CN102918118A - 荧光色素材料及其使用方法 - Google Patents
荧光色素材料及其使用方法 Download PDFInfo
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- CN102918118A CN102918118A CN2011800271332A CN201180027133A CN102918118A CN 102918118 A CN102918118 A CN 102918118A CN 2011800271332 A CN2011800271332 A CN 2011800271332A CN 201180027133 A CN201180027133 A CN 201180027133A CN 102918118 A CN102918118 A CN 102918118A
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Abstract
Description
技术领域
本发明涉及含有金属salen络合物的荧光式材料及其使用方法。
背景技术
通常,药物被给药至生物体后到达患部,通过在该患部局部发挥药理效果而产生治疗效果,但即使药物到达患部以外的组织(即正常组织),也不能治疗。
因此,如何有效地将药物引导至患部很重要。将药物引导至患部的技术被称为药物递送(drug delivery),是近年研究开发活跃进行的领域。该药物递送具有至少两个优点。
一个优点是可在患部组织中得到充分高的药物浓度。如果患部中的药物浓度没有达到一定值以上则不产生药理效果,低浓度时无法期待治疗效果。
第二个优点是能够将药物仅引导至患部组织,抑制对正常组织的副作用。
这样的药物递送对于使用抗癌剂进行的癌症治疗而言最发挥效果。抗癌剂由于大部分是抑制细胞分裂活跃的癌细胞的细胞增殖的物质,因此在正常组织中也会抑制细胞分裂活跃的组织,例如骨髓或发根、消化道粘膜等的细胞增殖。
因此,接受了抗癌剂给药的癌症患者会产生贫血、脱发、呕吐等副作用。由于这些副作用对于患者而言成为沉重的负担,因此必须限制给药量,从而存在无法充分获得抗癌剂的药理效果的问题。
这些抗恶性肿瘤药中,烷化剂系抗恶性肿瘤药是具有使烷基(-CH2-CH2-)结合在核酸蛋白等上的能力的抗癌剂的总称。通过使DNA烷基化而阻碍DNA复制,从而导致细胞死亡。
该作用与细胞周期无关地起作用,对G0期的细胞和增殖活跃的细胞的作用都强,从而容易对骨髓、消化道粘膜、生殖细胞、发根等造成损害。
另外,抗代谢系抗恶性肿瘤药是具有与核酸、蛋白合成过程的代谢物类似结构的化合物,通过阻碍核酸合成等而损害细胞,从而对分裂期的细胞起特异性作用。
另外,抗肿瘤性抗生素是由微生物产生的化学物质,具有抑制DNA合成、切断DNA链等作用,从而表现出抗肿瘤活性。
另外,微管抑制剂通过在细胞分裂时形成纺锤体,或直接作用于对细胞内小器官的配置、物质输送等细胞正常功能的维持发挥重要作用的微管,从而表现出抗肿瘤效果。微管抑制剂对细胞分裂活跃的细胞、神经细胞等起作用。
另外,铂制剂通过形成DNA链或链间结合或DNA蛋白结合从而阻碍DNA合成。顺铂为代表性药物,但对肾损害强,需要大量的补液。
另外,荷尔蒙类似药系抗恶性肿瘤药对于荷尔蒙依赖性的肿瘤是有效的。对于男性荷尔蒙依赖性的前列腺癌,给药女性荷尔蒙或给药抗男性荷尔蒙剂。
另外,分子靶向药是在各种恶性肿瘤中把对应于特异性分子生物学特征的分子作为目标的治疗法。
另外,拓扑异构酶抑制剂是通过临时在DNA上引入切口来改变DNA链的链环数的酶。拓扑异构酶I是在环状DNA的一条链上引入切口,使另一条链通过后,关闭切口的酶;拓扑异构酶抑制剂II是临时切断环状DNA的2条链,在其间使另外的2条链DNA通过,再重新连接切口的酶。
另外,非特异性免疫增强剂通过活化免疫系统来抑制癌细胞的增殖。
由于大多数抗癌剂抑制细胞分裂活跃的癌细胞的细胞增殖,因此在正常组织中也抑制细胞分裂活跃的组织,例如骨髓或发根、消化道粘膜等的细胞增殖。因此,在接受了抗癌剂给药的癌症患者中会产生贫血、脱发、呕吐等副作用。
由于这些副作用对于患者而言成为沉重的负担,因此必须限制给药量,从而存在无法充分获得抗癌剂的药理效果的问题。此外,最坏的情况,可能由于副作用而导致患者死亡。
因此,期待通过药物递送引导抗癌剂到达癌细胞,并集中于癌细胞,使其发挥药理效果,由此能够在抑制副作用的同时有效地进行癌症治疗。同样的问题也存在于局部麻醉剂。
局部麻醉剂用于处理痔疮、口腔炎症、牙周病、龋齿、拔牙或手术等引起的粘膜、皮肤等局部的发痒、疼痛。作为代表性局部麻醉剂,已知有利多卡因(商品名:苦息乐卡因),但利多卡因虽然速效性优异,但具有抗心律不齐作用。
