CN108129673B - 一种高灵敏度水溶性树枝状大分子f19显影剂的制备及其应用 - Google Patents
一种高灵敏度水溶性树枝状大分子f19显影剂的制备及其应用 Download PDFInfo
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Abstract
本发明公开了一种高灵敏度水溶性树枝状大分子F19显影剂的制备及其应用，属于有机化学合成与医药化工领域。本发明的F19显影剂以简单易得的季戊四醇为起始原料，首先通过单烷基化和Williamson醚合成的方法引入丙烯基和聚乙二醇，然后通过氧化得到亲水链部分；另一部分从季戊四醇出发，通过单烷基化引入丙烯酸叔丁酯，通过Mitsunobu反应引入全氟叔丁醇，接着通过一系列的酰胺化、脱保护，引入亲水链部分得到水溶性的含氟片段部分；最后通过酰胺缩合将功能性母核与含氟片段组装起来，得到F19显影剂。本发明方法反应简单高效、条件温和，制备得到的显影剂灵敏度高、水溶性好并且生物相容性好，可应用于体内的F19MRI成像和药物的可视化传递与缓释等领域。
Description
技术领域
本发明涉及核磁共振成像显影剂领域，具体涉及一种高灵敏度水溶性树枝状大分子F19显影剂的制备及其应用。
背景技术
磁共振成像(MRI)技术是临床上非常重要的医学成像手段，目前已广泛应用于临床疾病的检测、诊断以及药物的疗效评估，随着MRI的快速发展，该项技术在生物医学领域方面的应用将越来越广泛，在揭示生命的奥秘以及自然科学研究方面发挥突出的作用。
19F MRI技术作为一种新兴的成像技术，由于本身具有的优势，如无电离辐射和背景干扰，可提供体内含氟分子的分布、形态和量化信息，适合化学生物学研究、药物开发、疾病定量诊断和个性化药物治疗等，逐渐成为近年来的研究热点。
树枝状大分子具有精确的分子结构，高度的几何对称性，分子内存在空腔可以用于装载药物，分子本身具有纳米尺寸可用于药物的传递。由于本身的这些特性，树枝状大分子特别适合作为药物传递系统应用于体内来进行药物的传递。通过将氟引入到树枝状大分子化合物中得到可以可以应用于体内的19F MRI显影剂，从而可以将其作为药物载体并应用于体内，以实现药物在体内的可视化追踪与治疗。
发明内容
本发明的目的在于提供一种高灵敏度水溶性树枝状大分子F19显影剂的制备及其应用。本发明提供的水溶性树枝状大分子F19显影剂具有单一的F19 NMR信号，较短的弛豫时间，较高的F19 MRI灵敏度以及较好的生物相容性。该树枝状大分子制备方法简单，条件温和，可大量制备，非常适合作为药物载体在体内进行药物的传递与可视化追踪。
本发明提供的高灵敏度水溶性树枝状大分子F19显影剂的制备及其应用，其特征在于，结构式如式1所示：
其中聚乙二醇链的长度n为6～100的正整数；
树枝状片段的个数m为1～10的正整数；
分子结构中的R基团为荧光母核、靶向基团等或者如下式R1，R2的结构：
优选地，所述R基团为荧光母核时，所述R基团包括：BODIPY(氟化硼二吡咯)、四苯乙烯、四苯基卟啉、罗丹明B。
优选地，所述靶向基团包括：叶酸、生物素、透明质酸。
本发明提供的高灵敏度水溶性树枝状大分子F19显影剂的制备方法，包括以下步骤：
(1)以季戊四醇为起始原料，通过单烷基化和威廉姆逊(Williamson)醚合成的方法引入丙烯基和聚乙二醇，然后通过氧化得到亲水链部分；
(2)另一部分从季戊四醇出发，通过单烷基化引入丙烯酸叔丁酯，通过光延(Mitsunobu)反应引入全氟叔丁醇，接着通过酰胺化、脱保护，引入步骤(1)所得亲水链部分得到水溶性的含氟片段部分；
(3)最后通过酰胺缩合将含R基团的功能性母核与步骤(2)得到的含氟片段连接起来，得到F19 MRI显影剂。
优选地，所述的光延(Mitsunobu)反应中所采用的催化剂为三苯基膦与偶氮二甲酸二异丙酯组合或三苯基膦与偶氮二甲酸二乙酯组合中的至少一种组合；酰胺缩合所采用的缩合剂包括二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺中的至少一种。
本发明的高灵敏度水溶性树枝状大分子F19显影剂可用于F19 MRI成像、药物在体内的可视化追踪量化以及组成药物传递系统。
