CN105854032A - 一种阿霉素前药及其释放度评价方法 - Google Patents
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Abstract
本发明公开了一种阿霉素前药，同时公开了其释放度的评价方法，该前药为含有不同取代基团的香豆素和阿霉素的偶联产物；本发明的阿霉素前药易于制备，成本低廉。该阿霉素前药在水溶液释放后可以同时发射两个波段的荧光，能够同时通过两个不同波段的荧光强度的检测评价该前药的释放效果；同时该前药可通过绿色和红色双重荧光成像方式对阿霉素前药的释放实现可视化测定，具有广阔的应用前景。
Description
技术领域
本发明涉及一种新型阿霉素前药及其释放度的评价方法，属于药物化学技术领域。
背景技术
以抗肿瘤药物为主的化学疗法依然是当今治疗癌症的三大手段之一。抗肿瘤药物的优点是能够对手术切除后残余的肿瘤细胞和转移的肿瘤细胞有杀伤作用。但是由于肿瘤细胞和正常细胞没有根本性的性状与代谢差异，往往会导致抗肿瘤药物也会对正常细胞亦有杀伤作用，带来较大的副作用。因此，发展有效的药物传递系统（Drug Delivery System,DDS）能够用来监测与控制抗肿瘤药物在细胞内的分布与释放、提高药物在肿瘤组织的富集、增加药物缓释作用等提高抗肿瘤药物的药效，降低对正常组织的损伤。
近年来，荧光成像技术因其能够在不破坏样品前提下，能够在活细胞和活动物体内实时原位追踪各种生物分子和药物分子而被广泛使用。除此之外，荧光成像技术还具有较高的灵敏度、响应速度快、能进行定量分析等优点。这些都为荧光成像技术应用到DDS中奠定了良好的基础。
采用荧光染料与抗肿瘤药物偶联构成荧光前药探针，一方面能够实时追踪药物在细胞组织的内外的分布与释放；另一方面荧光与药物是依据肿瘤微环境的特点而被激活分别释放荧光与药物分子，能够起到靶向缓释作用，降低毒性。尽管目前已经报道了多种有机荧光前药探针，但是还没有应用本身具有荧光性质的抗肿瘤药物阿霉素（Doxorubicine,DOX）与有机荧光染料构成比率型荧光探针。
发明内容
为了解决以上技术问题，本发明提供了一种阿霉素前药，其能够通过生物医学成像对阿霉素的释放进行可视化检测。
本发明所述的新型阿霉素前药为香豆素和阿霉素的偶联化合物：所述阿霉素前药的化学结构通式如式（）所示：
式（）
其中：R= H，命名为1a；或R=Cl，命名为2a；或R= CH3，命名为3a；或R= CH2CH3，命名为4a。
本发明所述阿霉素前药优选的实施方式是：所述阿霉素前药的化学结构通式如式（）所示，其中：R= H。
式（Ⅱ）
本发明所述阿霉素前药的制备方法为：将式（Ⅱ）所示的化合物a1 (1 mmol)、a2 (1mmol)、三乙胺（2.2 mmol）和二甲基亚砜（5 mL）加入到50 mL单口烧瓶中，室温避光搅拌48小时。使用制备液相将所得反应液进行纯化，得到棕红色产物即为本发明所述检测阿霉素前药。
本发明所述的阿霉素前药具有优良的缓释效果，并通过组织成像对其缓释效果进行可视化检测。该阿霉素前药具有羰基和氨基形成的亚胺结构，可在水中水解，生成能够发射蓝绿荧光的香豆素a1和能够发射红色荧光的阿霉素a2。通过荧光分析法，确定这两种荧光的强度，即可检测阿霉素的释放度。
具体测定方法为：室温条件下，配制5 μM阿霉素前药的DMSO溶液，加入到具有不同pH值的B-F缓冲液体系中，测定溶液荧光强度作为阿霉素释放的评价指标。
本发明所述的阿霉素前药尽管含有香豆素和阿霉素两个荧光团，但是由于结构中含有能够自由旋转的N-N单键，本身不具备荧光发射能力。在弱酸溶液中，阿霉素前药的亚胺结构在酸的催化下发生水解，使得一分子阿霉素前药释放为一分子香豆素和一分子阿霉素。所释放的香豆素在水中可以发射强烈的蓝绿色荧光，阿霉素可以发射强烈的红色荧光。阿霉素前药在水中水解时，可以同时出现两个增强的荧光波段。因此，所设计的阿霉素前药在水中的水解过程可以通过检测香豆素和阿霉素的荧光来评价。由于阿霉素前药释放的香豆素和阿霉素比值恒定，在整个前药释放过程中，香豆素和阿霉素的荧光比值也恒定不变。可采用荧光检测器实现阿霉素释放的快速灵敏检测；检测条件为：激发波长为420 nm，在430-750 nm之间进行荧光发射光谱的检测，其中450-520 nm波段内的荧光来自于香豆素，530-700 nm波段内的荧光来自于阿霉素。这样两种荧光团的相互作用关系的变化会直接表明药物的释放，并且能够依据彼此去定量分析；同时两种荧光团的相互作用关系能够降低细胞组织背景干扰，提高信噪比；最后两者可断裂的化学键偶联后能够影响阿霉素作用效果，降低毒副作用。