另外,进行脊椎麻醉时,如果在脊髓液中注入作为麻醉药的利多卡因,则会在脊髓液中扩散,有人担心最坏的情况是由于到达颈部的脊髓而导致呼吸功能停止从而造成严重副作用。
因此,期待通过药物递送引导抗癌剂到达癌细胞,并集中于癌细胞,使其发挥药理效果,由此能够在抑制副作用的同时有效地进行癌症治疗。
另外,期待通过药物递送防止局部麻醉剂的扩散,并实现药效持续和副作用的减轻。
作为药物递送的具体方法,例如有使用载体(carrier)的方法。该方法是将药物负载在容易集中于患部的载体上,并将药物运送至患部。
作为载体,被视作最有希望的是磁性体,提出了使作为磁性体的载体附着在药物上并通过磁场聚集于患部的方法(例如,参照专利文献1)。
然而,将磁性体载体用作载体时,已知:口服给药困难,载体分子通常特别大,载体与药物分子间的结合强度、亲和性方面存在技术问题,从而终究难以实用化。
因此,本发明人提出:对有机化合物的基本骨架结合用于赋予正或负的自旋电荷密度的侧链,相对于外部磁场,整体具有磁性共同诱导的范围的适应性,在适用于人体、动物时,通过来自体外的磁场从而保持在局部提供磁场的范围内,以在前述范围内发挥原本保有的药物效果的局部治疗药。该公报中,记载了铁salen络合物作为这样的药物。(参照专利文献2)。
另外,也公开了含有铁salen络合物的抗肿瘤药物。(例如,参照专利文献3)。
现有技术文献
专利文献
专利文献1:日本特开2001-10978号公报
专利文献2:WO2008/001851号公报
专利文献3:日本特开2009-173631号公报
发明内容
发明要解决的课题
本发明的目的在于扩大铁salen络合物的有用性。
解决课题的方法
为了实现该目的,本发明为含有下述化学式(I)的新的荧光色素材料。(N,N’-双(亚水杨基)亚乙二胺金属)
(N,N’-Bis(salicylidene)ethylenediamine metal)
化学式(I)
其中,M为Fe(铁)、Cr(铬)、Mn(锰)、Co(钴)、Ni(镍)、Mo(钼)、Ru(铷)、Rh(铑)、Pd(钯)、W(钨)、Re(铼)、Os(锇)、Ir(铱)、Pt(铂)、Nd(钕)、Sm(钐)、Eu(铕)或Gd(钆)。
特别是M为铁的化合物发出300nm至500nm的波长的磷光。因此,像日本特开2009-173631号公报中记载的那样将化合式(I)的金属salen络合物作为抗肿瘤药物,给药至人体、动物等个体,并磁引导至目标癌症组织后,在患部组织的切除手术时,向患部组织照射激光、荧光,从而使金属salen络合物发光,可以通过视觉来确认患部组织。
对于所述金属salen络合物的平均粒径,粒径过大时,化合物有可能会堵塞血管。另一方面,粒径小时,有可能失去化合物的磁性。因此,化合物的平均粒径适合为2~60μm,优选为5~20μm,进一步优选为8~15μm,特别优选为9~12μm,最佳为10μm。
将粒径调整在该范围内可在重结晶工艺中实施。例如,在后述的合成步骤7中,有“使所得的化合物在二乙醚与石蜡的溶液中重结晶”,重结晶前暂时使温度上升至80℃,然后经12小时冷却至室温,从而可得到目标粒径。
本发明人进行研究的结果,所述金属salen络合物的磁化特性根据粒径而变化。粒径小至超过必要的程度时,金属salen络合物磁化特性不充分,被给药至人体、动物等个体时,有可能通过外部磁场无法引导至目标区域,另一方面,粒径增大至超过必要的程度时,有可能在血管内磁性粒子凝聚。
如日本特开2009-173631号公报所述,化学式(I)所表示的铁salen络合物作为具有在不利用磁性载体的情况下被给药至个体后,对个体使用外部磁场(例如,0.3T)时,所述分子被引导至施加了所述磁场的区域的磁性的抗肿瘤药物有用。
发明效果
如上所述,根据本发明,可得到所述化学式(I)的新的荧光材料。
附图说明
图1是表示金属salen络合物的发光试验结果的特性图。
图2是表示金属salen络合物的粒径测定结果的特性图。
具体实施方式
金属salen络合物(铁salen)的制造
步骤1:
在25g、0.18mol的作为化合物1(compound1)的4-硝基苯酚(4-nitrophenol)中加入混合25g、0.18mol的六亚甲基四胺(hexamethylenetetramine)、200ml聚磷酸(polyphosphoric acid),将该混合物在100℃搅拌1小时。之后将该混合物投入500ml的乙酸乙酯和1L的水中,搅拌直至完全溶解。再在该溶液中继续加入400ml的乙酸乙酯,结果该溶液分离为2个相。接着,从这些相中除去水相,将剩余的化合物用碱性溶剂洗涤2次,并用无水MgSO4使其干燥,结果合成了17g(收率57%)的化合物2(compound 2)。
步骤2:
在17g、0.10mol的化合物2(compound 2)中加入200ml乙酸酐(aceticanhydride)、少量硫酸(H2SO4),在室温下搅拌1小时。接着,将所得的溶液在2L冰水中混合0.5小时,进行水解。将所得的溶液通过过滤器,并在大气中进行干燥,结果得到白色粉末状的物质。使用含有乙酸乙酯的溶液使该粉末重结晶,结果可得到24g(收率76%)的化合物3(compound 3)的白色晶体。
步骤3:
在24g、77mmol的化合物3(compound 3)中混合500ml甲醇和负载了10%钯的碳2.4g,将该混合物在1.5个气压的氢还原气氛中还原一夜。结束后,使用过滤器过滤,结果合成了茶色油状的化合物4(compound 4)21g。
步骤4、5:
在200ml无水二氯甲烷(DCM)中加入21g、75mmol的化合物4(compound4)和18g、82mmol的二叔丁基二碳酸酯(di(tert-butyl)dicarbonate),在氮气气氛中搅拌一夜。之后,使所得的溶液(化合物5(compound 5))在真空中蒸发后,用100ml甲醇进行溶解。之后,加入15g、374mmol的氢氧化钠和50ml水,回流5小时。之后冷却,用过滤器过滤、用水洗涤后,在真空中干燥,结果得到茶色化合物。所得的化合物进行2次使用了硅胶的闪式色谱,从而得到10g(收率58%)的化合物6(compound 6)。
步骤6:
在无水乙醇400ml中加入10g、42mmol的化合物6(compound 6),一边加热一边进行回流,在无水乙醇20ml中加入1.3g、21mmol的数滴乙二胺并搅拌0.5小时。然后,将该混合溶液放入冰的容器中进行冷却并搅拌15分钟。之后,用200ml的乙醇洗涤并通过过滤器,在真空下进行干燥,结果合成了8.5g(收率82%)的化合物7(compound 7)。
步骤7:
在50ml无水甲醇中加入8.2g、16mmol的化合物7(compound 7)和22ml、160mmol的三乙胺(triethylamine),将在10ml甲醇中加入2.7g、16mmol的氯化铁(FeCl3)所得的溶液在氮气气氛下、室温混合1小时,结果获得茶色化合物。然后在真空中进行干燥。
用二氯甲烷400ml对所得的化合物进行稀释,用碱性溶液洗涤2次,用硫酸钠(Na2SO4)进行干燥后,在真空中进行干燥,使所得的化合物在二乙醚和石蜡的溶液中重结晶,并通过高效液相色谱进行测定,结果得到5.7g(收率62%)的纯度95%以上的络合物A(complex A:铁salen络合物)。
使用铁salen络合物以外的金属络合物的情况下,只要利用铁以外的金属的氯化物(MCl3:其中,M为金属)来代替氯化铁(FeCl3)即可。另外,铁salen络合物以外的锰salen络合物、铬salen络合物、钴salen络合物中具有可通过外部磁场进行引导的程度的磁性如本申请申请人的日本专利申请2009-177112号公报中所示。并且,金属铁salen络合物等具有抗肿瘤作用也在日本特开2009-173631号公报中明确。
<发光试验>
对于化学式(I)所表示的铁salen络合物,利用光致发光测定进行发光试验。
测定是通过堀场制作所制高分解分光分析用PHOTOLUMINOR-S来进行的。测定在使铁salen溶解于氯仿中的状态下进行。
将所得的结果示于图1。根据图1,可以确认在380nm附近产生了化学式(I)所表示的铁salen络合物的固有的峰。另外,图1中,虽然在270nm、530nm、800nm附近确认到峰,但其为受激激光(将RGB的几种波长同时振荡而发出白色光的激光)的参照峰。峰波长根据铁salen络合物的结晶状态而变动。
<粒径测定>
使用激光衍射法来测定化学式(I)的铁salen络合物的粒径。测定所使用的装置为Microtrac粒度分析仪(日机装株式会社制MT-3000II)。将试样投入六偏磷酸Na溶液中,对使用均化器分散10分钟所得的试样照射激光线,测定其衍射(散射),求出粒度。测定条件与测定结果如下。
<测定条件>
测定时间:30秒
粒子透过性:透过
粒子形状:非球形
粒子折射率:1.81
溶剂:水
溶剂折射率:1.333
<测定结果>
将测定的结果示于图2和以下。
平均粒径:11.79μm
标准偏差:6.289
测定的结果可知,铁salen络合物的粒径为十分适合用于个体的11.8μm。
如上所述,将上述铁salen络合物等的、能够荧光生色的金属salen络合物给药至个体,从外部对个体使用磁场而将金属salen络合物引导至目标区域后,使用外部光时,可以确认金属salen络合物的发光。
权利要求书(按照条约第19条的修改)
1.(修改后)一种荧光色素材料,其含有金属salen络合物,发光波长的峰位于可见区域。
2.(追加)根据权利要求1所述的荧光色素材料,所述金属salen络合物由下述化学式(I)构成。
化学式(I)
N,N’-双(亚水杨基)亚乙二胺金属