本发明的高灵敏度水溶性树枝状大分子F19显影剂以赖氨酸作为功能性骨架来连接含氟部分、聚乙二醇亲水链片段以及功能性母核，分子中以全氟叔丁醇提供单一的氟信号，单分子量的聚乙二醇链增加化合物的水溶性，不同功能性的母核可以增加显影剂的应用。该树枝状大分子显影剂具有大量空腔，可以用来通过非共价键作用来包裹小分子药物，可用于体内的可视化追踪与药物缓释。该水溶性树枝状大分子F19显影剂具有较好的理化性质，在生物医药和医用新材料等方面具有非常好的市场应用前景。
本发明制备的高灵敏度水溶性树枝状大分子F19显影剂具有以下突出优点：
(1)具有较好的水溶性；
(2)水溶液中可以提供单一的F19 NMR信号，信号强度好，灵敏度高；
(3)具有较好的生物相容性，可以应用于体内进行监测；
(4)分子中的空腔可以用来装载和传递药物；
(5)合成原料便宜易得，成本较低，方法简单，条件温和，可用于大量制备。
附图说明
图1是实施例1所得高灵敏度水溶性树枝状大分子显影剂对L02、A549和HepG2细胞的细胞毒性图；
图2是实施例1所得高灵敏度水溶性树枝状大分子显影剂在水溶液中的F19 NMR图和体外F19 MRI图。
具体实施方式
下面结合实施例以均苯三酸为母核对本发明做进一步详细的描述，但本发明的实施方式不限于此。
实施例1树枝状大分子F19显影剂的合成
合成过程包含三个步骤：(1)亲水链部分的合成；(2)水溶性含氟片段的合成；(3)树枝状大分子F19显影剂的合成。
(1)亲水链部分的合成
在反应瓶中加入季戊四醇1(68.0g,0.5mol)和NaOH(9.6g，200mL水)溶液，缓慢滴加溴丙烯(Allyl bromide,24.2g,0.2mol)，滴加2h结束后将反应液加热到70℃反应8h，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩后柱层析得化合物2(14.1g,42％)。
无水无氧氩气保护条件下，将化合物2(7.0g,40.0mmol)的N,N-二甲基甲酰胺(DMF)溶液缓慢滴加进NaH(5.8g,240.0mmol)的N,N-二甲基甲酰胺(DMF)溶液中，搅拌30min后加入七聚乙二醇单甲醚的对甲苯磺酸酯(79.0g,160.0mmol)，反应液在60℃下搅拌反应24h然后将N,N-二甲基甲酰胺蒸干，柱层析得化合物3(38.4g,84％)。
将化合物3(37.7g,33.0mmol)加入混合溶剂乙腈(MeCN)：四氯化碳(CCl4)：水(1:1:1.5,210mL)中，接着加入高碘酸钠(NaIO4,42.4g,198.0mmol)和水合三氯化钌(RuCl3·3H2O,66.0mg,0.33mmol)，反应液在室温下搅拌3h，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩经柱层析得化合物4(25.3g,66％)。
(2)水溶性含氟片段的合成
在反应瓶中将季戊四醇1(68.1g,0.5mol)溶于二甲基亚砜(DMSO,100mL)中，将反应液加热到80℃，加入氢氧化钠的水溶液(4.0g in 9mL H2O)，缓慢滴加丙烯酸叔丁酯(tert-Butylacrylate,76.9g,0.6mol)滴加结束后反应液在80℃下过夜反应，反应结束后加入水，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩后柱层析得化合物5(46.2g,35％)。
在反应瓶中加入化合物5(13.2g,50.0mmol)、三苯基膦(Ph3P,59.0g,225.0mmol)和
分子筛(MS,15.0g)，以四氢呋喃(THF)为溶剂，在冰浴条件下缓慢滴加偶氮二甲酸二异丙酯(DIAD,45.5g,225.0mmol)，滴加结束后继续搅拌20min，然后一次性加入全氟叔丁醇(53.0g,225.0mmol)，将反应液升温至45℃反应48h，反应结束后加入水，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩柱层析得化合物6(26.2g,57％)。