阿霉素前药在生物成像应用研究主要内容有探针对活细胞的毒性、活细胞和活组织荧光成像。采用MTT比色法，通过分析细胞在加入阿霉素前药之后的存活率，讨论阿霉素前药对细胞的毒性。在此基础上，应用本发明所述的阿霉素前药对活细胞或活组织进行检测，能够对该样品中阿霉素释放实现可视化检测，达到阿霉素前药的药效评估目的。
本发明的有益效果为：
本发明所述的阿霉素前药可经化学合成获得，合成工艺简单易行，原料廉价易得，制备成本低，易于推广。
本发明所述的阿霉素前药在水溶液释放后可以发射两个波段的荧光，能够通过荧光强度的检测评价该前药的释放效果，同时可通过荧光成像对阿霉素前药实现可视化测定，具有广阔的应用前景。
本发明所述的阿霉素前药，具有良好的荧光发射光谱特性（450~750 nm），通过绘制标准曲线进行细胞内或组织内阿霉素释放速率，可以对阿霉素前药在细胞或组织内的释放实现快速准确的可视化检测。
附图说明
图1是阿霉素前药1a的1H NMR图谱。
图2是阿霉素前药1a的13C NMR图谱。
图3是阿霉素前药1a的HPLC图谱。
图4是阿霉素前药1a在pH 4.5条件下不同时间的荧光光谱。
图5是阿霉素前药1a在pH 7.4条件下不同时间的荧光光谱。
图6是阿霉素前药1a组织中释放1h和3h的荧光成像。
具体实施方式
下面结合实施例和附图对本发明做进一步说明，但本发明保护内容不仅限于此。
实施例1：本发明所述阿霉素前药1a的制备
将式（Ⅱ）所示的化合物a1 (1 mmol)、a2 (1 mmol)、三乙胺（2.2 mmol）和二甲基亚砜（5 mL）加入到50 mL单口烧瓶中，室温避光搅拌48小时。使用制备液相将所得反应液进行纯化，得到棕红色产物即为本发明所述检测阿霉素前药（32 mg），产率4%。
上述检测细胞内溶酶体pH的荧光探针1a的1 H NMR图谱见图1，13 C NMR图谱见图2，HPLC图谱见图3。
实施例2：本发明所述阿霉素前药1a在pH4.5条件下不同时间的荧光光谱
预先准备5mL的 5 μM探针B-F缓冲溶液，含5% DMSO，pH为4.5。然后进行荧光检测（λEx=410 nm）；计算各荧光强度；评估该前药在pH4.5条件下的释放效果（见图4）。分析溶液在pH4.5时，480 nm、560 nm、600 nm处的荧光强度，见图4，评价该前药在此pH条件下的药物释放性能。
实施例3：本发明所述阿霉素前药1a在pH 7.4条件下不同时间的荧光光谱
预先准备5mL的 5 μM探针B-F缓冲溶液，含5% DMSO，pH为7.4。然后进行荧光检测（λEx=410 nm）；计算各荧光强度；评估该前药在pH4.5条件下的释放效果（见图5）。分析溶液在pH7.4时，480 nm、560 nm、600 nm处的荧光强度，见图5，评价该前药在此pH条件下的药物释放性能。
实施例4：阿霉素前药1a在活组织中的成像应用
取活小鼠新鲜肝组织，PBS清洗3次。用微量进样器吸取本发明所述阿霉素前药1a (10μM)，与小鼠肝组织培养1h、2h、3h，进行成像测试。测试条件：绿色通道，激发波长为488 nm，收集波长为500-550 nm；红色通道，激发波长为561 nm，收集波长为570-620 nm。
结果见图6。
Claims (3)
1.一种阿霉素前药，其特征在于：其化学结构通式如式（）所示：
式（）
其中：R= H，命名为1a；或R=Cl，命名为2a；或R= CH3，命名为3a；或R= CH2CH3，命名为4a。
2.根据权利要求1所述的阿霉素前药，其特征在于，由以下方法制备而成：
将1 mmol a1 、1 mmol a2 、2.2 mmol三乙胺和5 mL二甲基亚砜加入到50 mL单口烧瓶中，室温避光搅拌48小时；液相纯化，得到棕红色产物即为阿霉素前药；其中a1，a2结构如下：
。
3.一种权利要求1或2所述的阿霉素前药的释放度评价方法，其特征在于，具体方法如下：
室温条件下，配制5 μM阿霉素前药的DMSO溶液，加入到具有不同pH值的B-F缓冲液体系中，测定溶液荧光强度；
检测条件为：激发波长为420 nm，在430-750 nm之间进行荧光发射光谱的检测。
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