反应得到所述含有两性离子基团的荧光聚合物;
所述第一化合物为:
所述第二化合物为:
所述第三化合物为:
所述第四化合物为:
所述主链对应的聚合物的结构通式为:
上述含有两性离子基团的荧光聚合物的制备反应方程式如下所示:
或者可以是:
本申请还提供一种所述的含有两性离子基团的荧光聚合物的应用,用于制备生物相容性材料和诊疗癌症的药物。
下面将结合具体实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限制本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
实施例1-3
本实施例提供一种电子给受体交替共聚物,其结构式如下所示:
其中,R1为n=7、11或20。
其制备方法如下所述:
第一步的反应方程式为:
该反应为缩聚反应,反应机理为:三二亚苄基丙酮二钯(Pd2(dba)3)是催化剂,三对苯甲氧基磷((o-MeOPh)3P)是上述催化剂的配体,碳酸钾(K2CO3)起到中和该反应产生的酸和激活催化剂的作用,三甲基乙酸(PivOH)可以降低C-H键的裂解能,促进反应的进行。
需要说明的是:
化合物1的制备反应方程式如下:
化合物2的制备反应方程式如下:
第一步的具体操作如下:
将0.01mmol化合物1、0.01mmol化合物2、0.005mmol三二亚苄基丙酮二钯(Pd2(dba)3),0.01mol三对苯甲氧基磷((o-MeOPh)3P),0.005mmol三甲基乙酸(PivOH)和0.3mmol碳酸钾(K2CO3)溶于0.5mL邻二甲苯,用氮气鼓泡15min去除反应体系中的氧气,然后加热至100℃反应24h。反应结束后,将溶液滴加到冷甲醇中,得到的沉淀过滤并置于索氏提取器中,使用甲醇去洗去杂质,用正己烷清洗得到n=7的聚合物3,将氯仿清洗得到n=20的聚合物3;使用同样的配方进行反应,将反应时长缩减到18h,反应结束后,将溶液滴加到冷甲醇中,得到的沉淀过滤并置于索氏提取器中,使用甲醇、正己烷一次洗去杂质,用氯仿清洗得到n=11的聚合物3。
第二步的反应方程式为:
第二步的具体操作如下:
将200mg光电聚合物3(n=7,11,20,分别参与反应)溶于100mL四氢呋喃和甲醇的混合溶液(9:1),并添加1mL盐酸溶液(12M),60℃反应6h后,使用甲醇沉淀三次;将120mg沉淀,138mg 4-氰基-4-(硫代苯甲酰)戊酸和3mg 4-二甲氨基吡啶(DMAP)溶于30mL无水二氯甲烷中,并将反应体系置于冰水浴中,氮气鼓泡15min,随后将5mL含有313mg二环己基碳二亚胺(DCC)的无水二氯甲烷溶液用注射器添加到反应体系中,温度缓慢升到室温,反应24h后,将反应溶液在甲醇中沉淀三次,得到带有RAFT引发剂的光电聚合物4(n=7,11,20)。
聚合物4的分子量及其分布如下表1所示:
表1聚合物4的分子量及其分布
聚合物4 | 数均分子量(Mn) | Mw/Mn |
n=7 | 7600 | 1.4 |
n=11 | 11400 | 1.6 |
n=20 | 20400 | 1.2 |
本实施例提供一种含有两性离子基团的荧光聚合物,其结构式如下所示:
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其中,n=7、11或20,R2为x、y表示正整数。
上述含有两性离子基团的荧光聚合物的制备反应方程式为:
RAFT反应机理:4-氰基-4-(硫代苯甲酰)戊酸酯作为链转移试剂,偶氮二异丁腈(AIBN)作为自由基引发剂,在70℃的温度下产生自由基,将反应单体插入到链转移试剂中,得到最终的聚合物。
具体操作如下:
将20mg光电聚合物4(n=7,11,20,分别参与反应),138mg 2-甲基丙烯酰氧乙基磷酸胆碱(MPC),1.7mg偶氮二异丁腈(AIBN),和54.2mg喜树碱单体(ACPT)溶于4mL氯仿和乙醇的混合溶液中(1:1),经过5个冻融循环除去反应体系中的氧气,反应48h后,将反应溶液在乙醚中沉淀三次得到含有MPC和CPT的荧光聚合物(MPC-7,MPC-11和MPC-20)。
本实施例提供一种含有两性离子基团的荧光聚合物,其结构式如下所示:
/>
其中,n=7、11或20,R2为x、y表示正整数。
其具体制备方法为:
将20mg聚合物4(n=7,11,20,分别参与反应),127mg 3-[[2-(甲基丙烯酰氧)乙基]二甲基铵]丙酸-1-叔丁酯(CBMA-1-tBu),1.7mg偶氮二异丁腈(AIBN),和54.2mg喜树碱单体(ACPT)溶于4mL氯仿和N,N-二甲基甲酰胺的混合溶液中(1:1),经过5个冻融循环除去反应体系中的氧气,反应48h后,将反应溶液在乙醚中沉淀三次得到聚合物,并将其溶于4mLN,N-二甲基甲酰胺和三氟乙酸的溶液中(3:1),反应过夜,在乙醚中沉淀三次,得到含有CBMA和CPT的荧光聚合物(CBMA-7,CBMA-11和CBMA-20)。
为了更好的对上述聚合物的性能进行测试,将其制备得到聚合物纳米颗粒,具体的:
(1)聚合物3和4纳米颗粒的制备:将聚合物3或4(1mg)和聚合物表面活性剂F127(2mg)溶于THF(1mL)中,再快速滴加到纯水中(5mL),在纯水中透析去除THF。
(2)MPC聚合物纳米颗粒的制备:将5mg/mL MPC系列聚合物溶于1mL四氢呋喃和乙醇的混合溶液(1:1),用注射器将其快速地注入到5mL纯水中,形成纳米颗粒,并在纯水中透析去除四氢呋喃和乙醇;
(3)CBMA聚合物纳米颗粒的制备:将5mg/mL CBMA系列聚合物溶于1mL DMF中,用注射器将其快速地注入到5mL纯水中,形成纳米颗粒,并在纯水中透析去除DMF。
主链是π-共轭结构的电子给受体交替共聚物,其具有荧光的原因在于单体2有很强的荧光,在形成聚合物后,单体2由于空间位阻的影响,分子扭转被限制,进一步提高了其荧光强度;此外,主链的荧光吸收和发射波长取决于各单体给予、接受电子的能力。
对比例1
以实施例1-3得到的聚合物3和4作为对照。
图2是聚合物3和聚合物4的四氢呋喃溶液(0.2mg/mL)及其纳米颗粒水溶液在自然光和紫外光(365nm)下的照片,显示聚合物3和4在四氢呋喃溶液中荧光较强,但分散到水溶液中后存在明显的荧光淬灭效应。图3是MPC聚合物纳米颗粒水溶液和CBMA聚合物纳米颗粒水溶液在自然光和紫外光(365nm)下的照片,结果显示在侧链上修饰两性离子基团可以有效抑制荧光淬灭效应。图4为聚合物纳米颗粒的紫外可见光吸收谱图,其中,在350nm波长处为CPT的吸收,500nm为聚合物主链的吸收,证明CPT成功地连接到聚合物主链上;图5为聚合物纳米颗粒的荧光发射光谱(激发波长365nm),其中,430nm为CPT的荧光,640nm为聚合物主链的荧光;图6为CBMA系列聚合物的傅里叶红外吸收光谱;其中,在1725cm-1处为C=O和C=N双键的特征吸收峰;在1450cm-1处为CBMA中的-N+CH2 -基团特征吸收峰;在1150cm-1处为CBMA中酯基的C-O特征吸收峰;图7为MPC系列聚合物的傅里叶红外吸收光谱。在1725cm-1处为C=O和C=N双键的特征吸收峰;在1450cm-1处为MPC中的-N+CH3基团特征吸收峰;在1237和1069cm-1处为MPC的-POCH2 -特征吸收峰。
需要说明的是:应用于生物体内的聚合物应考虑考虑生物相容性,π-共轭结构主链具有强的荧光,在生物学研究中起到标记和示踪的作用,在侧链上连接两性离子基团,使该荧光主链可溶于水,在生物体内发挥相应的功能,此外,根据之前文献中的研究,两性离子基团可提高该聚合物的血液循环时间,两亲离子基团的添加增加了该聚合物的生物相容性。对于阳离子聚合物和阴离子聚合物来说:由于生物体内的蛋白,细胞膜等成分都呈负电性,阳离子聚合物容易吸附在其表面(阳离子聚合物一般应用于核酸的递送),降低该聚合物的生物学功能,增加系统毒性;而阴离子聚合物则很难跨越血管,细胞膜等屏障,从而限制了其生物学作用发挥。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
此外,本领域的技术人员能够理解,尽管在此的一些实施例包括其它实施例中所包括的某些特征而不是其它特征,但是不同实施例的特征的组合意味着处于本发明的范围之内并且形成不同的实施例。例如,在上面的权利要求书中,所要求保护的实施例的任意之一都可以以任意的组合方式来使用。公开于该背景技术部分的信息仅仅旨在加深对本发明的总体背景技术的理解,而不应当被视为承认或以任何形式暗示该信息构成已为本领域技术人员所公知的现有技术。
Claims (4)
1.一种含有两性离子基团的荧光聚合物,其特征在于,其主链为具有π-共轭结构的电子给受体交替共聚物,侧链包括两性离子基团;
所述含有两性离子基团的荧光聚合物的结构通式为:
,
其中,R2为:
或
;
n为7、11或20,x、y为正整数。
2.一种权利要求1所述的含有两性离子基团的荧光聚合物的制备方法,其特征在于,包括:
将2-甲基丙烯酰氧乙基磷酸胆碱或3-[[2-(甲基丙烯酰氧)乙基]二甲基铵]丙酸通过可逆加成-断裂链转移聚合引入所述主链对应的聚合物;
所述主链对应的聚合物的结构通式为:
;
所述R1为。
3.根据权利要求2所述的含有两性离子基团的荧光聚合物的制备方法,其特征在于,所述制备方法具体包括:
将第一化合物与第二化合物反应得到第三化合物,然后与第四化合物反应得到所述主链对应的聚合物;
将所述主链对应的聚合物与2-甲基丙烯酰氧乙基磷酸胆碱或3-[[2-(甲基丙烯酰氧)乙基]二甲基铵]丙酸反应得到所述含有两性离子基团的荧光聚合物;
所述第一化合物为:
;
所述第二化合物为:
;
所述第三化合物为:
;
所述第四化合物为:
;
所述主链对应的聚合物的结构通式为:
。
4.一种权利要求1所述的含有两性离子基团的荧光聚合物的应用,其特征在于,用于制备生物相容性材料和诊疗癌症的药物。
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