在反应瓶中加入化合物6(25.7g,28.0mmol)和苯甲醚(Anisole,4.5g,42.0mmol)以二氯甲烷(DCM)为溶剂，加入三氟乙酸(TFA,63.9g,560.0mmol)，室温下搅拌反应4h，反应结束后将反应液旋干，柱层析得化合物7(21.7g,90％)。
在反应瓶中加入化合物7(21.5g,25.0mmol)和浓硫酸(4.0mL)，以甲醇为溶剂，加热回流反应6h，反应结束后加入水，用乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩柱层析得化合物8(20.8g,95％)。
在反应瓶中加入化合物8(21.0g,24.0mmol)和乙二胺(30mL)，以甲醇为溶剂，80℃下加热回流反应48h，反应结束后直接旋干溶剂，柱层析得化合物9(15.8g,73％)。
无水无氧氩气保护条件下，将1-羟基苯并三唑(HOBt,4.6g,33.7mmol)的N,N-二甲基甲酰胺(DMF)溶液加入到N-α-笏甲氧羰基-N-叔丁氧羰基-L-赖氨酸(Fmoc-Lys-NHBoc,10.5g,22.5mmol)的N,N-二甲基甲酰胺(DMF)溶液中，0℃缓慢加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC,6.46g,33.7mmol)，继续搅拌反应20min后加入化合物9(13.5g,15.0mmol)的N,N-二甲基甲酰胺(DMF)溶液，加热到45℃反应12h，反应结束后加入水，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩柱层析得化合物10(13.0g,64％)。
在反应瓶中加入化合物10(12.9g,9.5mmol)和苯甲醚(Anisole,1.5g,14.3mmol)，以二氯甲烷(DCM)为溶剂，加入三氟乙酸(TFA,21.7g,190.0mmol)，室温下搅拌反应4h，将反应液旋干，柱层析得化合物11(11.2g,94％)。
无水无氧氩气保护条件下，将1-羟基苯并三唑(HOBt,1.9g,14.4mmol)的N,N-二甲基甲酰胺(DMF)溶液加入到化合物4(11.1g,9.6mmol)的N,N-二甲基甲酰胺(DMF)溶液中，在0℃下缓慢加入加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC,2.8g,14.4mmol)的N,N-二甲基甲酰胺(DMF)溶液，搅拌反应20min后，加入化合物11(10.0g,8.0mmol)的N,N-二甲基甲酰胺(DMF)溶液，将反应液加热到45℃反应12h反应结束后加入水，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压浓缩柱层析得化合物13(15.0g,78％)。
在反应瓶中加入化合物12(7.2g,3.0mmol)和哌啶(Piperidine,6mL)，以N,N-二甲基甲酰胺(DMF)为溶剂，室温下反应4h，反应结束后减压蒸除N,N-二甲基甲酰胺(DMF)，柱层析得化合物13(HRfPeg,5.4g,83％)。
(3)树枝状大分子F19显影剂的合成
无水无氧氩气保护条件下，将1-羟基苯并三唑(HOBt,304.0mg,2.25mmol)的N,N-二甲基甲酰胺(DMF)溶液加入到均苯三酸(Trimesic acid,105.0mg,0.5mmol)的N,N-二甲基甲酰胺(DMF)溶液中，0℃下缓慢滴加1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC,431.0mg,2.25mmol)的N,N-二甲基甲酰胺(DMF)溶液，搅拌反应20min后一次性加入化合物13(4.9g,2.25mmol)，然后将反应液在45℃下反应24h，反应结束后加入水，用二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，柱层析得化合物14(2.1g,62％)。
实施例2树枝状大分子F19显影剂水溶性的测定