其中,M为Fe、Cr、Mn、Co、Ni、Mo、Ru、Rh、Pd、W、Re、Os、Ir、Pt、Nd、Sm、Eu或Gd。
3.(修改后)根据权利要求1所述的荧光色素材料,所述化学式(I)的M为Fe,在380nm附近存在发光波长的峰。
4.(修改后)根据权利要求1至3中任一项所述的荧光色素材料,所述化学式(I)的金属salen络合物给药至个体后,通过来自个体外的磁场而被引导至目标区域并发挥药理效果。
5.(修改后)根据权利要求4所述的荧光色素材料,所述化学式(I)的M为Fe,金属salen络合物具有在不利用磁性载体的情况下被给药至个体后,对个体使用外部磁场时,被引导至施加了所述磁场的区域的磁性。
6.(修改后)根据权利要求1至5中任一项所述的荧光色素材料,所述化学式(I)的化合物的粒径为2~60μm。
7.(修改后)一种荧光色素材料的使用方法,将含有由下述化学式(I)构成的金属salen络合物的荧光色素材料给药至个体,并从外部对该个体使用磁场,从而将该材料引导至目标区域后,使用外部光,使位于所述目标区域的所述荧光色素材料发光。
化学式(I)
N,N’-双(亚水杨基)亚乙二胺金属
其中,M为Fe、Cr、Mn、Co、Ni、Mo、Ru、Rh、Pd、W、Re、Os、Ir、Pt、Nd、Sm、Eu或Gd。
Claims (6)
2.根据权利要求1所述的荧光色素材料,所述化学式(I)的M为Fe,发出300nm~500nm的波长的磷光。
3.根据权利要求1或2所述的荧光色素材料,所述化学式(I)的金属salen络合物给药至个体后,通过来自个体外的磁场而被引导至目标区域并发挥药理效果。
4.根据权利要求3所述的荧光色素材料,所述化学式(I)的M为Fe,金属salen络合物具有在不利用磁性载体的情况下被给药至个体后,对个体使用外部磁场时,被引导至施加了所述磁场的区域的磁性。
5.根据权利要求1至4中任一项所述的荧光色素材料,所述化学式(I)的化合物的粒径为2~60μm。
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PCT/JP2011/002651 WO2011151978A1 (ja) | 2010-06-01 | 2011-05-12 | 蛍光色素材料及びその使用方法 |
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CN103517895A (zh) * | 2010-12-21 | 2014-01-15 | 株式会社Ihi | 金属沙仑配位化合物及其制造方法 |
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US20090169484A1 (en) * | 2007-12-28 | 2009-07-02 | Ihi Corporation | Iron-salen complex |
JP2012167067A (ja) * | 2011-02-15 | 2012-09-06 | Ihi Corp | 自己磁性金属サレン錯体化合物 |
JP6017766B2 (ja) | 2011-07-26 | 2016-11-02 | 株式会社Ihi | 新規な金属サレン錯体化合物の抗がん剤 |
KR102054751B1 (ko) * | 2017-12-27 | 2019-12-11 | 주식회사 디엔에스 | 코어 셀 구조를 갖는 청색 형광체 나노입자를 포함하는 고분자 필름 |
WO2023075778A1 (en) * | 2021-10-28 | 2023-05-04 | Hewlett-Packard Development Company, L.P. | Printing material including salen compound |
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EP2578643B1 (en) | 2019-07-10 |
EP2578643A1 (en) | 2013-04-10 |
EP2578643A4 (en) | 2014-01-22 |
US9282923B2 (en) | 2016-03-15 |
RU2012151491A (ru) | 2014-07-20 |
RU2540311C2 (ru) | 2015-02-10 |
JPWO2011151978A1 (ja) | 2013-07-25 |
WO2011151978A1 (ja) | 2011-12-08 |
JP5554408B2 (ja) | 2014-07-23 |
US20130090539A1 (en) | 2013-04-11 |
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