采用紫外分光光度法测定化合物14在PBS缓冲液中的溶解度。首先，测不同浓度的化合物14溶液在波长为254nm处的吸光度，以这些数据绘制标准曲线，可以得到标准曲线方程。然后配制化合物14的饱和溶液，将饱和溶液离心后取上清液稀释到特定的浓度，然后测定其在波长为254nm处吸光度值，将该值引入标准曲线方程计算得到化合物饱和溶液稀释后的浓度，再乘以稀释倍数即可得该化合物在PBS缓冲液中的溶解度，测定结果显示化合物14的溶解度大于200mg/mL，说明化合物14具有非常好的水溶性。
实施例3树枝状大分子F19显影剂细胞毒性的测定
细胞毒性测定选用人非小细胞肺癌(A549)、人肝癌细胞(HepG2)和人正常肝细胞(L02)
(1)以人非小细胞肺癌(A549)测定方法为例说明
A549细胞使用含10％胎牛血清和1％双抗的DMEM培养基，培养条件为37℃、含5％CO2的恒温培养箱。具体步骤：
1)取对数生长期的细胞，用DMEM培养基将其稀释至浓度为3×104/mL。
2)在96孔板的每个孔里加入100μL稀释的细胞悬液，在培养箱37℃孵育24h待细胞贴壁。
3)弃掉培养基，将化合物14用培养基稀释至0.15mM、0.45mM、0.75mM，加药量100μL/孔，培养箱37℃孵育24h。
4)加入20μL浓度为5mg/mL的MTT溶液，培养箱37℃温育4h。
5)加入200μL DMSO将细胞溶解，酶标仪测定在490nm下的OD值。
6)处理数据，得到细胞存活率，L02细胞和HepG2细胞的细胞毒性采用相同的方法来测定。
(2)细胞毒性测定结果
细胞毒性测定的结果(图1)显示在浓度为0.15mM、0.45mM、0.75mM的条件下，化合物14对三种细胞无明显的细胞毒性，说明化合物14具有较好的生物活性。
实施例4树枝状大分子F19显影剂体外F19 MRI成像效果
F19 MRI研究发现，上述得到的树枝状大分子F19显影剂化合物14中含有81个对称的氟原子，这些氟原子可以在-72.28位移处提供单一的F19 NMR信号，这有利于提高化合物14的F19 MRI信号强度和灵敏度。F19 MRI成像结果显示，化合物14能够在10mM浓度水溶液中下实现成像，相比于目前已经报道的水溶性F19 MRI显影剂成像浓度有了很大的提高(图2)。
Claims (7)
1.一种高灵敏度水溶性树枝状大分子F19显影剂，其特征在于，所述显影剂结构如式1所示：
其中聚乙二醇链的长度n为6～100的正整数；
树枝状片段的个数m为1～10的正整数；
分子结构中的R基团为荧光母核、靶向基团或者如下式R1，R2的结构：
2.根据权利要求1所述的高灵敏度水溶性树枝状大分子F19显影剂，其特征在于，所述R基团为荧光母核时，所述R基团包括：BODIPY、四苯乙烯、四苯基卟啉、罗丹明B。
3.根据权利要求1所述的高灵敏度水溶性树枝状大分子F19显影剂，其特征在于，所述靶向基团包括：叶酸、生物素、透明质酸。
4.根据权利要求1-3任一项所述的高灵敏度水溶性树枝状大分子F19显影剂的制备方法，其特征在于，包括以下步骤：
(1)以季戊四醇为起始原料，通过单烷基化和威廉姆逊醚合成的方法引入丙烯基和聚乙二醇，然后通过氧化得到亲水链部分；
(2)另一部分从季戊四醇出发，通过单烷基化引入丙烯酸叔丁酯，通过光延反应引入全氟叔丁醇，接着通过酰胺化、脱保护，引入步骤(1)所得亲水链部分得到水溶性的含氟片段部分；
(3)最后通过酰胺缩合将含R基团的功能性母核与步骤(2)得到的含氟片段连接起来，得到F19显影剂。
5.根据权利要求4所述的制备方法，其特征在于，所述的光延反应中所采用的催化剂为三苯基膦与偶氮二甲酸二异丙酯组合或三苯基膦与偶氮二甲酸二乙酯组合中的至少一种组合。
6.根据权利要求4所述的制备方法，其特征在于，步骤(3)中所述的酰胺缩合所采用的缩合剂包括二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺中的至少一种。
7.根据权利要求1，2或3所述的高灵敏度水溶性树枝状大分子F19显影剂的应用，其特征在于，可用于F19 MRI成像、药物在体内的可视化追踪量化以及组成药物传递系统。
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